John2038's Research News

[John2038]

sciencedaily

New Hope For Immunocompromised Individuals With Drug-resistant Fungal Infections
Even the most drug-resistant fungi can be eradicated in multiple in vitro and in vivo models using a lethal combination of an antifungal agent and inhibition of the heat shock protein Hsp90, according to a new study by Whitehead Institute and University of Toronto researchers. The findings could enable development of novel antifungal therapies for patients with compromised immune systems.

Immunocompromised individuals--including HIV, chemotherapy, and organ transfer patients--with resistant fungal infections suffer mortality rates ranging from 50 to 90 percent.

"Being a pediatric oncologist, I have seen many unfortunate patients die from resistant fungal infections," says Luke Whitesell, a scientist in the lab of Whitehead Member Susan Lindquist. "It's incredibly frustrating to see a child with their cancer in remission being slowly eaten alive by a fungus like Aspergillus, and there's nothing you can do about it."

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Anti-HIV Gel Shows Promise In Large-scale Study In Women
An investigational vaginal gel intended to prevent HIV infection in women has demonstrated encouraging signs of success in a clinical trial conducted in Africa and the United States. Findings of the recently concluded study, funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, were presented Feb 9 at the Conference on Retroviruses and Opportunistic Infections in Montreal.

The study investigators found the microbicide gel—known as PRO 2000 (Indevus Pharmaceuticals, Inc., Lexington, Mass.)—to be safe and approximately 30 percent effective (33 percent effectiveness would have been considered statistically significant). This is the first human clinical study to suggest that a microbicide—a gel, foam or cream intended to prevent the sexual transmission of HIV and other sexually transmitted infections when applied topically inside the vagina or rectum—may prevent male-to-female sexual transmission of HIV infection.

"Although more data are needed to conclusively determine whether PRO 2000 protects women from HIV infection, the results of this study are encouraging," says NIAID Director Anthony S. Fauci, M.D.

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Washington Post

Drugs Are Found to Block HIV In Monkeys


The Truvada pill, made by Gilead Sciences, contains two antiretroviral drugs and was tested on monkeys in a scientific study.

AIDS researchers who were gathered in Montreal yesterday heard encouraging results from studies of three strategies for preventing HIV infection using pharmaceuticals, particularly in women.

Two experiments in monkeys showed that antiretroviral (ARV) drugs, given by mouth or by vaginal gel, were highly effective in blocking infection by the virus that causes AIDS.

A third study, in 3,100 women in the United States and Africa, showed a small amount of protection from a vaginal gel that acts by binding up the AIDS virus and preventing it from invading cells.

Many experts believe that, short of a vaccine, a virus-blocking substance that could be inserted in the vagina or rectum before sexual activity would be the most important tool in fighting the AIDS pandemic. Numerous topical microbicides have been tried, but none have worked, and two have actually increased the risk of infection.

"The field of microbicide gels is now moving into a new generation," said Walid Heneine, a virologist at the U.S. Centers for Disease Control and Prevention, who led one of the monkey studies.

Microbicides can be applied without the knowledge of sexual partners. They are seen as being especially important in cultures where the subservient status of women makes it difficult for them to insist on abstinence or condom use, the two proven methods of preventing infection through sexual contact. In sub-Saharan Africa, nearly 60 percent of HIV-positive people are women.

The gel used in the human study reduced the risk of infection by 30 percent over the course of about two years, an effect that did not reach the level of statistical significance. The women -- from the United States, South Africa, Malawi, Zambia and Zimbabwe -- also used condoms in about three-quarters of their sexual encounters.

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[John2038]

eurekalert

Indiana University discovery may provide new approach to HIV treatment
INDIANAPOLIS — Researchers at the Indiana University School of Medicine have identified a potential new target in the war on HIV/AIDS. The information was published in the Jan. 16 issue of the journal Molecular Cell.

The study revealed that a variant of a protein involved in HIV pathogenesis can suppress production of an HIV protein, known as Nef. Nef is required for the human immunodeficiency virus to develop into AIDS through a series of complex events involving viral elements and cellular proteins. Nef has never been a target for drug treatment in HIV patients.

Johnny J. He, Ph.D., principal author of the research and the director of the Indiana University Center for AIDS Research, said a drug affecting Nef could complement existing therapies to provide protection against the virus.

The current treatment for HIV/AIDS is highly active anti-retroviral therapy (HAART). It is a combination of drugs that target two HIV enzymes – reverse transcriptase (RT) and protease (PR) or RT or PR inhibitors.

Dr. He said another encouraging outcome of the research was the discovery that Nef could be suppressed on the molecular level to prevent it from translating into protein.

"These scientific advances have therapeutic potential to interrupt the progression of the virus into AIDS," said Dr. He, who also is a professor of microbiology and immunology and medicine.

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Model of pre-exposure prophylaxis against HIV forecasts benefits, potential cost-effectiveness
WHAT: For every two people who begin treatment for HIV infection globally, five others become newly infected. Therefore, preventing new HIV infections is the foremost strategy for ending the HIV/AIDS epidemic. One potential prevention strategy involves giving antiretroviral drug regimens to people who are at high risk for HIV to protect them from infection. Important questions about this experimental approach, known as pre-exposure prophylaxis (PrEP), remain unanswered, including, Could PrEP cut the lifetime risk of HIV infection? Would PrEP be cost-effective?

A new mathematical model of PrEP use in U.S. populations at high risk for HIV infection takes these and other questions into account and predicts the prevention strategy could substantially reduce the lifetime risk of HIV infection. According to the model, the cost-effectiveness of PrEP could vary substantially depending on the age of the target population, their risk behaviors, the annual rate of new HIV infections in the target population, and the efficacy and cost of antiretroviral PrEP drugs. These findings are reported by a team of scientists led by A. David Paltiel, Ph.D., of Yale University, and supported by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Mental Health and the National Institute on Drug Abuse, all part of the National Institutes of Health.

Dr. Paltiel says his team's model is the first to establish performance benchmarks that clarify the clinical, epidemiologic and economic circumstances under which PrEP would represent good patient care, good public health and good value.

To create their model, the researchers made several conservative assumptions: 1) PrEP is 50 percent effective; 2) the target population is American men who have sex with men who average 34 years of age; 3) 1.6 percent of this population becomes newly infected with HIV annually; and 4) the antiretroviral drugs (tenofovir and emtricitabine) cost $9,000 per year. With these parameters, the model predicts PrEP would cut the lifetime risk of HIV infection from 44 percent to 25 percent. However, the life expectancy of the target population from the time after beginning PrEP would increase by less than a year (from 39.9 years to 40.7 years) and PrEP would not be cost-effective by current U.S. standards. Yet with modest improvements in the efficacy of antiretrovirals used preventively, more realistic estimates of their cost (potentially as low as $900 per year), or a target population that is younger and at higher risk, the model predicts PrEP might be as cost-effective as other widely recommended public health and medical interventions in the United States. With large improvements in these parameters, the potential benefits of PrEP could be substantial, according to the model. For example, assuming PrEP will be 90 percent effective leads the predicted lifetime risk of HIV infection to fall from 44 percent to 6 percent.

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news-medical

Idenix Pharmaceuticals, Inc. and GlaxoSmithKline (GSK) today announced the execution of a license agreement granting GSK exclusive worldwide rights to IDX899
IDX899 is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) in Phase II clinical development being developed by Idenix for the treatment of HIV/AIDS. New NNRTIs are needed to address the increasing prevalence of viral resistance and side effects associated with this drug class. To date, IDX899 has demonstrated high potency with low milligram doses, a high barrier to drug resistance, favorable risk/benefit profile, and the convenience of once-a-day administration.

Under the terms of the agreement, GSK will assume all development responsibility and associated costs for IDX899, and Idenix will receive an upfront payment of $34 million and will be eligible to receive up to $416 million in development, regulatory and sales milestones. Furthermore, if IDX899 is successfully developed and commercialized, Idenix will receive double-digit, tiered worldwide royalties.

"GSK, with a well-established HIV franchise and substantial drug development experience, is the ideal collaborator to help maximize the potential of IDX899," said Jean-Pierre Sommadossi, Chief Executive Officer of Idenix. "For Idenix, the significant value created through the license of IDX899 enables us to focus all of our resources on advancing our core strategic HCV assets, which include drug candidates from the three major classes of direct-acting HCV antivirals."

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aegis

Low-level HIV replication versus latency: identifying the source of viral rebounds during treatment interruption
In HIV research, there is a persistent and vigorous debate around the question of whether or not viral replication persists in the face of successful antiretroviral therapy. During a plenary session at the International AIDS Conference in Mexico City back in August, Bob Siliciano made a compelling argument that, in most cases, antiretroviral therapy completely shuts down virus production.[1]

Now, a new paper in PNAS provides additional support for this view.[2]

Beda Joos and colleagues evaluated a staggering 1,753 genetic sequences from the envelope region of HIV, sampled over the course of a treatment interruption trial known as SSITT (Swiss-Spanish Intermittent Treatment Trial). The study design involved a series of two-week treatment breaks followed by a prolonged interruption (therapy was subsequently reinitiated according to the CD4 and viral load thresholds used in current treatment guidelines).

The researchers used the sequence data to plot the relationships between the different viruses, using a technique called phylogenetic analyses. For each study participant analyzed, the sequences were used to define “the most recent common ancestor” (MRCA), which is the virus sequence from which all the others derived. Viruses that appeared during treatment interruptions (TIs) were then compared to the MRCA, to see if the sequences suggested that there had been ongoing replication and evolution while the study participants were on ART. The results showed that the rebounding viruses during TI were actually more distant from the MRCA than the viruses detected when the participants first entered the study. The researchersconclude: “the striking lack of a temporal relationship between rebounding virus and pretreatment viruses strongly suggests that rebounding virus originates from reactivated, latently infected cells rather than from a cellular pool or compartment engaged in low-level replication.”

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Recent reports on new drug interactions
A selection of the latest news and reviews from the Liverpool University pharmacology team at hiv-druginteractions.org are included below.

http://www.hiv-druginteractions.org

Drug interactions with integrase inhibitors

This is an outstanding review on the pharmacology of integrase inhibitors with a substantial section on raltegravir drug-drug interactions and elvitegravir drug-drug interactions. There are four tables summarising all known interactions to date. The authors conclude that overall raltegravir has a low propensity for clinically meaningful drug interactions, whereas elvitegravir (with the presence of ritonavir) has modest potential for interactions.

The review is highly recommended and will appear in 2009. An advance version is available online, but minor changes may still occur before final publication.

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Serum bilirubin increases when PEG-interferon and ribavirin are used with atazanavir
This was a retrospective study of 72 HCV/HIV co-infected patients who initiated HCV therapy (peg-IFN weekly and ribavirin 1000-1200 mg/day) and were on either an atazanavir-containing regimen (n=36) or other antiretrovirals (not including indinavir, n=36). Fourteen subjects in the atazanavir group and six in the control group were then excluded from analysis due to poor drug adherence.

The major finding was that on average serum bilirubin increases following initiation of peg-IFN and ribavirin were 1.9-fold higher in patients on atazanavir than in controls. In the atazanavir group, the proportion of patients with grade 3-4 hyperbilirubinaemia increased from 2/22 to 10/22 after beginning hepatitis therapy. No controls developed hyperbilirubinaemia.

The elevation in serum bilirubin levels is directly related to the haemoglobin decline as a result of ribavirin use and haemolysis. The clearance of the increased bilirubin is compromised by atazanavir.

Ref: Rodriguez-Novoa S et al. Increase in serum bilirubin in HIV/hepatitis-C virus co-infected patients on atazanavir therapy following initiation of pegylated-interferon and ribavirin.

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Drug interactions between efavirenz and itraconazole
This is a case report of the interaction between itraconazole and efavirenz in a woman with disseminated histoplasmosis and HIV-1 infection. Previous data in healthy volunteers have shown a decrease of about 40% in exposure of itraconazole and its active metabolite (hydroxyitraconazole) and a recommendation to consider alternative antifungal treatment. Here the authors recommend that by the use of therapeutic drug monitoring of both efavirenz and itraconazole individual optimization of dosage can be made so that a change in therapy is not necessary. In this case the patient had a good clinical response and obtained therapeutic concentrations with a regimen including efavirenz 400 mg once daily and itraconazole 800 mg once daily.

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Effect on tacrolimus when switching from nelfinavir to fosamprenavir
This case report outlines the change in tacrolimus trough blood concentrations when 4 HIV-infected orthotopic liver transplant patients were switched from nelfinavir (1250 mg twice daily) to fosamprenavir (1400 mg twice daily without ritonavir) due to the EMEA ruling on nelfinavir in June 2007. After the switch, tacrolimus trough concentrations dropped significantly (>50%) and a marked dosage increase was required to attain the desired target concentration. The cases highlight the need for caution in immunosuppressed patients when switching or starting a protease inhibitor.

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[John2038]

hivandhepatitis

Two New Pharmaco-enhancers -- GS 9305 and SPI-452 -- May Rival Ritonavir (Norvir) as a Boosting Agent
The discovery that a small dose of ritonavir (Norvir) can be used to "boost" plasma levels of other protease inhibitors contributed to a dramatic improvement in the efficacy and convenience of antiretroviral therapy. This is due to the fact that ritonavir interferes with the action of the cytochrome P450 3A (CYP3A) enzyme, which metabolizes many drugs including other protease inhibitors (PIs). When drug clearance is slowed by ritonavir, concentrations in the body remain higher for longer periods.

Ritonavir is not without problems however -- including its association with metabolic side effects such as elevated blood lipids and its control by a single company (Abbott) -- leading researchers to explore new "pharmaco-enhancing" agents that can serve the same function.

Data on 2 such candidates were presented on Monday, February 9, at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009), taking place this week in Montreal.

GS-9350

Brian Kearney from Gilead Sciences presented early data on GS 9350, the result of a development program that sought a pharmaco-enhancing agent that works by the same mechanism as ritonavir, but without anti-HIV activity of its own.

The company wanted a suitable agent to include in coformulations with other drugs, including its investigational integrase inhibitor elvitegravir, which requires boosting to reach optimal therapeutic levels (an in-progress study of elvitegravir is using ritonavir as a booster).

Preclinical Studies

Gilead reported data from pre-clinical and early clinical studies of GS 9350. Antiviral activity was assessed using standard assays. The drug's effects on CP450 enzyme inhibition and metabolism (including lipid and glucose accumulation) were studied in cultured human liver cells.

Results

    * GS 9350 was shown to slow systemic drug clearance by inhibiting CYP3A.
    * GS 9350 appeared to be a more specific inhibitor CYP3A than ritonavir, with less effect on other
       CP450 enzymes.
    * GS 9350 exhibited no activity against HIV at concentrations up to 90 mcM.
    * GS 9350 was not associated with lipid accumulation in adipocytes (fat cells) at 30 mcM and only
       minimally (< 10%) inhibited insulin-stimulated glucose uptake at 10 mcM.
    * GS 9350 had a favorable pharmacokinetic profile, including high aqueous solubility (about 200 times
       that of ritonavir), making it suitable for coformulation with other drugs.

Phase 1 Trial

Following these promising laboratory findings, the pharmacokinetics, safety, and boosting activity of GS 9350 were studied in Phase 1 clinical trials.

In Study GS-216-0101, healthy HIV negative volunteers (18 per cohort) were randomly assigned to receive GS 9350 (at doses of 50, 100, or 200 mg once-daily) or 100 mg ritonavir or placebo, both as a single dose and as multiple doses administered over a 14-day period. Investigators used the benzodiazepine midazolam -- a known CYP3A substrate -- as a "probe" to assess how well GS 9350 boosted drug levels.

Results

    * GS 9350 doses of 100 and 200 mg inhibited midazolam clearance by 92% and 95%, respectively,
       compared with 95% using ritonavir.
    * GS 9350 was generally well tolerated, both single and multiple doses.
    * No drug-related grade 3 or 4 laboratory abnormalities or grade 4 clinical adverse events were
      observed; the single grade 3 clinical event was a woman who said she could no longer juggle while
      taking the drug, which was classified as "discoordination").
    * GS 9350 was reported to have little taste, in contrast to the notoriously bitter ritonavir.

Quad Pill

After this successful proof-of-concept trial, researchers created fixed-dose "quad" coformulations containing GS 9350 plus 150 mg elvitegravir, 300 mg tenofovir, and 200 mg emtricitabine -- a complete once-daily regimen in a single pill smaller than Atripla (efavirenz/tenofovir/emtricitabine, a collaborative effort of Gilead and Bristol-Myers Squibb).

Study GS-236-0101 (also Phase 1) assessed the bioavailability, pharmacokinetics, and safety of the quad pill in 44 healthy HIV negative volunteers. In this open-label trial, participants were assigned to receive a quad pill containing either 100 or 150 mg GS 9350.

The pharmacokinetic profile of elvitegravir administered in the single-tablet coformulation regimen was compared to the profile when the drug was boosted with 100 mg ritonavir and administered with the same doses of tenofovir and emtricitabine (the Truvada combination pill).

Results

    * Both the 100 mg and 150 mg GS 9350 coformulations boosted plasma concentrations of
       elvitegravir.
    * The tablet containing 150 mg GS 9350 produced elvitegravir concentrations previously determined
       to be therapeutic, including maintenance of an adequate trough concentration (lowest level
       between doses).
    * Here again, treatment was generally well tolerated.
    * There were no drug-related grade 3 or 4 clinical adverse events and no grade 4 laboratory
       abnormalities; the sole grade 3 lab abnormality was a transient ALT elevation.

Future Plans

Gilead is now planning Phase 2 trials to further evaluate GS 9350, including a head-to-head study comparing the quad coformulation versus Atripla in treatment-naive patients (scheduled to start in the second quarter of 2009) and an ongoing study of GS 9350 as a stand-alone agent as a booster for atazanavir (Reyataz).

"These data represent the first major step forward in Gilead's clinical development of a new integrase-based, single tablet, once-daily regimen for HIV," said Gilead's Chief Science Officer Norbert Bischofberger, PhD, in a press release issued by the company. "Results also indicate that GS 9350 holds promise as a stand-alone alternative to ritonavir for patients receiving boosted HIV protease inhibitor-based treatment regimens."

SPI-452

In the second conference presentation, Robert Guttendorf from Sequoia Pharmaceuticals reported preclinical and Phase 1 clinical data on the company's novel pharmaco-enhancer, SPI-452. Like Gilead, Sequoia sought a boosting agent with activity similar to that of ritonavir, but with no anti-HIV activity and better tolerability.

Preclinical Studies

The preclinical pharmacology of SPI-452 was evaluated in vitro in human liver cells. Its ability to boost levels of the PIs saquinavir (Invirase), lopinavir (a component of Kaletra), and atazanavir was evaluated in rats and dogs.

Results

    * In vitro, SPI-452 inhibited metabolism of all HIV PIs.
    * It also slowed metabolism of the investigational HCV protease inhibtor boceprevir.
    * SPI-452 demonstrated no inherent antiviral activity.
    * In animals, SPI-452 potently inhibited CYP3A, boosting levels of saquinavir, lopinavir, and atazanavir.

First Human Trial

In Study 0452-001 -- the first human clinical trial evaluating the safety, tolerability, and pharmacokinetics of SPI-452 -- 58 healthy HIV negative volunteers first received single ascending doses of SPI-452 (25, 50, 100, 200, 400, or 600 mg); in part 2, they were assigned to receive either 50 mg or 200 mg SPI-452 plus 1000 mg saquinavir, or saquinavir alone, or placebo alone.

Results

    * SPI-452 pharmacokinetics was described as "unremarkable" and "fairly well behaved."
    * SPI-452 increased mean levels of saquinavir, demonstrating its boosting effect.
    * SPI-452 was generally safe and well tolerated in single ascending doses of 25 to 600 mg, and in
       combination with saquinavir.
    * Adverse events were typically mild, with no severe events reported.
    * The most commonly reported adverse events were headache and pharyngitis (sore throat).

Proof-of-concept

Finally, the pharmacokinetic profile of multiple doses of SPI-452 and the drug's boosting ability were assessed in a Phase 1 proof-of-concept trial. A total of 67 healthy HIV negative volunteers first received single doses of 600 mg darunavir (Prezista) or 300 mg atazanavir or placebo, in order to establish PI plasma concentrations.

Then, after a 7 day washout period, participants were randomly assigned to receive 25, 50, or 200 mg once-daily SPI-452 or placebo for 15 days. On day 15, they also received darunavir, atazanavir, or placebo co-administered with the final dose of SPI-452. On day 16, they received darunavir, atazanavir, or placebo only.

Results

    * SPI-452 drug levels reached a steady state by day 14.
    * Co-administration of SPI-452 significantly increased minimum plasma concentrations (Cmin) of the
       PIs at 12 and 24 hours:

        Darunavir: up to 37-fold increase;
        Atazanavir: up to 13-fold increase.

    * The boosting effect was durable through day 16 (the day after the last dose).
    * SPI-452 was generally safe and well tolerated at doses of up to 200 mg for 15 days.
    * Again, most adverse events were mild and no serious events were reported.
    * The most common adverse event was headache, followed by nausea/vomiting and diarrhea.
    * No significant changes were observed in laboratory parameters -- including liver function tests -- or
       ECGs.
    * Participants taking SPI-452 experienced no significant changes from baseline in LDL ("bad")
      cholesterol or triglycerides.

The researchers concluded that SPI-452 is a potent CYP3A inhibitor that was well tolerated and safe when administered at doses of up to 200 mg once-daily for 15 days.

Speaking at a press conference following his presentation, Guttendorf said the Sequoia believes SPI-452 has "great potential." The company now plans to move forward with further clinical trials looking at SPI-452 both as a stand-alone agent and as a component of fixed-dose coformulations.

In addition to pursuing SPI-452 as a booster for HIV PIs, he added, Sequoia is exploring its use in treatment of hepatitis C, and it -- as well as other pharmaco-enhancer drugs in the pipeline, including those targeting other CP450 enzymes -- might be used for other, non-viral diseases.

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[John2038]

natap

HIV-1 infection induces premature aging of both memory T cells and naive CD4+ T cells
in particular, the fast progressors (FPs) experience accelerated aging of lymphocytes.....Whether highly active antiretroviral therapy can reverse or retard this process is not yet clear and needs to be investigated, although 1 study has shown that accumulation of aged T cells continues in highly active antiretroviral therapy-treated patients with increased CD4+ T cells and long-term viral suppression....

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CROI: World Health Organization CD4 Criteria Fall - Far Short in Predicting Antiretroviral Failure
16th CROI - February 8-11, 2009
Two studies headlined in the opening press briefing of this meeting underlined the often mortally inadequate HIV care still offered in sub-Saharan Africa and the usually insoluble choice policy makers face in speeding antiretroviral access to the millions who need treatment [1,2].
 
On the one hand, a four-country study involving more than 13,000 people demonstrated the substantial risk of delaying antiretroviral therapy until the CD4 count falls below 200. On the other hand, a 1133-person study in rural Uganda showed that relying on World Health Organization (WHO) CD4-count criteria to signal treatment failure rarely identifies people with actual virologic failure.
 
The four-country study by investigators from the International Epidemiological Database to Evaluate AIDS (IeDEA) compared age-, gender-, and country-specific non-HIV death rates with mortality in five antiretroviral programs--two in South Africa and one each in Cote d'Ivoire, Malawi, and Zimbabwe [1]. Of the 13,249 people in these group, two thirds were women and the median age was 34. During 14,695 person-years of follow-up, 1177 people (8%) died.
 
For people who began antiretroviral therapy with fewer than 25 CD4 cells and WHO stage 3 or 4 disease, the death rate exceeded the non-HIV death rate 47.1 times (95% confidence interval [CI] 39.1 to 56.6). For people who started antiretrovirals with at least 200 CD4s and WHO stage 1 or 2 disease, mortality was 3.44 times higher than non-HIV mortality (95% CI 1.91 to 6.17). For people in the latter group who survived the first year of antiretroviral therapy, the death rate was only 1.72 times higher than the non-HIV death rate (95% CI 0.44 to 1.17).
 
Half of the entire antiretroviral-treated study group had a death rate more than 5 deaths per 100 person-years higher than the non-HIV group.
 
The IeDEA investigators concluded that "much of the excess [mortality] might be prevented by more timely initiation of antiretroviral therapy."

But starting antiretrovirals in programs that cannot afford viral load monitoring poses grave risks of its own, according to results of a collaborative study by Johns Hopkins University and Makerere University in Kampala, Uganda [2]. Because this HIV program in Rakai, Uganda measures both CD4 counts and viral loads regularly, the investigators could determine how many people who met WHO CD4 failure criteria suffered virologic failure. At the same time, they could calculate how many people with virologic failure met WHO CD4 failure criteria.
 
WHO CD4 failure criteria are (1) persistent CD4 count below 100, or (2) more than a 50% drop from peak CD4 count, or (3) a CD4 count lower than the first measured CD4 count without a coinfection that might explain the decline. The investigators defined virologic failure with three cutoffs: above 10,000, above 5000, and above 400.
 
The study involved 1133 people who began their first antiretrovirals between June 2004 and September 2007. Median follow-up measured 20.2 months (interquartile range 12.4 to 29.5 months). In that time, 125 people (11%) met WHO criteria for CD4 failure. Viral load monitoring showed, however, that only 18 of those 125 (14%) had a virologic failure at the 10,000-copy cutoff. Eighty people did endure virologic failure with a viral load above 10,000. But WHO CD4 criteria identified only 18 of them (23%) as failures. Those numbers meant WHO CD4 standards had a sensitivity of 23% and a positive predictive value of only 14% in identifying virologic failure at the 10,000-copy mark. WHO CD4 sensitivity and positive predictive value were also low with a 5000-copy failure cutoff (28% and 8%) and a 400-copy failure cutoff (26% and 21%).

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discovery

HIV Mutates to Death With New Drug
HIV is notorious for its ability to mutate and evade drugs designed to destroy it. Now scientists are testing a new drug that actually speeds up that rate of change in the hope that the deadly virus will mutate itself to death.

"The HIV virus is so dependent on mutation that it really lives on the edge of existence," said John Reno, Chief Operating Officer for Koronis Pharmaceuticals, the company developing a drug called KP-1461. "But we figured that if we could increase this mutation rate, [HIV] might finally fall off that edge."

KP-1461 is a mutagen, meaning it encourages mutation, and has been in development for several years by the scientists at Koronis Pharmaceuticals.

When any cell or virus reproduces, there are inevitable mistakes, or mutations, as the four building blocks of DNA pair together into a double helix. Usually, the base adenine pairs up with the base thymine, and one called guanine pairs with cytosine.

KP-1461 looks like both thymine and cytosine, and will occasionally replace one of the normal bases in DNA, causing more errors.

"It really mucks up the genetic information inside the viral DNA," said Reno.

Disrupting HIV's replication doesn't directly destroy the virus, however, at least not immediately. It's the build-up of genetic mistakes that finally destroys it.

That build-up can take time, and could vary depending on the patient and the strain of HIV. The results of the latest Phase Two clinical trial, completed last year with 13 patients, were mixed; some patients saw no drop in their viral load, while others saw a dramatic drop. The scientists are currently working to publish the study results.

What's clear is that KP-1461 does eventually destroy HIV in some patients, unlike the current batch of antiretroviral drugs, which limit the reproduction of the virus but fail to destroy it.

KP-1461 doesn't have any known side effects, but the worry from the Food and Drug Administration is that a drug that induces mutation in a virus could also cause dangerous mutations in the patient's own DNA.

So far it doesn't appear to cause short-term mutations in animal models, but longer-term studies are necessary to eliminate the possibility, said Robert Smith, a professor at the University of Washington who studies other lethal mutagenic drugs.

Mutagenic drugs could be used to fight other diseases as well, such as polio, hepatitis C and influenza. KP-1461 is at the forefront of this new avenue of research.

"Intellectually this is exciting; it's a very creative approach," said Smith. "From a practical perspective, there are still a lot of questions."

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businesswire

Aethlon Medical Announces Expansion Into the Infectious Disease Diagnostic Market
Aethlon Medical, Inc. (OTCBB:AEMD) announced today that it has expanded the applications of its Hemopurifier® platform technology to address voids in the infectious disease diagnostic market.
The Aethlon Hemopurifier® is a first-in-class artificial adjunct to the immune system able to provide real-time capture of infectious viruses and immunosuppressive particles from the entire circulatory system. The device is a leading broad-spectrum treatment candidate for acute and chronic virus infections. Scientific techniques that established the therapeutic potential of the Hemopurifier® will be leveraged to introduce ultra-sensitive clinical and research diagnostic tools that offer significant potential for previously unrecognized revenue channels.

In diagnostic applications, Aethlon will concentrate viruses from large blood volumes to increase sensitivity of viral load testing standards, which previously have been limited to detecting viruses from small blood samples. By concentrating virus directly from a patient or from donated blood units, the sensitivity of viral load tests may be increased up to 5,000 fold as compared to 1ml blood sample testing. Thus allowing for the accurate detection of viruses such as HIV and HCV even when viral load may be deemed undetectable through current testing standards. Additional market opportunities include the identification of viral pathogens that trigger the rejection of stem-cell therapies, bone marrow, and organ transplants. Upon confirmation of such viruses, the Hemopurifier® would then become a treatment candidate to improve stem-cell therapy and transplant outcomes. Aethlon’s diagnostic techniques would provide superior detection of viruses in donated blood and may unlock the ability for researchers to discover viral biomarkers that underlie a multitude of disease conditions. Aethlon also disclosed its diagnostic capabilities will be deployed to further reinforce the therapeutic benefit of the Hemopurifier® to capture deleterious viruses from circulation. In this regard, Aethlon has initiated a diagnostic program to screen and identify all viral species captured in the recent Hemopurifier® treatment of a Hepatitis-C infected patient.

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[mark86]

John 2038,

Really interesting stuff there but i thought i should mention KP1461 died a death a long time ago. I wonder if any company is doing any other research along the same lines though?

Mark86

[freewillie99]

The return of KP-1461?  Color me skeptical.

[John2038]

i thought i should mention KP1461 died a death a long time ago. I wonder if any company is doing any other research along the same lines though?

The return of KP-1461?  Color me skeptical.

I was thinking exactly like you guys.
Just found interesting that Discovery is talking about this drug in an article dated from Feb. 9, 2009
Either a mistake, or a come back.
As you, I am sure it is a mistake.

[John2038]

eurekalert

IL-2 immunotherapy fails to benefit HIV-infected individuals already taking antiretrovirals
Providing a synthetic form of the immune system protein interleukin-2 (IL-2) to HIV-infected individuals already taking combination antiretroviral therapy boosts their numbers of CD4+ T cells, the key white blood cells destroyed by HIV, but fails to reduce their risk of HIV-associated opportunistic diseases or death compared with combination antiretroviral therapy alone.

These are the findings of two large international clinical trials presented today at the Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal.

The Phase III trials, known as the ESPRIT and SILCAAT studies, were sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and funded respectively by NIAID and Chiron Corp. of Emeryville, Calif. (since 2006 part of Novartis Pharmaceuticals).

Marcelo H. Losso, M.D., of Hospital José María Ramos Mejía, Buenos Aires, Argentina, presented the results of ESPRIT, and Yves Levy, M.D., of Hôpital Henri Mondor, Créteil, France, presented the results of SILCAAT.

IL-2 is produced naturally in the body and plays an important role in regulating CD4+ T cell production and survival. As their CD4+ T cell levels drop, people infected with HIV become more vulnerable to AIDS-related opportunistic diseases and death. Earlier research established that giving synthetic IL-2 plus antiretroviral therapy to people with HIV infection boosts their CD4+ T cell counts more than does antiretroviral therapy alone, but it was unknown whether this boost translated into better health. ESPRIT and SILCAAT were designed to test whether giving IL-2 to HIV-infected individuals already on antiretroviral therapy would keep them healthier longer than HIV-infected individuals taking only antiretrovirals.

Together, the ESPRIT and SILCAAT studies involved more than 5,800 HIV-infected volunteers in 25 countries. Participants were assigned at random to receive either combination antiretroviral therapy alone or combination antiretrovirals plus injections of Proleukin (Novartis Pharmaceuticals, Basel, Switzerland), a synthetic form of IL-2, over several five-day cycles. To evaluate the effects of IL-2 treatment at different stages of HIV infection, the ESPRIT study enrolled people with early-stage infection (CD4+ T cell counts at or above 300 cells per cubic millimeter, or mm3), while the SILCAAT study enrolled volunteers with later-stage HIV infection (CD4+ T cell counts between 50 and 299 cells/ mm3).

"In both studies, the volunteers who received IL-2 and antiretrovirals experienced notable, sustained increases in CD4+ T cell counts, as anticipated," notes NIAID Director Anthony S. Fauci, M.D. "Unfortunately, these increases did not translate into reduced risks of HIV-associated opportunistic diseases or death when compared with the risks in volunteers who were taking only antiretrovirals. Although further analyses may help us better understand these findings, the two studies clearly demonstrated that the use of IL-2 did not improve health outcomes for HIV-infected people."

It is unclear why increased CD4+ T cell counts did not translate into better health outcomes. James D. Neaton, Ph.D., of the University of Minnesota, principal investigator of the global clinical trials network that conducted ESPRIT, offers two possible explanations. "It could be that the types of CD4+ T cells induced by IL-2 play no role in protecting the HIV-infected patient, and therefore the administration of IL-2 has no benefit," says Dr. Neaton. "A second possibility is that the CD4+ T cells are at least somewhat functional or that IL-2 has some modest benefit, but that the side effects of IL-2 may neutralize any possible benefit."

"In the end, the results of these two studies indicate that although a person's number of CD4+ T cells is a key measure of success in the treatment of HIV with antiretroviral drugs, we can't rely on CD4+ T cell counts to predict whether immune-based therapies such as IL-2 will improve the health of HIV-infected individuals," concludes Dr. Levy, the principal investigator of SILCAAT.

"The purpose of clinical research is to clearly state and accurately test hypotheses with an ultimate goal of improving patient care," notes H. Clifford Lane, M.D., director of clinical research at NIAID and a member of the executive committee of ESPRIT. "These two clinical trials successfully reached a definitive answer about the utility of IL-2 therapy for treating HIV infection. NIAID thanks the thousands of dedicated volunteers and investigators who made these studies possible. The results will have significant implications for the future development of immune-based therapies for HIV and studies of HIV pathogenesis."

Background Information on ESPRIT and SILCAAT

The ESPRIT study—which stands for "Evaluation of Subcutaneous Proleukin in a Randomized International Trial"—began in March 2000 and ended as scheduled in November 2008. It was coordinated by the international centers of the NIAID-sponsored International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). These centers are the Medical Research Council Clinical Trials Unit in London; the Copenhagen HIV Program in Denmark; the National Centre in HIV Epidemiology and Clinical Research at the University of New South Wales in Sydney, Australia; and the Community Programs for Clinical Research on AIDS (CPCRA) unit in Washington, D.C. The study's statistical and data management center was based at the University of Minnesota in Minneapolis.

The study investigators followed 4,111 HIV-infected men and women ages 18 and older in 25 countries at 252 clinical trial sites. Half of the volunteers were injected with 7.5 million international units (MIUs) of Proleukin twice a day for five consecutive days every eight weeks for at least six months. After six months, volunteers could receive additional IL-2 cycles at the discretion of their physicians to maintain CD4+ T cell counts at twice their baseline levels or greater than 1,000 cells/mm3 for as long as possible. All volunteers were assessed every four months for an average of seven years to monitor CD4+ T cell counts, viral load (the amount of HIV in the blood) and signs of illness.

In analyzing the ESPRIT results, researchers found that although volunteers who received IL-2 maintained a higher CD4+ T cell count (an average of 160 cells/mm3 higher) than those in the antiretroviral-only study group, there was no difference in the rate of HIV-associated opportunistic diseases or death between the two groups.

The SILCAAT study—short for "Subcutaneous, Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy"—began in April 1999, ended in November 2008, and was conducted by the same international coordinating center structure that conducted ESPRIT. While SILCAAT was funded primarily by Chiron Corp., sponsorship of SILCAAT shifted from the Chiron Corp. to NIAID's Division of Clinical Research in 2003. The study investigators followed 1,695 HIV-infected adults in 11 countries at 114 clinical trial sites. Volunteers assigned to the IL-2 group received 4.5 MIUs of Proleukin twice a day for five consecutive days every eight weeks for one year. After that point, participants could receive additional IL-2 cycles to maintain their CD4+ T cell counts at 125 to 175 cells/mm3 above baseline. All volunteers were assessed every four months for approximately seven years.

As in the ESPRIT study, the SILCAAT volunteers who received IL-2 experienced a higher CD4+ T cell count (an average of 59 cells/mm3 higher) than those who received only antiretrovirals, but there was no difference in health outcomes between the two groups.

Additionally, IL-2 recipients in both studies experienced a greater number of serious clinical events already known to be associated with IL-2, including disorders of the heart and blood vessels, injection site reactions and such psychiatric disorders as depression and suicidal behavior.

Participants in the ESPRIT and SILCAAT clinical trials were promptly informed of the findings. Additionally, NIAID has discontinued the use of IL-2 in a separate, 20-country clinical trial known as STALWART (which stands for "Study of Aldesleukin with and Without Antiretroviral Therapy"). The study was comparing the effects of providing no treatment with the effects of intermittent cycles of IL-2 alone or IL-2 plus antiretrovirals in participants with early-stage HIV infection who do not yet meet the criteria to begin antiretroviral treatment. STALWART began in November 2005, and routine follow-up of the participants will continue until the end of February as originally planned.

Proleukin is approved by the U.S. Food and Drug Administration to treat adults with metastatic melanoma or metastatic kidney cell carcinoma. As a cancer treatment in the United States, it is administered to hospitalized patients for a shorter duration and at a higher dosage than those used in the ESPRIT and SILCAAT clinical trials.

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yahoo

Increasing Diversity of HIV Strains Impacts Diagnostic Test Accuracy
Reports at CROI Meeting Confirm Rising Prevalence of Non-B HIV Subtypes in the United States
As genetically divergent strains of the HIV virus become increasingly prevalent in the United States, the ability of clinicians to effectively monitor progress of anti-viral drug therapies depends on the capacity of viral load assays to accurately quantitate, or measure, these variant HIV strains, according to research reported today at the 16th Conference on Retroviruses and Opportunistic Infections (CROI).

A study by the Global HIV Surveillance Program at Abbott (NYSE: ABT) showed significant variation in the ability of diagnostic tests to accurately monitor viral load in patients infected with differing strains, or subtypes, of the HIV virus. The study evaluated HIV-infected specimens using the Abbott RealTime HIV-1 test and the Roche COBAS Taqman HIV-1 test.

According to the study, the Abbott RealTime HIV assay quantitated HIV more accurately than the widely used COBAS Taqman assay in an analysis of 317 seropositive samples from seven countries: Argentina, Brazil, Cameroon, Saudi Arabia, South Africa, Thailand and Uganda. The samples included six different HIV subtypes and eight circulating recombinant forms. Only 18 samples were subtype B, the most common HIV strain in the United States.

The research showed the Taqman assay failed to detect five infected samples and underquantified viral load in 38 samples, compared to the Abbott assay.

"The differences in viral load quantitation between assays is likely due to the impact of HIV genetic variation on assay performance," said John Hackett, Ph.D., lead author from the Abbott HIV Global Surveillance Program. "Since viral load measurement is critical for optimal patient management, clinicians must recognize that HIV diversity can influence the accuracy and reliability of assay performance."

The Abbott RealTime HIV-1 test is used in conjunction with clinical presentation and other laboratory markers as an indicator of disease prognosis, and as an aid in assessing viral response to antiretroviral treatment as measured by changes in plasma HIV-1 RNA levels. The RealTime assay is not intended for use as a donor-screening test for HIV-1 or as a diagnostic test to confirm the presence of HIV-1 infection.

Increasing Prevalence of Diverse HIV Subtypes

Further evidence of the growing impact of diverse HIV subtypes for monitoring AIDS patients in the United States was reported by the University of Maryland School of Medicine. The study showed the prevalence of non-subtype B strains in the Baltimore metro area is about two percent, based on tests of 2,200 HIV patients. However, in the Maryland portion of the Washington D.C. area, 13 percent of the positive samples sequenced were non-B. The majority of non-B subtypes (80.8 percent) were from recent immigrants from Africa, of which 62.5 percent were women.

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[John2038]

aidsmap

When to start HIV treatment: cohort studies disagree on how early
Two major analyses of the risk of death or AIDS-related illness in people who started treatment at different CD4 counts have produced conflicting evidence about the benefit of starting treatment substantially earlier than current guidelines recommend, the Sixteenth Conference on Retroviruses and Opportunistic Infections heard on Monday.

A North American cohort study found that people who started treatment with a CD4 count below 500 cells/mm3 had a 60% higher risk of death than people who started treatment above this level, but a collaborative study by European and North American cohorts failed to find any extra benefit of starting above 400 cells/mm3. The second study found that while there was a clear benefit to starting treatment at a CD4 count in the range 350-450 cells/mm3 when compared with a lower count, starting treatment at CD4 count in the range 450-550 cells/mm3 did not provide a further benefit in terms of reducing the risk of AIDS or death.

Treatment guidelines in the developed world all concur that antiretroviral treatment should start around the time the CD4 cell count falls to 350 cells/mm3, although some groups of people, such as those with high viral load or with HIV/hepatitis C co-infection, should consider starting treatment before this point is reached.

However some physicians now believe that treatment should start considerably earlier, when the CD4 count is above 500 cells/mm3, in order to minimise the time during which individuals with HIV are immunosuppressed (the normal CD4 count in healthy adults is in the range of 700-1200 cells/mm3). Immunosuppression might increase the risk of some non-AIDS-defining cancers, which occur more frequently in people with HIV, and might also exacerbate the damage caused by hepatitis C infection, which appears to be more virulent and damaging to the liver in people with lower CD4 cell counts.

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Certain protease inhibitors and abacavir linked to heart attacks in two large cohort studies
The latest follow-up data from two large cohort studies, presented on Monday at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal, adds further evidence that specific protease inhibitors (PIs) and nucleos(t)ide reverse transcriptase inhibitors (N(t)RTIs) are associated with a higher risk of cardiovascular problems in people with HIV.

While several past observational studies have seen an increased risk, controlled trials have produced conflicting results. Furthermore, the mechanisms explaining heightened cardiovascular risk in HIV-positive people - whether on or off antiretroviral therapy - are not fully understood.

D:A:D study
The D:A:D study (Data Collection on Adverse Events of Anti-HIV Drugs) has collected information about the side effects of antiretroviral treatment for the past decade. This multinational collaboration includes eleven prospective cohorts from the US, Australia and Europe.

Several years ago D:A:D researchers began reporting a link between PI use and cardiovascular events. At last year’s Retrovirus conference, they reported the controversial finding that recent use (within six months) of the NRTI abacavir (Ziagen, also in the Kivexa and Trizivir coformulations) appeared to increase the risk of myocardial infarction (MI), or heart attack, by 90%, whilst ddI (didanosine, Videx) increased this risk by 49%.

At last summer's International AIDS Conference in Mexico City, investigators with the large SMART treatment interruption trial also reported a link between cardiovascular events and recent use of abacavir (though not ddI), but a pooled analysis of more than 50 clinical trials conducted by abacavir manufacturer GlaxoSmithKline did not find any increase in risk.

The D:A:D analysis presented this week included longer follow-up data. A total of 33,308 patients were followed from the time of enrolment through February 2008, reflecting 178,835 total person-years of follow-up. Over this period, 580 participants experienced a heart attack.

The impact of specific antiretroviral drugs on heart attack risk was assessed using Poisson regression analysis. The study looked at seven N(t)RTIs; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz (Sustiva, also in the Atripla co-formulation) and nevirapine (Viramune); and the PIs indinavir (Crixivan), saquinavir (Invirase), nelfinavir (Viracept) and lopinavir/ritonavir (Kaletra).

D:A:D has a policy of only reporting findings for drugs that have been used by a significant number of people for a considerable length of time (more than 30,000 total person-years of follow-up). The N(t)RTI tenofovir (Viread, also in Truvada and Atripla) was left out last year due to insufficient data, but included in this year's analysis. There is not yet enough data for the newer PIs, the newly approved NNRTI etravirine (Intelence) or the fusion inhibitor, integrase inhibitor and CCR5 antagonist drug classes.

Since cardiovascular risk is influenced by many variables, risk ratios were adjusted for demographic characteristics, blood lipid levels and other metabolic measurements and other cardiovascular risk factors (such as age, smoking and family history). People with a moderate Framingham cardiovascular risk accounted for about 15% of total follow-up time, while those with a high risk accounted for about 5%. The researchers also adjusted for HIV disease status, including CD4 cell count and viral load.
The investigators found no association between heart attack risk and recent or cumulative exposure to either of the studied NNRTIs, two of the PIs (nelfinavir and saquinavir), or most of the N(t)RTIs.

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[John2038]

aidsmap

HIV sporadically detectable in semen of men with undetectable plasma viral loads
At the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal on Monday morning, two back-to-back oral presentations affirmed that HIV is indeed often detectable in semen despite undetectable viral loads in blood plasma. The two studies found measurable HIV RNA ("viral shedding") in 3% to 14% of seminal fluid samples taken from study participants with undetectable plasma viral loads.

Since the 'Swiss statement' of January 2008, which described HIV-positive individuals on effective antiretroviral therapy and without sexually transmitted infections (STIs) as "sexually non-infectious", the issue of how antiretroviral treatment affects sexual infectiousness has been hotly debated. In particular, case reports have indicated that HIV may indeed be present in the semen of men who are on successful antiretroviral therapy, with undetectable blood plasma viral loads.

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Seminal HIV: cell-free virus, not infected cells, leads to transmission between men
At the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal on Monday morning, David Butler of the University of California San Diego presented data on four cases of male-to-male sexual transmission, showing that cell-free virus in semen – not proviral DNA in infected cells – was the means of transmission in all four cases.

HIV is present in semen both as cell-free virus, measurable as RNA in the seminal fluid itself, and as proviral DNA contained within lymphocytes (white blood cells) in the semen. Until now, it has not been known which of these is responsible for sexual transmission. Little is also known about the genetic characteristics that distinguish transmitted from non-transmitted virus. The objective of this study was to study cases of male-to-male sexual transmission, to determine whether the infected partner's viral genome was more closely associated with the cell-free RNA (CF-RNA) or the cell-associated DNA (CA-DNA) in the source (infecting) partner, and explore some of the genetic differences between transmitted and non-transmitted virus strains.

The study team selected four male sexual couples, in which HIV transmission was known to have recently occurred, from a cohort study of primary infection. Samples were collected from the source partner's semen a mean of 72 days after infection took place, and from the newly infected partner's blood a mean of 59 days after infection. First of all, the link between the infecting and infected partner was verified by analysis of the viral pol gene. More detailed genomic sequencing was then performed on HIV RNA from the newly infected partner's blood, and on cell-free RNA and proviral DNA from the source partner's seminal fluid.

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PrEP could work even if taken several days in advance
A study using tenofovir and FTC (Truvada) to prevent rectal SHIV infection in monkeys – so-called pre-exposure prophylaxis (PrEP) - has shown that it is as effective for the medication to be given up to three days before exposure as it is one day before. Even giving Truvada a full week before exposure resulted in a considerable reduction in the risk of infection.

In contrast, giving the medication only two hours before exposure resulted in a smaller protective effect, possibly because intracellular concentrations of the drugs had not reached high enough levels.

The study is not a ‘pure’ trial of the PrEP concept because in all cases the monkeys were also given a single post-exposure dose of Truvada. However it does demonstrate that constant PrEP is not necessary to confer significant protection and that intermittent dosing may, if anything, be even more effective, at least in the case of Truvada.

The study population consisted of a total of 51 male rhesus macaques. They had 14 weekly rectal exposures to SHIV, an artificial form of HIV adapted to infect monkeys (except one group that was exposed every two weeks).

The control arm included 27 animals that received no treatment. There were five treatment arms including a total of 30 animals all given two doses of drug. The dosing intervals in the five treatment arms were:

    * 1. Two hours before viral exposure and 22 hours afterwards
    * 2. Twenty-two hours before and two hours afterwards
    * 3. Three days before and two hours afterwards
    * 4. Seven days before and two hours afterwards (this group was exposed to the virus once every
           two weeks)
    * 5. An entirely post-exposure prophylaxis group, given Truvada two and 26 hours after viral
          exposure.
   
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Test can predict non-Hodgkin's lymphoma in people with HIV
The risk of non-Hodgkin’s lymphoma developing in people with HIV within two to five years can be predicted with a high degree of accuracy using an assay already used to monitor for the development of multiple myeloma, according to findings presented on Monday at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal, Canada.

Non-Hodgkin’s lymphoma is a relatively common cancer in people with HIV, and the most common type of lymphoma seen in people with HIV. It is a tumour that involves the uncontrolled multiplication of a type of white blood cells called lymphocytes. The vast majority of non-Hodgkin’s lymphomas are B-cell lymphomas, which are a result of uncontrolled proliferation of B-lymphocytes, the antibody-generating group of lymphocytes.

A range of cancers are related to B-cell proliferation, and a variety of markers of proliferation have been proposed as potential monitoring tools for predicting the development of these types of cancers.

Multiple myeloma, a cancer that emerges in the plasma cells of the bone marrow, is already routinely monitored using a free light chain assay. A light chain is a molecule that is normally bound to an immunoglobulin, or antibody, produced by B-cells. In the presence of myeloma, levels of unlinked, or free, light chain levels are elevated.

Researchers from the US National Cancer Institute and the Mayo Clinic in Rochester, New York, conducted a case-control study that matched 66 HIV-positive cases of non-Hodgkin’s lymphoma occurring between 1985 and 2004, each with four HIV-positive control cases selected on the basis of matching sex, race, age and CD4 count (225 total controls).

Levels of immunoglobulin (Ig) G, IgM and IgA levels were measured from stored plasma samples, together with levels of kappa and lambda free light chains, and their predictive value for the development of NHL was assessed.

Levels of kappa and lambda free light chains were found to strongly predict the development of NHL two to five years in advance, and levels of these molecules were elevated in all HIV-positive individuals compared with reference levels in the general population. The kappa/lamda free light chain ratio did not predict NHL, and nor did changes in free light chain levels over time.

Immunoglobulin levels did not predict the development of NHL.

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Risk of cancers with infectious cause going down in people with HIV
A large study of HIV-positive people in the US, followed for an average of four years, shows that people with HIV have an approximately sixfold greater risk of developing a non-AIDS-defining cancer with an infectious cause compared to HIV-negative people, with the majority of these cancers potentially related to human papilloma virus (HPV). The findings, from the Kaiser Permanente healthcare database in California, were presented on Monday at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal, Canada.

Nevertheless the study found that for people with HIV, the risk of developing a non-AIDS-defining cancer with an infectious cause has declined since the introduction of antiretroviral therapy, whereas it has remained constant in HIV-uninfected people since 1996.

Non-AIDS-defining cancers are becoming more common as the population of people with HIV lives longer and ages. Some non-AIDS-defining cancers, such as lung cancer, occur more frequently in people with HIV than in the general population, and a recent US study showed that nine non-AIDS-defining cancers occurred more frequently in people with HIV than in the general US population.

However, it is not clear if the risk of developing such cancers is increasing, or diminishing due to the effects of antiretroviral therapy.

The analysis reported today looked at the incidence of cancers in HIV-positive people receiving care through the Kaiser Permanente managed healthcare programme, which provides care for around one in four Californians. The researchers identified 18,890 HIV-positive patients and 189,804 HIV-negative patients.

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[John2038]

natap

BMS Co-Payment Assistance Program
Bristol-Myers Squibb will begin offering a co-payment assistance program within the first half of this year for new and existing REYATAZ (atazanvir) and SUSTIVA (efavirenz) patients with commercial insurance. We recognize that especially in this economic environment, out-of -pocket costs for HIV medicines may be prohibitive even for patients who have prescription drug benefits. This program reflects our ongoing commitment to ensuring patients who need our medicines are able to access them. As you know, Bristol-Myers Squibb already has initiatives in place to support access to medicines for uninsured and underinsured patients living with HIV. For example, BMS participates in the pharmaceutical industry's Together RX Program. In addition, BMS provides our medicines free of charge for those who qualify through our Patient Assistance Program. We are working quickly to finalize the structure of the co-payment assistance program and will provide more detailed information to you in the near future. In the meantime, we would like to thank the many individuals and groups within the community who have lent their insights to the continued development of Bristol-Myers Squibb's access programs. We appreciate your collaboration in our efforts to continue to meet the needs of the community.

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CROI: GS-9350: A Pharmacoenhancer Without anti-HIV Activity
-- GS-9350 is a potent, selective, mechanism-based CYP3A inhibitor that lacks anti-HIV activity and has limited effects on adipocyte function in vitro
-- GS-9350 boosts CYP3A substrates comparable to RTV in humans
-- EVG/FTC/TDF/GS-9350 FDC tablet achieves desired exposures of EVG, FTC and TFV

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GS 9350 doses of 100 mg and 200 mg inhibited midazolam clearance by 92 percent and 95 percent, respectively, compared with 95 percent for the 100 mg dose of ritonavir, thereby providing clinical proof-of-concept of GS 9350 as a pharmacokinetic booster in humans.
 
Both single and multiple doses of GS 9350 were well tolerated. One drug-related Grade 3 adverse event (discoordination) occurred in one trial participant during multiple dose administration of GS 9350 100 mg. No trial participants developed drug-related Grade 3 or 4 laboratory abnormalities or Grade 4 adverse events.

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Note
Remember the CYP3A4 ?
CYP3A4 is the most important enzyme for drug metabolism, and many medications can interact with ED drugs by decreasing or increasing CYP3A4 activity, causing ED drug levels to increase or decrease, respectively.  It's the enzyme that is decreased for eg by Prezist, Reyataz, Diflucan, etc or increased with Viramune, Sustiva, etc. GS-9350 is a booster (pharmacoenhancer) developed by Gilead

Switching from Stable Lopinavir/Ritonavir (LPV/r)-Based to Raltegravir (RAL)-Based Combination Antiretroviral Therapy (ART) Resulted In a Superior Lipid Profile at Week 12 but Did Not Demonstrate Non-Inferior Virologic Efficacy at Week 24 (SWITCHMRK)





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In SWITCHMRK 1:
 
• Total cholesterol: -13% raltegravir vs +1% lopinavir, P < 0.001
• Triglycerides: -41% raltegravir vs +4% lopinavir, P < 0.001
• Non-high-density lipoprotein cholesterol: -15% raltegravir vs +2% lopinavir, P < 0.001
 
The groups did not differ significantly in high-density lipoprotein (HDL) cholesterol change, and the researchers did not present changes in total-to-HDL cholesterol ratio, which gives a balanced view of overall cholesterol shifts. Lipid results were similar in SWITCHMRK 2.
The SWITCHMRK trials enrolled people taking a suppressive lopinavir/ritonavir regimen for at least 3 months. Because about 80% of participants had taken lopinavir/ritonavir for more than 1 year and because people taking lipid-controlling drugs were excluded from the trials, one can assume most enrollees were tolerating lopinavir/ritonavir well. Eron and colleagues randomized 178 people to stay on lopinavir/ritonavir (400/100 mg twice daily) and 176 to switch to raltegravir (400 mg twice daily). Everyone kept the same background regimen, which had to include at least two nucleosides and could include no other PI.

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CROI: Smoking Emerges as Top Death Risk Factor in FRAM Participants With HIV
Current smoking (but not past smoking) nearly tripled the death risk (hazard ratio 2.73, 95% CI 1.64 to 4.53, P = 0.0001).
Every added 10 years of age raised the risk more than 60% (HR 1.61, 95% CI 1.27 to 2.05, P < 0.0001).
And every log2 higher current CD4 count lowered the risk 35% (HR 0.65, 95% CI 0.58 to 0.73, P < 0.0001).
The link between current smoking and death held true in all three CD4 count strata.

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CROI: HIV and Diabetes/Hyperlipidemia Cause Kidney Decline
In this study of a cohort of patients Andy Choi reported that HIV+ individuals showed decline in kidney function as measured by GFR more quickly than expected, more quickly than in the general population, and of note HAART may reverse or slow decline but GFR still declined in HIV+ individuals in this study while on HAART. So, this means HIV can cause kidney decline and HAART can slow it but decline may continue despite fully suppressive HAART. Choi also reported importantly that patients that intermittent viral blips were strongly associated with "kidney harm" (GFR decline) suggesting that ART interruptions can cause GFR decline.; each log increase in viral load was assoiated with an accekerated GFR loss of -6.9 mL/min/1.73m2 per year. He also reported that traditional risk factors, which are common in HIV+ are important risk factors for kidney disease in this study population: diabetes and hyperlipidemia cause GFR to decline. HIV gets into the kidney upon infection with HIV. As well, HIV gets into the CNS immediately after HIV infection, within 24-48 hours. In addition, HIV causes inflammation, which is associated in HIV+ and HIV- individuals with the development of comorbidities. HAART suppresses but does not eliminate inflammation, it may still persists despite complete viral suppression. HIV is the main culprit in the development of comorbidities due to HIV accelerating the aging of important naive and memory CD4 cells. In brief, these are the reasons why aging with HIV has become the major issue today, because this underlies all the discussion about the development of non-AIDS events and death. These issues also underlie the question about when to begin HAART, because the results of numerous cohort studies find earlier HAART reduces rates for non-AIDS events and death.

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aidsmap

Kaletra superior to nevirapine-based ART for women already exposed to single-dose nevirapine
An antiretroviral regimen based on the boosted protease inhibitor lopinavir/ritonavir (Kaletra, or Aluvia) was significantly more effective than a nevirapine-containing regimen in mothers previously exposed to single-dose nevirapine, according to results from the randomised OCTANE study presented on Tuesday at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montréal.

However the difference in response to the two regimens was less pronounced among women who started treatment at a longer interval after exposure to single-dose nevirapine. There was no difference in the risk of treatment failure between the regimens among women who started antiretroviral therapy more than two years after exposure to single-dose nevirapine.

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Maternal resistance to nevirapine following single dose reduced by AZT/ddI or one month's ART
Two Thai studies have provided further evidence that short courses of more than one antiretroviral drug after delivery almost eliminate the risk of nevirapine resistance in mothers when it is used to prevent mother to child transmission, thus preserving nevirapine as an option for maternal treatment when eventually needed.

The findings were presented on Tuesday at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montréal.

In one study researchers compared a triple regimen of AZT/ddI and lopinavir/ritonavir (Kaletra) taken for one month or one week with AZT/ddI taken for one month, while in the second study another research group compared one month of postpartum AZT/ddI to a historical control group that received AZT postpartum. Both studies evaluated the regimens in women who did not need antiretroviral therapy for their own health.

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hivandhepatitis

HIV Patients with Chronic Viral Hepatitis Coinfection Experience Greater Reductions in CYP3A Activity when Taking Ritonavir
A large proportion of HIV patients use low doses of the antiretroviral drug ritonavir (Norvir) to "boost" levels of other protease inhibitors (PIs) in the body. This works because ritonavir interferes with the action of the cytochrome P450 3A (CYP3A) enzyme, which metabolizes many antiretroviral agents -- as well as drugs for numerous other diseases.

Because CYP3A drug processing occurs mainly in the liver (with some also occurring in the intestines), Tasmin Knox and colleagues from Tufts University evaluated whether the inhibitory effect of ritonavir on CYP3A activity differed in HIV positive patients with and without chronic viral hepatitis. Findings were reported in the December 1, 2008 Journal of Acquired Immune Deficiency Syndromes.

Results

    * Among patients who were not on therapy, CYP3A activity was similar in those with chronic viral
       hepatitis coinfection and those with HIV monoinfection (mean oral clearance 23.2 vs 28.5
       mL/min/kg; not a statistically significant difference).

    * Among all patients taking ritonavir, CYP3A activity was about 7% that of all control subjects not on
       therapy (mean 2.1 vs 28.5 mL/min/kg, respectively; P < 0.0004).

    * Among ritonavir recipients with chronic viral hepatitis, CYP3A activity was further reduced, to 4%
      that of control subjects not receiving therapy (mean 1.0 vs 2.1 mL/min/kg, respectively; P < 0.006).

Based on these results, the study authors concluded, "Ritonavir markedly decreases CYP3A activity. In the presence of chronic viral hepatitis, ritonavir-based therapy further reduces CYP3A activity by half. Coinfection with chronic viral hepatitis impairs CYP3A activity in the presence of the CYP3A inhibitor ritonavir."

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[John2038]

news.gov.hk

Flu vaccine recall monitored
The Department of Health is monitoring the recall of an influenza virus vaccine manufactured by the British plant of Novartis Vaccines & Diagnostics.

The drug company is asking customers to stop using doses from five lots of FLUVIRIN Influenza vaccine Luer-Lok pre-filled syringes manufactured in Britain.

Routine stability testing of FLUVIRIN revealed a minor deviation in the potency of the A/Brisbane (H1N1) component of the vaccine.

The problematic vaccines have not been imported to Hong Kong, the department said today, adding Novartis' vaccines in Hong Kong are manufactured in another country.

The vaccines are tested to be effective for the current strains of influenza virus recommended by the World Health Organisation.

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[John2038]

aidsmap

Half of HIV/HCV co-infected early responders are cured with 72-week treatment

HIV/HCV co-infected individuals who achieve a complete early response to interferon-based therapy for chronic hepatitis C have a 51% chance of achieving a sustained virological response using an extended 72-week course of treatment, researchers reported on Tuesday at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal, Canada.

Raymond Chung from Massachusetts General Hospital in Boston reported the latest results from the American SLAM-C (Sustained Long-term Antiviral Maintenance with Pegylated Interferon in HCV/HIV Co-infected Patients) trial, also known as ACTG A5178.

Co-infected individuals tend to respond less well to interferon-based therapy than people with hepatitis C virus (HCV) alone, and this study was designed to look at extended treatment and long-term pegylated interferon maintenance in non-responders.

SLAM-C consisted of three steps. First, 329 HIV/HCV co-infected patients were treated with 180 mcg/week pegylated interferon alfa plus weight-based ribavirin (1200mg/day for those weighing more than 75kg and 1000mg/day for those 75kg or less) for 12 weeks. At this point, participants were tested to see if they had achieved early virological response (EVR), that is, at least a two log10 decrease or undetectable (less than 600 IU/ml) HCV viral load.

In step 2, early responders continued to receive pegylated interferon plus ribavirin for a total duration of 72 weeks, while non-responders dropped ribavirin and continued on the same dose of pegylated interferon monotherapy. (The standard duration of hepatitis C treatment for co-infected people is 48 weeks regardless of HCV genotype.) Results from non-responders in step 2 were reported at last year's Retrovirus conference.

This year's report focused on step 3, looking at the 183 patients (56%) who achieved a partial or complete early virological response. Of these, 169 opted to continue on combination therapy through 72 weeks. Information about sustained virological response (SVR) - continued undetectable HCV viral load 24 weeks after the end of treatment - was available for 146 participants.

In the continuing group, most (89%) were men, the median age was 48 years, 52% were white, 29% were African-American, and 15% were Hispanic. This represented a shift from 43% white and 37% African-American in the original full study population, reflecting the fact that more blacks were non-responders.

Participants generally had well-controlled HIV disease, with 89% on antiretroviral therapy, 86% with HIV viral load below 50 copies/ml, and the median CD4 count was 316 cells/mm3 (lower than the median of nearly 500 cells/mm3 in the original population). Finally, just over three-quarters had hard-to-treat HCV genotypes 1 or 4, nearly one-third had prior interferon treatment experience, and 9% had cirrhosis.

About three-quarters of early responders were classified as having achieved complete EVR, defined as HCV viral load below 600 IU/ml, while the remainder were classified as having achieved partial EVR, with at least a two log10 drop, but 600 IU/ml or higher.

Overall, 51% of patients who achieved early virological response went on to achieve sustained virological response. The SVR rate was about twice as high amongst patients with HCV genotypes 2 or 3 compared with genotypes 1 or 4 (82% vs 42%, respectively). Participants with previous unsuccessful treatment attempts were half as likely to achieve sustained response as treatment-naive patients (30% vs 60%, respectively).

Furthermore, participants who had achieved complete EVR were nearly four times more likely to achieve sustained virological response than those with partial EVR (62% vs 17%, respectively).

As expected, the overall SVR rate was lower amongst African-Americans (38%) than amongst "non-black" patients (57%). This disparity was also seen in the partial responder group, but amongst patients who achieved complete EVR, the difference in SVR rates between blacks and whites was not statistically significant (54% vs 65%, respectively).

Many patients found extended duration therapy difficult to tolerate, and just over one-third (35%) stopped treatment before 72 weeks. The most common adverse events were known interferon or ribavirin side-effects such as muscle aches, depression, and blood-cell deficiencies. Fatigue and poor quality of life were the most frequently reported reasons for stopping therapy. A majority of early discontinuations and drug dose reductions due to side-effects occurred during the final 24 weeks of treatment.

Given the large disparity in sustained virological response rates between complete and partial early responders, Dr Chung noted that failure to achieve complete HCV clearance by week 12 identifies most patients who will not go on to achieve sustained response, thereby allowing likely non-responders to avoid further futile therapy.

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[John2038]

NATAP [CROI]

French Hospital Study and Further D:A:D - Analyses Suggest MI Risk With Abacavir
Work from the French Hospital Database on HIV supported a finding from last year's Conference on Retroviruses--an apparent link between recent abacavir use and myocardial infarction (MI)

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Non-AIDS Illness More Common Than AIDS--and More Deadly--in EuroSIDA
Since January 2002, non-AIDS diagnoses proved more common than AIDS diagnoses in 10,341 EuroSIDA cohort members, and non-AIDS diseases killed substantially more people than AIDS. New diagnoses of non-AIDS illnesses exceeded diagnoses of AIDS among people with CD4 counts above 100 and in those with better-controlled viral replication.
Non-AIDS illnesses considered were malignancies, end-stage renal disease, liver failure, pancreatitis, and cardiovascular disease (including acute myocardial infarction or stroke). They did not count recurrences of AIDS or non-AIDS diseases.

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MI Rates Converge in California Health System Groups With and Without HIV: trend down in HIV+
Researchers from the Kaiser Permanente healthcare system in California were among the first to record a higher myocardial infarction (MI) rate in people with HIV than in uninfected people [1]. In an updated analysis at this meeting, the same investigators reported that MI rates in Kaiser clients with and without HIV have converged to the point of statistical nonsignificance [2]. The new study involved 20,305 people with HIV seen from 1996 through June 2008 and 203,050 people without HIV matched to the HIV group for age and gender. Patient age averaged 41 years, 90% were men, 56% of the HIV group were white, as were 47% of the non-HIV group.
The difference between the HIV group and the non-HIV group lost statistical significance only in 2006-2008 (P = 0.088).

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Peginterferon (Pegasys) and Weight-Based Ribavirin for 72 Weeks in HIV+ Early Responders
Complete early virologic response (EVR) predicted sustained virologic response (SVR) in a three-part AIDS Clinical Trials Group (ACTG) study called SLAM-C and numbered A5178 [1]. But partial EVR did not predict sustained response. Raymond Chung and ACTG colleagues proposed that complete EVR "should be utilized in the guidance of HCV/HIV-co-infected [patients], particularly when extended treatment regimens are used."

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High HCV Load Doubles the Death Risk in People Coinfected With HIV
HIV-infected EuroSIDA cohort members with high HCV RNA ran a significantly greater risk of death from any cause and liver-related death than people with a lower HCV load, according to results of a 1952-person analysis [1] That finding differs from results in people infected with HCV but not HIV, in whom HCV load does not predict death. The study also determined people with HCV genotype 3 have a significantly lower death risk than people with genotype 1. Earlier work by Jurgen Rockstroh and EuroSIDA colleagues found that HCV serostatus did not influence virologic or CD4 response to potent antiretroviral therapy [2]. This and previous studies relied on anti-HCV antibody positivity to identify coinfected people. The new study set out to determine the influence of HCV RNA load and HCV genotype on HCV and HIV progression in coinfected EuroSIDA cohort members.

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Extra CD4s With IL-2 Confer No Clinical Benefit in Two Randomized Trials
"A potential clinical benefit of IL-2, even [a] moderate [benefit], can be definitively ruled out."
 
Interleukin 2 (IL-2) investigator Yves Levy pronounced that verdict in summarizing a combined analysis of two clinical endpoint trials that randomized people to combination antiretroviral therapy alone or to antiretrovirals plus IL-2. The massive studies, ESPRIT and SILCAAT, involved nearly 6000 people monitored for over 7 years [1,2] (from Jules: and cost up to $150 million). The two trials yielded remarkably consistent results that can be summarized in three points:
 
• People taking IL-2 gained significantly more CD4 cells than those taking antiretrovirals alone.
 
• The extra T cells with IL-2 did not protect people from disease progression or death.

• In ESPRIT, taking IL-2 posed a significantly greater risk of life-threatening grade 4 events, including deep venous thrombosis and depression. In the first year of SILCAAT, grade 4 events were significantly more frequent with IL-2.

Why didn't IL-2 work? Marcello Losso, who spelled out the ESPRIT findings, suggested two possibilities: First, CD4 cells resulting from IL-2 expansion are not functionally equivalent to CD4 cells that arise through antiretroviral-induced suppression of HIV replication. Second, IL-2 may have harmful effects that counterbalance any CD4 benefit (from Jules: one theory offered is that IL-2 disregulates cytokines). Harvard's Daniel Kuritzkes, who was not involved in either trial, offered a third possibility after Losso's talk: In a population with well-controlled viral replication, like ESPRIT and SILCAAT participants, the CD4 difference afforded by IL-2 is not enough to make a clinical difference.

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Risk of non-Hodgkin Lymphoma Death Still Higher With HIV Infection
Despite improvements in antiretroviral therapy, HIV-infected people with non-Hodgkin lymphoma (NHL) still have a higher 2-year all-cause death rate than NHL patients without HIV, according to results of a 10,000-person study in California's Kaiser Permanente health system [1]. Kaiser investigators confirmed the higher death rate with HIV regardless of NHL subtype or stage--and even though more people with HIV got chemotherapy earlier after their diagnosis than people without HIV.

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Lower CD4 Count Linked to Non-AIDS Cancers in EuroSIDA Study
Every doubling of a person's CD4 count independently lowered the incidence of a non-AIDS cancer 11% in a study of 12,865 EuroSIDA cohort member [1]. The finding confirms results of a recent meta-analysis tying immunodeficiency to non-AIDS cancers in people with HIV and transplant patients [2]. The EuroSIDA investigators established the correlation between CD4 count and anal cancer, digestive organ cancers, lung cancer, hematologic cancers, and urinary and genital cancers.
 
The study involved 12,865 HIV-infected people with a CD4 count measured before enrollment in EuroSIDA and with follow-up after enrollment, including CD4 count, viral load, and antiretroviral treatment status within 6 months of any non-AIDS cancer diagnosis. The model used to determine factors related to non-AIDS cancer diagnosis adjusted for year of follow-up, gender, HIV exposure group, race, region of Europe, time on combination antiretroviral therapy, hepatitis B and C status, nadir CD4 count, and whether the patient ever smoked.

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Replacing Enfuvirtide With Raltegravir in France
A switch from enfuvirtide to raltegravir yielded no virologic or CD4 advantage 6 months later, according to results of a randomized trial of 170 heavily pretreated French patients already taking a suppressive enfuvirtide-containing regimen [1]. (from Jules: another way to look at this is that after switching from Fuzeon to raltegravir there was no fall off in the overall viral load suppression, patients maintained suppression, which was high in both arms (89%) and only 1.2% experienced viral failure in each arm, I take it as a positive in these 3-class resistant patients). As the study name (EASIER) suggests, many people probably prefer swallowing a twice-daily raltegravir pill than injecting themselves twice a day with enfuvirtide, if they are confident of sustained viral control. But raltegravir had no safety advantage in these patients, who had been taking enfuvirtide for a median of more than 2 years.

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3 Studies on Abacavir & MI Risk: French Cohort, D.A.D. (slides), ALLRT with 2 Different Results











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No Association of Abacavir Use with Risk of Myocardial Infarction or Severe Cardiovascular Disease Events: Results from ACTG A5001
In contrast to D:A:D and SMART, we did not find a significant association between recent ABC use and MI or severe CVD risk for ART-nave patients randomized to an initial ABC regimen. Our results suggest the association with recent ABC use in other studies may be a marker for other factors not discerned in their analyses.

Abacavir and Cardiovascular Risk
Although differences in study design, statistical power, endpoint definitions, and procedures to capture and validate endpoints may each contribute to these discrepant findings, additional possible explanations also need to be considered. Reviewing the characteristics of the various patient populations which were studied, one could for instance speculate whether the likelihood of identifying the CVD risk associated with ABC may be greater in those who are first exposed after their HIV infection is already suppressed. Data suggest a pathogenic mechanism (possibly of a proinflammatory nature) involving acute processes, such as plaque rupture or subesquent thrombosis, rather than a chronic one affecting atheroma formation. For now, it seems prudent to withold ABC from patients with high underlying CVD risk if suitable alternative regimens are available. If not, patients absolute CVD risk in the presence of ABC should be minimized by aggressive management of traditional CVD risk factors.

Risk of Myocardial Infarction with Exposure to Specific ARV from the PI, NNRTI, and NRTI Drug Classes: The D:A:D Study
Of the ARV considered, only IDV, LPV/r, ddI and ABC were associated with a significantly increased risk of MI. Additional follow-up will allow us to more definitively establish which of the specific (ritonavir-boosted) PI are most associated with MI risk. As with any observational study, our findings must be interpreted with caution given the potential for confounding.

Simplification with Fixed-dose Tenofovir/Emtricitabine or Abacavir/Lamivudine in Adults with Suppressed HIV Replication
The STEAL Study, a Randomized, Open-label, 96-Week, Non-inferiority Trial
In this population, TDF+FTC and ABC+3TC had similar virological efficacy and protection against AIDS. ABC+3TC was associated with more serious non-AIDS events.

Impact of Specific NRTI and PI Exposure on the Risk of Myocardial Infarction: A Case-Control Study Nested within FHDH ANRS CO4
In our study, we found that the risk of MI was increased by cumulative exposure to LPV and to APV or fPV. Initiating ABC was also associated with an increased risk of MI while longer exposure to ABC was not.

Platelet Hyper-Reactivity in HIV-1-infected Patients on Abacavir-containing ART
This study demonstrates consistently hyper reactive platelets in patients on ABC-containing ART and may help explain the increased rates of MI in ABC-treated patients. Further research is required to determine if this effect is reversible.

Inflammatory Markers among Abacavir and non-Abacavir Recipients in the Womens Interagency HIV Study and the Multicenter AIDS Cohort Study
ABC use was not independently associated with elevated plasma levels of hsCRP, IL-6, and D-dimer. While changes in the levels of these markers were seen between the baseline and index visits (D-dimer and IL-6 decreases, hsCRP increases), they were comparable among persons who initiated ABC versus non-ABC containing HAART. Women had higher D-dimer and lower CRP levels than men.

Assessment of Renal Findings of Abacavir/Lamivudine Compared with Tenofovir/Emtricitabine in Combination with Once-daily Lopinavir/Ritonavir over 96 Weeks in the HEAT Study
These results show that improvement in kidney function, as measured by eGFR and eCrCl, was slightly greater, though small in absolute terms, with ABC/3TC compared to TDF/FTC when combined with once-daily LPV/r through 96 weeks. In addition, fewer subjects in ABC/3TC group progressed to stage 3 CKD. Proximal tubule renal dysfunction, though not common, was seen only in those on TDF/FTC.

96-Week Effects of Suppressive Efavirenz-containing ART, Abacavir, and Sex on High-sensitivity C-reactive Protein: ACTG A5095
Durably suppressive therapy with EFV-based regimens did not improve hs-CRP levels over a 96-week period. Overall, an increase was seen which was greater for women than men. Inclusion of ABC had no significant effect on changes in hs-CRP levels.

Association of Abacavir and HIV Disease Factors with Endothelial Function in Patients on Long-term Suppressive ART
Endothelial function, a central mechanism in atherosclerosis and a marker of cardiovascular risk, is impaired among long-term HAART-treated patients with undetectable viral loads. Current use of ABC was independently associated with impaired endothelial function; this effect was not readily explained by measured confounders, including traditional risk factors. Further studies will need to determine whether ABC-associated changes in endothelial function contribute to the clinically observed relationship between ABC use and myocardial infarction.

Similar Reductions in Markers of Inflammation and Endothelial Activation after Initiation of Abacavir/Lamivudine or Tenofovir/Emtricitabine: The HEAT Study
Similar decreases in markers of inflammation and endothelial activation were observed over 96 weeks of treatment with ABC/3TC or TDF/FTC. These data do not suggest that ABC/3TC or TDF/FTC contribute to an increase in cardiovascular risk mediated by inflammation or worsening endothelial activation. The findings from this randomized, prospective data do not support the hypothesis of increased inflammation attributed to ABC from recent observational, cohort studies.

Viral Dynamics and Pharmacokinetics in vivo of Tenofovir Disoproxil Fumarate and Abacavir: Evidence of a Non-additive Antiviral Effect

TDF+ABC did not demonstrate additive antiviral potency compared to ABC alone. This lack of additive antiviral potency was not explained by differences in intracellular concentration of dNTP between mono- and dual-therapy

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96-Week Results from BENCHMRK 1&2, Phase III Studies of Raltegravir (RAL) in Patients (pts) Failing Antiretroviral Therapy (ART) with Triple-Class Resistant HIV
In HIV-infected, treatment-experienced patients failing antiretroviral therapy with triple-class resistant HIV:
 
Raltegravir 400 mg b.i.d. plus OBT, compared to placebo plus OBT, had potent, superior, and durable antiretroviral and immunological effi cacy sustained through Week 96.
 
   * 57% of patients receiving raltegravir maintained HIV RNA < 50 copies /mL -- up to 79% in patients
      receiving new, active ART in OBT
 
Virologic failure was generally associated with mutations at one of three primary residues, Q148, N155, or Y143, in combination with at least one other mutation.
 
Rates of ADC and death during double-blind phase were lower for raltegravir than placebo at Week 96, regardless of endpoint, although these differences did not reach statistical significance.
 
Raltegravir 400 mg b.i.d. plus OBT was generally well tolerated as compared to placebo in combination with OBT.
   * Few adverse experiences led to discontinuation
   * Risk of developing malignancy was comparable between raltegravir and comparator groups.

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Review of Cancer Incidence in Raltegravir (RAL) Clinical Trials
In 5 randomized clinical trials,
   * with follow-up of at least 48 to 120 weeks (over 1700 PYR RAL exposure), cancer rates were lower
   for RAL but not significantly different from comparator during double-blind treatment
   * with approximately 600 PYR additional RAL exposure during open-label phases, cancer rates
      remained similar to those during double-blind phase
 
In expanded access setting,
   * with median follow-up of 24 weeks for over 5400 patients (over 2200 PYR RAL exposure), cancer
      rates were similar to those observed in clinical trials
 
Data to date showed no difference in risk of cancer in HIV-infected patients receiving RAL vs. other ARTs, regardless of case defi nitions used

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Preclinical and Early Clinical Evaluation of SPI-452, a New Pharmacokinetic Enhancer (PKE)







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[John2038]

medicalnewstoday

Progenics Selects Subcutaneous Form Of PRO 140, A Novel HIV Antibody Therapy, For Further Development
Progenics Pharmaceuticals, Inc. (Nasdaq: PGNX) today announced that it has selected for further development the subcutaneous form of PRO 140 for the treatment of HIV infection. The decision follows positive results from a recently completed phase 2 clinical trial as well as feedback from key opinion leaders, treatment advocates and people living with HIV. Results from the phase 2 study were presented late yesterday at the 16th Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal. In this clinical trial, the subcutaneous dosage form of PRO 140 demonstrated potent and highly significant antiviral effects compared to placebo at all doses of active drug examined and was generally well tolerated.

"These phase 2 clinical results confirm our previously announced interim findings which showed that subcutaneous PRO 140 therapy was potent, long-acting and well tolerated," said Paul J. Maddon, M.D., Ph.D., Progenics Pharmaceuticals' Founder, Chief Executive Officer and Chief Science Officer. "We plan to meet with the U.S. Food and Drug Administration to discuss registrational studies for subcutaneous PRO 140. Similar to intravenous PRO 140, the subcutaneous form has demonstrated significant antiviral activity and favorable tolerability in clinical trials to date, with the additional potential benefit of convenient self-administration by patients. Given that all currently available HIV drugs are given between one and three times daily, a weekly therapy could have many advantages related to adherence."

*To view the abstract and poster, as well as a graph depicting the mean change in viral load over time for the four dose groups, please visit the following link.

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HIV-Positive People Might Benefit From Early Treatment, Study Presented At CROI Indicates
HIV-positive people who begin drug regimens soon after infection might have better treatment outcomes than those who delay taking medication, according to a study presented Monday at the 16th Conference on Retroviruses and Opportunistic Infections in Montreal, Canada, Bloomberg reports.

During the first few weeks after contracting HIV, often called the "acute phase," HIV grows rapidly in the body. To determine the benefits of treating people during the acute phase, the researchers provided early treatment for six to 15 months to 55 HIV-positive people and did not provide early treatment to another group of 47 people. The researchers found that the 55 HIV-positive people who received treatment soon after infection generally progressed to taking long-term treatment after an average of 45 months. The 47 patients who did not receive early treatment generally progressed to long-term treatment after 32 months. According to Steingrover, the study suggests that immediate HIV treatment can delay the need for long-term drugs by about one year.

"To the question of whether this is beneficial [to the patient], I think the answer is yes," Steingrover said. "Until now, the benefits to the patient have just been theoretical," Leone said. According to Bloomberg, previous recommendations and findings for when to begin treatment range from CD4+ T cell levels of 350 copies per milliliter of blood to 500. According to Bloomberg, health workers often encounter difficulty in detecting HIV at the earliest stages because the immune proteins responding to the virus do not typically appear until a few weeks after infection. Therefore, tests to diagnose the virus during the acute phase could help people begin treatment earlier and improve treatment outcomes. According to Leone, the study "suggests that there's an opportunity to do more, if we have more research on what's going on in this early period of infection."

According to Bloomberg, additional studies presented at the conference indicate that HIV-positive people who begin long-term treatment earlier have better treatment outcomes. One study, presented by University of Washington HIV/AIDS researcher Mari Kitahata, found that the mortality risk among HIV patients who delayed long-term treatment was 60% higher than the risk among patients who began long-term treatment before their T cell counts decreased to 500. Another study -- led by Jonathan Sterne of the research group When to Start Consortium and colleagues from the University of Bristol -- examined treatment outcomes for patients with a variety of T cell levels. The study found that patients who began long-term treatment earlier had better survival rates and treatment outcomes than those who delayed treatment (Lauerman, Bloomberg, 2/9).

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aidsmap

HIV infection has similar impact on hardening of arteries as smoking, diabetes
HIV infection independently increases the severity of atherosclerosis as much as traditional cardiovascular risk factors such as smoking and diabetes, researchers reported on Wednesday at the at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montréal.

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Rosiglitazone improves fat loss and insulin resistance in people with lipoatrophy
The diabetes drug rosiglitazone (Avandia) improved limb lipoatrophy in HIV-positive people taking antiretroviral therapy, researchers reported Wednesday at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montréal. However the researchers did not study the drug's effect on facial fat loss.

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More treatment failure in people on TB treatment who start once daily nevirapine-based ART than efavirenz-based ART
People on TB treatment who started a once-daily antiretroviral therapy (ART) regimen of nevirapine/ddI/3TC were significantly more likely to fail ART than those who started on a once-daily regimen of efavirenz/ddI/3TC, according to a randomised prospective study from Chennai, India. In fact, the nevirapine arm performed so poorly that the study’s Data Safety and Monitoring Board (DSMB) ended accrual to that study arm and closed the study ahead of schedule.

“The once-daily nevirapine arm was definitely inferior to the efavirenz regimen in terms of virological failure and death and therefore is not recommended to be used when patients are on rifampicin-containing anti-TB treatment,” said Dr Soumya Swaminathan of Chennai’s Tuberculosis Research Centre, who presented the findings this week at the Sixteenth Conference on Retrovirus and Opportunistic Infections in Montréal.

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ART use in mothers with low CD4 cell counts reduces breastfeeding transmission fivefold: Malawi
The use of antiretroviral therapy (ART) by breastfeeding mothers greatly reduced the risk of HIV transmission to their infants after a 14-week course of infant HIV prophylaxis was stopped, according to a study performed in Malawi and presented to the Sixteenth Conference on Retroviruses and Opportunistic Infections (CROI) on Tuesday. However, ART use did not significantly reduce transmission risk in mothers with CD4 cell counts above 250 cells/mm3.

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Abacavir may increase blood coagulation risk
Two studies presented at the CROI Conference in Montreal presented contrasting findings on the relationship between the nucleoside reverse transcriptase inhibitor (NRTI) drug abacavir (Ziagen; also in (Kivexa (Epzicom) and (Trizivir). Ever since a relationship was found between current abacavir use and cardiovascular heart disease in 2008 (see report), with abacavir raising the risk of heart attack by 90%, a search has been on to find the reason for this apparent association.

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[John2038]

Update about this well-known story.


Stem Cells Cut AIDS Virus in Patient in Germany, Ending Need for Drugs, New England Journal of Medicine Reports 2/12/2009

CNN

A 42-year-old HIV patient with leukemia appears to have no detectable HIV in his blood and no symptoms after a stem cell transplant from a donor carrying a gene mutation that confers natural resistance to the virus that causes AIDS, according to a report published Wednesday in the New England Journal of Medicine.

Bloomberg

Feb. 11 (Bloomberg) -- A German AIDS patient was able to stop drugs he had been taking for 10 years after getting a transplant of stem cells from a donor with a rare gene variant known to resist the deadly disease. The transplant also cured his leukemia, researchers reported.

The stem cell donor was among the 1 percent of Caucasians who have the variant gene that lacks a section known as CCR5 that helps the AIDS virus enter a cell, according to a report today in the New England Journal of Medicine. Doctors in Berlin hoped that putting the donor’s stem cells in the patient would rebuild his immune system and blood cells so they would lack the CCR5 piece.

The results of the experiment may point researchers to a new way of controlling the AIDS virus HIV that doesn’t force patients to take drugs for the rest of their lives. Scientists will now intensify their search for therapies that achieve the same effect, predicted Jay Levy, a University of California, San Francisco, AIDS researcher.

“I think this article is going to stimulate a lot of companies to put more emphasis on gene therapy,” Levy said yesterday in a telephone interview. He wasn’t involved in the research and wrote an editorial published today that accompanied the study.

One such trial sponsored by Sangamo Biosciences of Richmond, California, recently began at the University of Pennsylvania. It will test a gene therapy that aims to modify the immune cells in 12 patients infected with HIV so they lack the CCR5 receptor.


Read at CNN
Read at Bloomberg
Read at Nature

[John2038]

medicalnewstoday

HIV/AIDS Preventive Vaccine Of Mymetics: Green Light From EU To Start Phase I Human Clinical Study
Mymetics Corporation (OTCBB: MYMX) announces the confirmed success of its preventive vaccine against HIV/AIDS. To this day, these results are the most promising and advanced in the world. They confirm a decisive breakthrough in the HIV/AIDS prevention. To such an extent that European authorities have just authorized the launch of the Phase I human clinical study.

On February 10th, in Montreal, for the 16th Conference on Retroviruses and Opportunistic Infections (CROI), Dr. Sylvain Fleury, Mymetics' Scientific Chief Officer, has presented the results of a second round of preclinical tests, which confirm the success of its preventive HIV/AIDS vaccine.

It is now known that some individuals are naturally resistant to the infection from HIV/AIDS virus, despite a high degree of exposure to this virus, in particular during non protected sexual activities (notably prostitutes in Kenya and Cambodia). Those rare individuals have been identified 20 years ago from diverse populations with different ethnic backgrounds. Despite their high exposure to the virus with different HIV positive individuals, these prostitutes for example, stay HIV negative. The explanation for this natural resistance is the presence, in vaginal secretions of women - or rectal secretions of men - of specific IgA antibodies. Replicating this natural protection, Mymetics' preventive vaccine formulation induces IgA antibodies at the mucosal level, rather than IgG antibodies circulating in the blood.

Thus, Mymetics' preventive vaccine is based on an approach targeting specifically IgA antibodies, whereas all other vaccine projects have opted to target IgG antibodies, or specific cytotoxic cells against the HIV virus. This innovative approach, with mucosal antibodies rather than blood antibodies, explains Mymetics' success compared with the deceptions met by other laboratories, since its vaccine stimulates defence mechanisms blocking the virus entry at the mucosal level, the first entrance door of the virus.

In the last step of the preclinical trials, Mymetics has done a viral challenge with macaques, the species closest to humans when it comes to the development of the pathology. One group is vaccinated and the other one is the control group. Both groups then receive numerous doses of the virus to test the vaccine's efficacy.

Mymetics viral challenge results in Beijing have proven excellent. The vaccinated group is almost completely resistant to the virus and the non vaccinated control group is completely infected. The results obtained with the Institute of Laboratory Animal Science (ILAS) of the Chinese Academy of Sciences were checked (blind test) by an independent lab, the Center for Diseases Control (CDC) of Beijing with the same final outstanding results, using a measuring technique 5 times more sensitive, corresponding to the occidental standards.

On the basis of these results and the excellence of the project, the Belgian Ministry of Health, in the name of European authorities, has authorized (in 16 days) launching the Phase I human clinical study.

What is more, so as to block possible critics, in particular the small number of animals used in the two test groups, Mymetics has presented those extremely promising results to Dr. Chris Miller, of the University of California, whose preclinical research centre on macaques is considered by the scientific community one of the best. Dr. Miller is one of the very few who has already developed a vaccine approach at the mucosal level. Having qualified Mymetics' results as excellent he has confirmed his interest for a joint collaboration, notably for new studies on groups of macaques. These results are unique in the world, and puts Mymetics clearly in a leading position in targeting neutralizing antibodies at the mucosal level versus the approach of most other laboratories which focus on blood antibodies. The goal of the repetitive study that Mymetics plans to do with Dr. Miller is to transform stable results in indisputable results, to be able, at last, to accelerate clinical tests on humans. Because HIV/AIDS prevention is a real issue at world level which calls for an urgent mobilisation.

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Disparities Exist Among Races In AIDS Mortality
A new study concludes that race disparities exist in AIDS mortality and that the risk of death is higher for non-Hispanic blacks and Hispanics than for non-Hispanic whites.

Researchers examined the correlations between survival and race/ethnicity, age and gender among persons who died from AIDS-related causes. The sample consisted of 11,022 persons diagnosed with AIDS reported through 2003 to the Chicago Department of Public Health. They found increased survival times with AIDS for all race/ethnicity groups after highly active antiretroviral therapy (HAART) became available. However, the rate at which survival improved was not uniform. The hazard of death due to AIDS between 1996-2001 was 51% higher for non-Hispanics blacks and 22% higher for Hispanics than for non-Hispanic whites.

"Enhancing efforts to prevent HIV-infected individuals from infecting susceptible individuals and developing new interventions to increase early recognition of disease and to remove barriers to accessing care will help Chicago's disadvantaged population achieve even greater increases in survival," the study's authors stated. "Effective community-level interventions to reduce health disparities require public engagement and support."

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Starting HAART Earlier Might Reduce Mortality Rates, Study Says
Earlier detection of HIV and initiation of highly active antiretroviral therapy might help reduce high mortality rates in sub-Saharan Africa, according to a study recently presented at the 16th Conference on Retroviruses and Opportunistic Infections in Montreal, Canada, Reuters reports. Martin Brinkhof of the University of Berne, who led the study, said that very high mortality rates in sub-Saharan Africa have "substantially declined" since the introduction of HAART, "but what remains unclear is to what extent this reduction in mortality approaches the levels seen in the general population."

Brinkhof and colleagues collected data on two-year mortality rates among HIV-positive people taking HAART in Cote d'Ivoire, Malawi, South Africa and Zimbabwe. The data were then compared with the expected number of deaths in the HIV-negative general population. The data for the general population were based on estimates from the World Health Organization's Global Burden of Disease project, which examined sex, age, country and mortality data unrelated to HIV. According to Reuters, data on 13,249 HIV-positive people were included, with women representing 67% of the participants. The participants had a median age of 34. Data on clinical stage were available for 12,720 people, and 10,811 had progressed to advanced stages of HIV when they began HAART. There were 1,177 deaths over 14,695 person-years of follow-up.

According to Brinkhof, the study found that people with extremely advanced HIV had mortality rates 400 to 500 times greater than the general population over the first three months of treatment. The researchers also found that even those with CD4+ T cell counts of 200 or more had mortality rates 20 to 30 times higher than the general population during the first three months. In addition, people who began HAART with extreme immunodeficiency had 50 times the mortality rate of the general population over the first two years of treatment, and the rates were three to four times greater for people who started treatment with T cell counts of 200 or higher.

Among patients who started treatment with T cell counts of less than 25 and WHO stage III/IV disease, the excess mortality was 17.5 per 100 person-years. This compares with 1.0 per 100 person-years among those who started treatments with a T cell count of at least 200 and WHO stage I/II disease. An excess mortality of 0.29 per 100 person-years was recorded among patients who began treatment with T cell counts of 200 or greater and WHO stage I/II disease and were alive one year later. Brinkhof said that "clearly it is critical that we have to start treating earlier" because very few patients -- less than 15% -- begin treatment with higher T cell counts and less advanced stages of the disease (Reuters, 2/9).

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irishhealth

HIV breakthrough by Irish scientists
New research by Irish scientists helps explain why some HIV patients treated with antiretroviral medications experience an increased incidence of heart attacks.

Last year, a major international study identified a higher than expected incidence of heart attacks among patients being treated with antiretroviral drugs for HIV. Building on this research, scientists at the Royal College of Surgeons in Ireland (RCSI) developed a novel test tied to HIV to measure platelet activity in blood.

Platelets are essential for blood clotting when the skin is broken. However if they do not work properly within the bloodstream, they can cause clots within arteries which can lead to heart attacks.

Using this new test, a team from University College Dublin (UCD) and the Mater Hospital in Dublin carried out clinical trials to investigate the activity of platelets among HIV patients in Dublin. They found a significant increase in platelet reactivity among those taking certain antiretroviral medications.

“The international research published last year showed the link between antiretroviral treatments and increased risk of heart attacks but not the reason why. We have now demonstrated that the use of certain drugs for HIV has a direct effect on platelets within the blood. The results provide invaluable information to help in the search for safe long-term therapies for HIV infection,” explained lead researcher, Dr Paddy Mallon, a consultant in infectious diseases at the Mater.

He said that these findings would ‘significantly affect the management of patients with HIV and have important implications for the treatment of HIV worldwide’.

The research was presented at the Retrovirus Conference in Montreal, Canada this week.

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bizjournals

As others come up dry, Virxsys hauls in $26M
For a biotech company in this ravaged economy, trying to raise $35 million by the fall seems like a goal that goes beyond naivete and borders on lunacy.

Except when you are already three-fourths of the way there.

Gaithersburg-based Virxsys Corp., which is working on an HIV treatment, has received $26 million so far this year in cash or commitments during a capital market that has been nothing short of a ghost town.

That has left biotechs, some of the riskiest businesses for investors, stranded and starving for money.

But Virxsys is closing in on its final clinical tests for an HIV treatment that causes the virus to essentially commit suicide in a patient’s body. Virxsys hopes that makes it a safer bet as the company tries to persuade longtime angel investors to toss in $9 million more this year.


“We’re in fairly good shape right now,” said Riku Rautsola, the chief executive officer. “But it’s not easy, I tell you.”

Virxsys’ 10-year total has now reached $105 million, including $10 million last year and $5 million thus far this year from Signature Capital Securities LLP, a Naples, Fla.-based network of angel and private equity investors that has been Virxsys’ primary financier. The company also signed commitments with an undisclosed German hedge fund to add $21 million in the next six months.

Virxsys opened this latest financing round, its eighth, before the slow economy turned into a full-blown recession. Originally the privately held company was seeking $25 million but has upped that goal to $35 million to tide it over for a longer time.

The cash will be used to help pay the remaining bills on two sets of second-phase clinical trials for the HIV treatment.

Virxsys plans to embark soon on the last tests required for potential federal approval of the treatment. Like many other local biotechs, it is on the hunt for large partners to help finance those final trials and, longer term, launch an approved product.

Under the Virxsys treatment regimen, HIV patients get an infusion once a year, and biological deliverymen called lentiviral vectors carry new gene sequences to white blood cells, the foot soldiers of the body’s immune system army.

Those gene sequences, engineered to be exactly the opposite of the HIV cell sequences, work to cancel the virus, taking particular aim at the protein that HIV uses to bind itself to white blood cells and spread in a patient’s body.

Although the process doesn’t kill HIV, it disables the virus while bolstering the patient’s white blood cell count.

“We are breaking the cycle of infection,” said Gary McGarrity, Virxsys executive vice president of scientific and clinical affairs. “When we look at the virus, we are seeing it’s highly mutated and has much, much, much less capacity to do anything.”

Virxsys’ model is a combination of its own research and that of Intronn Inc., a local biotech that McGarrity once led and Virxsys acquired in 2007.

That approach is rare biological route to healing patients who now must swallow a chemical cocktail of drugs every day.

“If this one passes a Phase 2 test, it would lay down important groundwork for the next round of new technologies,” said Baek Kim, an associate professor of microbiology and immunology and HIV specialist at the University of Rochester Medical Center. “This is definitely scientifically important.”

And financially important to Virxsys, which hopes this year’s fundraising round is the last it needs.

Good clinical results mean better chances for a potential initial public offering when the markets recover in the next three years, and, ultimately, a profitable sale of the 67-person company.

“The question is when is the right time,” Rautsola said. “This will end up being a platform technology within a big pharma company in the next five to seven years.”

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aegis

AFP: HIV-positive prostitute who accused client of rape jailed in Estonia
TALLINN, Feb 11, 2009 (AFP) - An Estonian court on Wednesday sentenced an HIV-positive prostitute to three years and seven months behind bars for failing to disclose her condition while engaging in unprotected sex.

"The prostitute is Russian and she admitted she knew she was HIV-positive," Maria-Elisa Rannajoe, spokeswoman for Estonian state prosecutors, told AFP.

"She has ten days to appeal the verdict," Rannajoe added.

It is the first case in Estonia of an HIV-positive person being sentenced to prison for engaging in unprotected sex despite knowing they were sick and so putting another person at risk of infection.

An investigation into the activities of the woman, identified only as Viktoria, was launched after she accused a client of rape.

The criminal probe did not confirm rape but did reveal she was aware she was HIV-positive but had failed to inform her client with whom she engaged in unprotected sex.

It remains unclear whether the man became infected with HIV.

The woman also faces narcotics charges after being found in possession of 0.8 grams of heroin.

Viktoria is a common name used among Estonia's Russian-speaking minority that makes up around quarter of the country's 1.3 million population.

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SAfrica aims to double AIDS drug scheme
CAPE TOWN, Feb 11, 2009 (AFP) - South Africa will boost its battle against AIDS by almost 90 million dollars (69.5 million euros) over the next three years, doubling the number of people receiving treatment, the finance minister said Wednesday.

The extra 932 million rand will go to treatment and prevention schemes, Trevor Manuel told parliament as he presented the annual budget.

"We are budgeting to extend screening of pregnant mothers coming into the public health system and to phase in an improved drug regimen to prevent mother-to-child HIV transmission," he said.

"Our anti-retroviral programme now covers 630,000 people, and the medium term expenditure framework provides for an increase to 1.4 million by 2011/12."

The three-year grant would boost the AIDS spending from 3.4 billion rand (341 million dollars) to 3.9 billion rand in this fiscal year, and up to over 5 billion rand in 2012.

Manuel also revealed 1.8 billion rand was budgeted to introduce three new child vaccines which will reduce infant deaths from pneumococcal pneumonia and rotavirus, which causes diarrhoea.

The leading causes of death for South Africa's 18 million children are AIDS, pneumonia, diarrhoea, malnutrition and low birthweight.

Additional allocations were aimed at expanding immunisation coverage, fighting malaria and tuberculosis, and halving new HIV infections by 2011.

South Africa has the world's highest AIDS rates, with some five million people infected. More than 600,000 are currently receiving anti-retroviral drugs in the world's biggest AIDS treatment programme.

The burdened public health system would be boosted with 728 million rand to a hospital revitalisation programme, in which 31 new hospitals would be built.

"We are profoundly conscious of the complexity of the challenges facing our health services, and the strain on resources associated with a rising disease burden," said Manuel.

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SOUTH KOREA: HIV Cases Top 6,000 for First Time
South Korea had 797 new HIV cases in 2008, an increase of 7.1 percent over the 744 cases recorded in 2007, health officials said recently. Among the new cases, 99 percent were acquired sexually; 94.2 percent were male; more than half were in their 20s or 30s; and 7 percent were over age 60, according to the nation's Center for Disease Control and Prevention. Since 1985, South Korea has recorded a cumulative total of 6,120 people who acquired HIV, including 1,084 who died.

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[John2038]

salk university

Possible new class of HIV therapeutics
The Salk Institute for Biological Studies and Burnham Institute for Medical Research today announced 295 host cell factors that are involved in human immunodeficiency virus (HIV) infection. The study, published in the Oct. 3 issue of Cell, could lead to the development of a new class of HIV therapeutics aimed at disrupting the human-HIV interactions that lead to viral infection.

The research, a collaborative effort between the laboratories of Sumit K. Chanda, Ph.D, previously at the Genomics Institute of the Novartis Research Foundation (GNF) and now at Burnham and John Young, Ph.D. at Salk, combined several layers of genome-wide analysis to identify cellular proteins that aid the virus in establishing an infection.

"HIV has just nine genes, coding for 15 proteins, compared to bacteria, which harbor several thousand genes, or humans, with over 20,000 genes," said Chanda, associate professor in the Infectious & Inflammatory Disease Center at Burnham and an adjunct faculty member at Salk. "We have known for a long time that HIV hijacks our cellular proteins to complete its life cycle. This study now lays out its flight plan."

Young, professor in the Infectious Disease Laboratory at Salk added, "Due to viral resistance, there is an urgent need for new classes of therapies aimed at preventing the virus from infecting new cells as opposed to merely keeping viral replication in check. To develop more effective therapies for HIV infection and AIDS we must identify and characterize the cellular factors that participate in early steps of HIV-1 replication and prevent the virus from becoming established."

Although more than two dozen drugs are available for the treatment of HIV infection, there is a growing need for new antiviral therapies. Recent studies indicate that HIV remains "hidden" in a latent form, even after long-term suppression with highly active antiretroviral therapy.

In the study, the team of researchers used short-interfering RNA (siRNA) which, when introduced into a cell, silences cellular gene expression, one gene at a time. Using high throughput transfection technology available at GNF and at Burnham, more than 144,000 siRNAs (6 siRNAs for each gene in the human genome) were screened for their effects on HIV-1 infection. Data from the siRNA genomic screen was combined with information from large-scale, protein-protein interaction databases to identify key protein complexes that affect discrete steps in the early stages of HIV infection.

"The integration of these systems-based analyses allowed us to build, for the first time, a functionally validated map of host-pathogen interactions that are required for viral infection," said Renate König, Ph.D., of Burnham, the first-author on the study.

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forbes

A 454 Sequencing Study Reveals New Insights in Drug Resistance and Tropism
New data from two studies, presented last week at the 16th Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal, Canada demonstrate that ultra-deep sequencing with the Genome Sequencer FLX System from 454 Life Sciences, in combination with traditional methods, may provide a deeper understanding of baseline viral resistance and tropism, leading to potential improvements in the way new drugs may be selected for HIV patients in the future. Effective drug selection for combination therapy is critical to ensure patients obtain optimal, long term suppression of HIV and prevent progression to AIDS.

The presentations at CROI outline research carried out by scientists from the University of Rome "Tor Vergata" and Virco BVBA, in the latest in a series of joint studies performed at Virco's laboratory to analyze and interpret data generated by sequencing HIV-infected research samples with the Genome Sequencer FLX System. The studies explore resistance to a new class of drug called integrase inhibitors, as well as an in-depth evaluation of viral tropism. The ultra-deep method enabled by 454 Sequencing systems offers dramatically improved sensitivity in detecting low-frequency viral variants, also known as viral quasispecies, compared to traditional population based sequencing.

The first study analyzed long-term antiretroviral users receiving a combination therapy of an integrase-inhibitor, raltegravir, and optimized backbone therapy. The investigators analyzed samples at multiple time-points using both traditional Sanger genotyping, in vitro phenotyping and the ultra-deep sequencing method. The researchers found, at levels far below normal detectability, an abundance of viral quasispecies in patients whose treatment failed, in contrast to a far lower number of quasispecies found among patients whose treatment was successful. They hypothesized that the co-presence of many different strains may favor the development of drug resistance and consequently drug failure.

Furthermore, the researchers suggest that the correlation between quasispecies identified at baseline and treatment failure may be occurring via pathways which are much more complex than simple drug-driven selection of the primary mutations currently identified. "The ability of the technology of the 454 Sequencing System to identify mutants at very low levels provides new insights on how HIV may develop resistance to new drugs such as Integrase inhibitors," said Professor Perno from Tor Vergata University. His colleague Dr. Ceccherini-Silberstein added, "This technology will compliment existing techniques and can provide a significant added value to HIV research."

In the second study, the researchers analyzed isolates from HIV-infected patients to characterize viral tropism by both traditional phenotyping and genotyping, as well as deep sequencing analysis. HIV tropism refers to the preference of a patient's particular HIV virus to select one of two co-receptors for entry into the patient's CD4 immune cell, where the virus reproduces. Determining the co-receptor that a HIV strain uses, either CCR5, CXCR4 or a combination of both, is a critical component of monitoring and treating HIV. Dual-tropic virus types have the ability to use either or both co-receptors for cell entry. In the research study, ten randomly-selected dual-tropic isolates were analyzed by V3 deep sequencing analysis with the 454 Sequencing System, and tested for research purposes in human immune cells for sensitivity to therapies, including the CCR5 antagonist maraviroc and the CXCR4 antagonist AMD3100.

From these research samples, they found that dual tropic viruses are mostly characterized as quasispecies with potential to use both R5 and CXCR4 receptors as opposed to quasispecies with mixtures of R5 and X4 using viruses, a new insight into how the HIV virus adapts in choosing a co-receptor to enter human target cells CD4 cells. "This analysis helps develop better understanding of the complex mechanisms of HIV co-receptor tropism," said Dr. Lieven Stuyver, Vice President R&D at VIRCO BVBA. "We believe that the use of current technologies such as phenotyping, combined with the newer tools such as ultra-deep sequencing with the Genome Sequencer FLX System, linked to clinical outcome data may allow us to unravel these complex viral mechanisms and ultimately could lead to better HIV treatment in future."

"These studies continue to demonstrate the utility of the 454 Sequencing System for research on viral diseases and their potential treatment," explains Christopher McLeod, President and CEO of 454 Life Sciences. "The development of novel therapies, such as the new classes of HIV drugs, often requires companion tools for proper selection of suitable treatment regimens for patient candidates. We believe that the sensitivity, accuracy, and speed of the 454 Sequencing System will transform the way HIV is monitored and treated in the near future."

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[John2038]

berkeley university

HIV in breast milk killed by flash-heating, new study finds

A simple method of flash-heating breast milk infected with HIV successfully inactivated the free-floating virus, according to a new study led by researchers at the Berkeley and Davis campuses of the University of California.

Notably, the technique - heating a glass jar of expressed breast milk in a pan of water over a flame or single burner - can be easily applied in the homes of mothers in resource-poor communities.

The findings, to appear in the July 1 print issue of the Journal of Acquired Immune Deficiency Syndromes, but now available online, provide hope that mothers with HIV in developing nations will soon be able to more safely feed their babies.

"We conducted this research to help HIV-positive mothers and their infants who do not have safe alternatives to breastfeeding," said Kiersten Israel-Ballard, a doctoral candidate at UC Berkeley's School of Public Health and lead author of the study. "HIV can be transmitted to the baby via breastfeeding. But for infants in developing countries where infant mortality is already so high from diarrhea and other illnesses, they can't afford to lose the antibodies, other anti-infective agents and the optimal nutrition found in breast milk. This study shows that an easy-to-implement heating method can kill the HIV in breast milk."

This line of research began when HIV-positive women in Zimbabwe asked how they could make their milk safe for their babies. Israel-Ballard conducted a study there that indicated that HIV-positive women wanted to attempt the flash-heating method. The World Health Organization (WHO) recommends heat treating HIV-infected breast milk, but there has been little research into a simple method that a mom in a developing country could use.

Studies by this research team have shown that flash-heating breast milk can kill bacteria while retaining most of the milk's nutritional and antimicrobial properties, as well as a majority of its important antibodies.

"Many people in this field were skeptical that this would work," said Barbara Abrams, UC Berkeley professor of epidemiology and maternal and child health, and senior author on the study. "We wanted to be sure that there was scientific evidence that flash-heated milk was truly free of HIV, nutritious and immunologically beneficial. This study was done in response to the concerns of the mothers in Zimbabwe, and in addition provides evidence that field studies are warranted."

Banks that collect, store and dispense human milk already pasteurize milk, but the method they commonly use requires thermometers and timers that may be hard to obtain in resource-poor communities.

Flash-heating is a type of pasteurization that brings the milk to a higher temperature for a shorter period of time, a method known to better protect the anti-infective and nutritional properties of breast milk than the one typically used in human milk banks. Moreover, the low-tech materials used for this study are readily available in local communities in the developing world, and the heating method can be easily incorporated into a mother's normal daily routine.

Of the 700,000 children who become infected with HIV each year, an estimated 40 percent contract the virus from prolonged breastfeeding. WHO recommends that HIV-positive mothers avoid breastfeeding when safe feeding alternatives are available.

But in regions of the world where mothers cannot afford the cost of infant formula, water is contaminated, or other socio-cultural conditions make replacement feeding difficult, WHO recommends exclusively breastfeeding for up to six months.

"The risks and benefits of heating HIV-contaminated breast milk are different for women in developing countries than for women in the United States," said Dr. Caroline Chantry, a pediatrician and infant nutrition researcher with UC Davis Children's Hospital, and co-author of the paper. "Here we have access to safe water and formula, so it makes less sense for HIV-positive mothers in developed countries to take the risks associated with feeding babies their breast milk."

Studies indicate that when babies are breastfed exclusively, there is a 3 to 4 percent risk of HIV transmission. However, when babies are given formula or other foods in addition to breast milk, there is a significant three- to four-fold increase in the risk of HIV transmission, possibly because allergens and contaminants in solid foods and formula can compromise the epithelial lining of a baby's digestive tract, making it easier for viruses to pass through.

For this reason, WHO guidelines have recommended that after six months of exclusively breastfeeding, HIV-positive mothers wean their babies as soon as other foods are available. Even then, while weaning may decrease the risk of HIV transmission, studies have shown that it increases the risk of malnutrition, diarrhea and other diseases that can lead to infant mortality.

"Early cessation of breastfeeding has been tried in several recent studies, and the results suggest that stopping breastfeeding early increased the risk of infant illness, growth failure and death, and actually outweighed the risk of transmitting HIV through breast milk," said Abrams. "This has been a desperate dilemma for mothers in developing countries. Our method of flash-heating breast milk could be particularly important at the time the mother stops nursing. Roughly 300,000 infants contract HIV from breastfeeding each year. Even if only a small proportion of HIV-positive mothers in resource-poor countries can successfully express and flash-treat their milk, this simple, inexpensive and potentially sustainable method could still save thousands of babies from HIV infection while providing most of the health benefits of human milk."

This study reflects results from the first stage of research, headed by Abrams, into the effects of flash-heating breast milk. Chantry will head the next stage of field trials, which involve moving this technique out of the lab and into the homes of women in Africa. The researchers are seeking funding to assess the flash-heating method's feasibility for babies in local communities in developing countries.

"Clinical trials are urgently needed to substantiate that mothers can express, flash-heat and store their milk safely, and to test the impact of this method on actual HIV transmission," said Chantry. "What is important about this study is that women have the right to an informed choice. It's amazing to me that in our paternalistic society, people so often readily dismiss the possibility that women would be willing to express and heat their milk to prevent their babies from getting infected with HIV."

Of the 98 samples of breast milk collected from 84 HIV-positive women in Durban, South Africa, only 30 had detectable levels of HIV before heating. Not all breast milk from HIV-positive mothers contains HIV naturally. Milk had been hand expressed into clean, locally purchased glass food jars provided by the researchers.

For each sample of HIV-infected milk, researchers set aside 50 milliliters in the original collection jars and used the remainder as unheated controls. The uncovered jars were placed in a 1-quart pan filled with 450 milliliters of water. The water and milk were heated together over a single-burner butane stove. Once the water reached a rolling boil, the breast milk was immediately removed and allowed to cool.

The researchers checked the temperature of the milk at 15-second intervals and determined that the flash-heated milk reached a peak temperature of 163 degrees Fahrenheit (72.9 degrees Celsius), and typically stayed hotter than 132 degrees Fahrenheit (56 degrees Celsius) for more than six minutes.

Viral analysis of the flash-heated and unheated breast milk found that cell-free HIV had been inactivated in all of the heated samples.

The researchers note that they used a reverse transcriptase (RT) assay to test for an enzyme produced by viable HIV since traditional tests for HIV do not distinguish between dead and live viruses. The RT test, however, cannot detect HIV within cells, but preliminary data suggest that flash-heat inactivates cell-associated HIV as well.

"We hope this technique will not only provide HIV-free breast milk that is safe to consume, but that the milk also retains the antibodies and nutrition that will help keep their infants healthy," said Israel-Ballard. "Mothers in Africa have told us they will do anything to keep their babies alive, and this work is ultimately about providing them with viable options to do just that."

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[John2038]

emory university

Blocking immune inhibitor improves response to HIV-like virus, prolongs survival in monkeys
By blocking PD-1 (programmed death-1), an immune receptor molecule known to inhibit the immune response to chronic viral infections, scientists have safely and significantly reduced the plasma viral load and also prolonged survival of rhesus macaque monkeys severely infected with simian immunodeficiency virus (SIV), the nonhuman primate version of human immunodeficiency virus (HIV). The therapeutic strategy worked by boosting the function of anti-viral killer cells (CD8 T cells) and improving antibody response to the virus.

Scientists at the Yerkes National Primate Research Center of Emory University, the Emory Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School and the University of Pennsylvania Medical School conducted the research, which will be published in the current online issue of Nature, Dec. 10.

"Our findings raise the possibility that PD-1 blocking antibody treatment not only could improve the anti-viral T cell response to chronic HIV infections, but it also could generate an effective antibody response against the mutated virus of the infected host," says Rama Amara, PhD, principal investigator of the study.

"It also is important to note that this therapy was effective without anti-retroviral drugs and in monkeys with severe AIDS. It is critical to induce protective immune responses targeting the mutated virus for developing a successful immune therapy to control HIV infection," Amara continues.

In the current study, which builds on findings from previous studies with mice, the researchers tested the potential of blocking PD-1 to control HIV infection using a macaque monkey model of SIV. They injected nine SIV-infected monkeys with an antibody to human PD-1 four times over 10 days. Gordon Freeman, PhD, of the Dana-Farber Cancer Institute and Harvard Medical School, provided the antibody.

Of the nine animals, five were infected for three months and four were infected for about 21 months at the time of antibody treatment. Another five SIV-infected monkeys received a control antibody at the same dose and schedule. The researchers then tested the function of the anti-SIV killer cells, antibody responses to the virus and plasma viral load.

Results showed that the improved anti-viral immune responses were associated with a reduction in plasma viral load and prolonged the survival of the infected animals. All nine animals receiving the PD-1 antibody survived more than seven months following initiation of treatment (the current time of the study), while four of the five animals receiving the control antibody died within four months following initiation of treatment.

The antibody treatment appeared to be safe and well tolerated. Within seven days of treatment, the number of anti-SIV killer T cells increased significantly and had improved function. This improvement was noted both in the blood and the gut, which is a major repository of SIV and HIV. The PD-1 antibody treatment also increased the proliferation of memory B cells and the level of antibody against SIV, a finding that had not been reported in earlier mouse studies.

"These findings are important not only because they highlight a potential therapy for HIV, but also because of the insights they offer for other challenging chronic infectious diseases such as hepatitis C virus and tuberculosis," says Emory Vaccine Center Director Rafi Ahmed, PhD, who is a Georgia Research Alliance Eminent Scholar. "Through the Grand Challenges in Global Health initiative, which also funded the current study, we soon will begin testing the effectiveness of the PD-1 blockade against HCV in nonhuman primates."

Several years ago, Ahmed and his colleagues discovered that the immune receptor PD-1 essentially functions as a molecular switch to turn off an effective immune response by overwhelming T cells in their fight against chronic viral infections. By injecting an antibody that binds to PD-1 into mice infected with chronic lymphocytic choriomeningitis virus (LCMV), they were able to switch the immune response back on and control the virus. Dr. Ahmed is a co-principal investigator of the current study.

Other studies have since shown that anti-viral CD8 T cells express high levels of PD-1 during many human chronic infections, including HIV, hepatitis C virus and tuberculosis. However, until now the safety and effectiveness of blocking PD-1 in an appropriate animal model for these human viral infections had not been shown.

The current research team plans to continue testing the antibody therapy in combination with anti-retroviral drugs to try and improve its effectiveness. They also will explore the benefits of prolonged treatment (up to three months as opposed to 10 days in the current study). In addition, they are studying the effectiveness of antibodies against PD-1 ligands (target molecules), a strategy that was part of the earlier mouse research

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hivandhepatitis

Hormonal Contraceptives Do Not Accelerate Disease Progression in HIV Positive Women
The natural history of HIV and its treatment have not been as well studied in women as in men. Past laboratory, animal, and human research has provided conflicting data about the effects of hormonal contraception -- such as the pill and implantable or injectable methods -- on HIV disease. While some studies have suggested hormonal contraception might increase susceptibility to HIV infection or accelerate disease progression in untreated women, others have not seen these effects.

In a presentation at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last week in Montreal, Elizabeth Stringer of the University of Alabama described data from an analysis of the impact of contraception among participants in the MTCT Plus Initiative, a family-based HIV care and treatment program in Africa and Asia.

..

Results

    * Overall, there was no evidence of hormonal contraception accelerating HIV disease progression.
    * A total of 66 women died and 881 became eligible for ART.
    * Using a reference hazard ratio of 1.0 for non-hormonal or no contraception:
        o  Progesterone-only injectables and implants had an adjusted hazard ratio (AHR) for disease
            progression of 1.0 -- that is, no difference.
        o  Combination oral contraceptive pills had an AHR of 0.90.
    * Risk factors for disease progression were:
        o  CD4 count of 200-350 cells/mm3 (AHR 5.69);
        o  WHO Stage II disease (AHR 1.52);
        o  WHO Stage III disease (AHR 3.46).

Based on these results, the researchers concluded, "In contrast to some other, smaller studies, this multi-country cohort analysis suggests that hormonal contraception does not accelerate HIV disease progression."

While these results are encouraging, they added, "further research is needed to examine the potential influence of individual components of contraceptive agents on disease progression."

Speaking at a press conference about the findings, Stringer said, "Hormonal contraception appears to be safe in HIV-infected women, but more research is needed," for example on the potential link between hormones and inflammation.

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Despite Infrequent "Blips," Tenofovir (Viread) Provides Good Hepatitis B Virus Suppression HIV-HBV Coinfected Individuals
Due to overlapping risk factors, a significant number of HIV positive individuals have also been exposed to hepatitis B virus (HBV), and an undetermined proportion have developed chronic hepatitis B, which over time can progress to liver cirrhosis or liver cancer.

Several antiviral agents are approved for treatment of hepatitis B, some of which also exhibit anti-HIV activity. Tenofovir (Viread, also in the Truvada and Atripla coformulation pills) and lamivudine (3TC, Epivir) are approved for both diseases, while emtricitabine (Emtriva) is currently approved only for HIV. As reported at the 2007 Retrovirus conference, entecavir (Baraclude), which is only approved for HBV, also has low-level anti-HIV activity.


Hep B virus

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iTherX Pharmaceuticals Announces Phase 2a Proof-of-concept Trial of First Hepatitis C Virus Entry Inhibitor
Pegylated interferon plus ribavirin is the current standard of care for chronic hepatitis C virus (HCV) infection, but researchers are exploring several oral agents that directly target different steps of the HCV lifecycle -- an approach dubbed "STAT-C."

Several HCV protease and polymerase inhibitors are already well along in the development pipeline. Now, iTherX Pharmaceuticals has announced its plan to start a Phase 2a trial of the first HCV entry inhibitor, ITX5061.

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[John2038]

sciencedaily

Vaccine Research Targets HIV In The Slower, Early Stage Of Infection
New research at Oregon Health & Science University's Vaccine and Gene Therapy Institute suggests vaccines that specifically target HIV in the initial stages of infection before it becomes a rapidly replicating, system-wide infection - may be a successful approach in limiting the spread of the disease.

To determine whether they could proactively "educate" the immune system, scientists used a monkey model of AIDS - simian immunodeficiency virus (SIV) – the monkey counterpart to HIV. They introduced an altered monkey form of cytomegalovirus (CMV) programmed to express SIV proteins and trigger specialized effector memory T-cells to look for and attack SIV in its early stages.

In total, 12 rhesus macaque monkeys at the Oregon National Primate Research Center were vaccinated using this method. When the animals were later infected with SIV, one-third were protected.

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upi

Japan HIV, AIDS cases reach all-time high
The number of people in Japan newly infected with the HIV virus and those contracting AIDS reached an all-time high of 1,545, Japan's health ministry reported.

Of the 1,113 people diagnosed as newly positive with the human immunodeficiency virus in 2008 and 432 diagnosed with AIDS, 1,442 were male, the ministry's AIDS Trend Committee report said.

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news8austin

AIDS becomes China's deadliest infectious disease
BEIJING — For the first time last year, AIDS was the top killer among infectious diseases in China.

A state news agency is reporting the increase, though it did not explain the jump. One possible factor is the Chinese government's improved reporting of HIV/AIDS statistics in recent years.

The report said nearly 7,000 people died of AIDS in China in the nine months through September. The numbers also show confirmed HIV infections have nearly doubled.

China has long denied that AIDS was a problem. But leaders have shifted in recent years, confronting the disease more openly and promising anonymous testing, free treatment for the poor and a ban on discrimination against people with the virus.

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hindustantimes

HIV+ man commits suicide in Gorai
A 40-year-old journalist was found dead in the toilet of the Vividh Bharti Complex in Gorai on Thursday. The police have recovered a suicide note from the man’s pocket.

The note said that he was committing suicide because he had contracted HIV and was frustrated. “In the note, Krishna Naik (name changed) had mentioned that he was taking his life and nobody else should be blamed for his death,” said Lalji Pawar, Sub-Inspector from Borivli police station. “It is still not known why Naik chose the Vividh Bharti Complex to commit suicide. Naik had used a knife to slit his throat.

It was found lying beside the body. Naik and his wife were HIV+ and were getting treated at JJ Hospital,” added Pawar. According to the police, Naik used to work with a local publication and stayed with his family in Gorai. He is survived by his wife, a schoolteacher, and two children. The police have sent Naik’s body for post mortem to Bhagwati Hospital and have called his wife to record her statement. “This is an open and shut case. It is clear that Naik has committed suicide so we have registered a case of unnatural death,” added Pawar.

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medicalnewstoday

Gene Therapy Study Shows Method Is Safe, Somewhat Beneficial, Researchers Report
A study of gene therapy to treat HIV has shown that the treatment is safe and somewhat beneficial -- a "major advance" in efforts to combat the virus -- researchers said in a study published recently in the journal Nature Medicine, AFP/Google.com reports. According to the researchers, the study -- which was headed by Ronald Mitsuyasu of the University of California-Los Angeles -- confirms that this avenue of gene therapy in HIV research is a valid approach (AFP/Google.com, 2/15). The study involved 74 HIV-positive people, half of whom received blood stem cells that included a molecule, called OZ1, which is designed to block HIV from replicating by targeting two key proteins (BBC News, 2/16). The other half were given a placebo. The study aimed to determine whether the stem cells would survive the body's immune system and if this would curb the replication of HIV. The researchers found that after 48 weeks, there was no statistical difference between the two groups. However, after 100 weeks, the group that received the RNA enzyme gene had higher levels of CD4+ T cells and low HIV viral loads. The study also showed that the new blood stem cells depleted over time -- although DNA tests showing that the modified cells were present in 94% of the gene group at four weeks, this fell to 12% by week 48 and 7% by week 100. According to the researchers, the study's results showed the treatment was "safe" and modestly effective. Mitsuyasu said that instead of putting the technique through to a Phase III trial, the team plans to modify the technique and introduce new tests on a smaller group of participants. He said the study "gives some hope" to the gene therapy approach as a treatment for HIV and other diseases, such as cancer, adding, "It's a positive finding for the field and should move the field forward" (AFP/Google.com, 2/15).

Reaction
Mitsuyasu said that the treatment is "not yet as effective or as complete as current antiretroviral therapy in controlling HIV," although the recent study "did show proof" that using a single gene in an HIV-positive patient's own blood cells could reduce the spread of the virus. Jo Robinson of the HIV/AIDS organization Terrence Higgins Trust said, "Gene therapy is an exciting area which aims to create a one off treatment for HIV, avoiding the need for people to take daily medication," adding that the therapy is in its "early days in research terms, so we're a long way from something like this being on the market." Robinson said that the new study "has shown some promising results, which definitely warrant further investigation." Keith Alcorn of the U.K.-based HIV information service NAM added that although the study's results are "very modest," the researchers showed "enough of an effect for us to be hopeful that a gene therapy approach to HIV treatment might eventually deliver effective treatments for the disease" (BBC News, 2/16).

An abstract of the study is available online

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Researcher Helps Discover A Way To Prevent The HIV Ability To Mutate
Trying to stop HIV early in its life cycle by preventing the virus from entering the body's cells and fusing is the job of drugs called fusion inhibitors. Currently, the last line of defense - the drug T20 - eventually fails as the virus mutates. A new study from researchers at the University of Missouri and Kyoto University in Japan shows that a modification to T20 can deliver a preemptive strike to the virus' ability to replicate. This new finding could give patients more options to stay healthy for a longer period of time.

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aidsmap

Treatment switches on basis of CD4 declines often unnecessary, Uganda research shows
witching people to second-line antiretroviral treatment on the basis of CD4 declines, without information from viral load tests, could result in a large numbers of unnecessary switches to more expensive second-line regimens in resource-limited settings, a study in Uganda has found.

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Disadvantage of late treatment start in Africa may persist for years, studies find
Starting antiretroviral therapy earlier, before the development of symptoms, is the most likely way to reduce the high death rates after treatment initiation seen in people with HIV in resource-limited settings, two large cohort analyses show. The studies also show that the major disadvantage of starting treatment late - an increased risk of death - may persist for some years, burdening already overstretched health systems with illness that could be avoided by earlier treatment.

The findings, presented last week at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montréal, are likely to strengthen the case for a stronger global recommendation that people with HIV should start treatment when the CD4 cell count falls below 350 cells/mm3 wherever resources permit.

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aegis

VGX Pharmaceuticals Proprietary DNA Vaccines Delivered with Electroporation Achieve Immune Responses Superior to Recombinant Adenovirus Serotype 5 (Ad5) Vectors: DNA Vaccine Developer Provides Clinical Update on PENNVAX(TM) HIV Vaccines Programs
BLUE BELL, Pa. -- VGX Pharmaceuticals Inc. (VGX), a leading developer of DNA vaccines and therapies for HIV infection, announced today that its collaborators from the University of Pennsylvania presented data showing enhanced magnitude and quality of immune responses induced by VGX's DNA vaccines with electroporation delivery compared to those induced by the recombinant Adenovirus Serotype 5 (Ad5) vector. The data was presented at the recent 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) held in Montreal, Canada.

VGX and its collaborators have previously reported that PENNVAX(TM) DNA vaccines delivered with its CELLECTRA(R) electroporation device induced dramatic increases in T-cell and antibody-based immune responses as well as improved control of viral replication following a simian immunodeficiency virus (SIV) challenge. The SIV model in non-human primates is considered to be the most relevant model for studying HIV infection in humans. Historically, recombinant Ad5 vector has been shown to be one of the most potent viral vectors for vaccine development.

This study was led by Professor David B. Weiner's team at the University of Pennsylvania and included collaborators from VGX and Merck. The collaborative study was the first study to directly compare a DNA plasmid-electroporation platform with a recombinant Ad5 vector in an SIV model in non-human primates. The study results showed significant enhancements in the magnitude, frequency, proliferative capacity, and polyfunctionality of the induced immune responses following DNA plasmid-electroporation vaccination compared to the Ad5 vector.

"VGX Pharmaceuticals along with our collaborators have the most active and dynamic HIV vaccine development programs in the industry," stated Dr. J. Joseph Kim, President and CEO. "We have demonstrated that our novel PENNVAX(TM) HIV DNA vaccines delivered with our CELLECTRA(R) electroporation device can induce significantly higher and broader T-cell responses in monkey models. We look forward to advancing studies with the aim of demonstrating the same outcome in humans."

PENNVAX(TM) HIV Vaccine Phase I Trial Update

Preventative PENNVAX(TM) HIV Vaccine Programs

PENNVAX(TM) is an optimized DNA vaccine for HIV developed by VGX using its SynCon(TM) technology. The Company's PENNVAX(TM)-B (targeting HIV clade B) vaccine without electroporation delivery is currently in a Phase I clinical trial sponsored by the National Institute of Allergy and Infectious Diseases' (NIAID) Division of AIDS (DAIDS) and being conducted by the HIV Vaccine Trials Network (HVTN) to evaluate the vaccine's safety and immunogenicity in healthy volunteers. The HVTN recently completed enrollment of this 120-patient study (HVTN protocol number 070). VGX and its collaborators are planning a follow-on Phase I clinical trial of PENNVAX(TM)-B vaccine delivered with the CELLECTRA(R) electroporation device (HVTN protocol number 080).

In October 2008, VGX was awarded a $23.5 million contract by the NIAID to develop another preventative DNA vaccine candidate, PENNVAX(TM)-GP (targeting HIV clades A, C, and D), in conjunction with its CELLECTRA(R) electroporation technology. The Company is presently focused on optimizing the combination of the HIV vaccine candidate and electroporation delivery in pre-clinical studies.

Therapeutic PENNVAX(TM) HIV Vaccine Programs

PENNVAX(TM)-B vaccine is also being tested as a therapeutic vaccine in a Phase I study conducted by investigators from the University of Pennsylvania and Drexel University. This 38-patient study is being funded by a grant from the NIAID and began enrolling patients in 4Q 2008. The investigators are planning a follow-on Phase I clinical trial of PENNVAX(TM)-B vaccine delivered with the CELLECTRA(R) electroporation device in a therapeutic setting.

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Tentative approval of Tenofovir Disoproxil
On February 18, 2009, FDA granted tentative approval for generic tenofovir disoproxil fumarate tablets, 300 mg, indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.

"Tentative approval" means that FDA has concluded that a drug product meets all required quality, safety and efficacy standards, but is not eligible for marketing in the U.S. because of existing patents and/or exclusivity rights. However, tentative approval does make the product eligible for purchase outside the United States under the President's Emergency Plan for AIDS Relief (PEPFAR).

The application was reviewed under expedited review provisions for PEPFAR.

Manufactured by Aurobindo Pharma Limited of Hyberdad, India, this is a generic version of Viread Tablets, 300 mg, made by Gilead Sciences, Inc. Effective patent dates for all approved drugs can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility, and of the facilities performing the bioequivalence studies, to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application prior to granting approval or tentative approval to these applications.

A list of all Approved and Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan is available on the FDA website.

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[John2038]

natap

CROI: New HIV Drugs: NNRTI, PR140, Maturation
At CROI there were posters on several apparently interesting new HIV drugs: PRO 140; new NNRTIs from Ardea (RDEA427/640); Myriad presented early data on their maturation inhibitor program after acquiring Bevirimat from Panacos
The pipeline is not empty although not as exciting as 3 years ago.. There are a lot of NNRTIs (see below) in the pipeline including TMC278 as well as several integrase inhibitors, all developers hope these will be active against resistance in their class.

Phase 1, Single Ascending Oral Dose Study of the Safety, Tolerability, and Pharmacokinetics of a Novel HIV-1 Maturation Inhibitor in HIV- Healthy Volunteers
MPC-9055 had a favorable safety and pharmacokinetic profile following single dose administration to healthy volunteers. A multiple dose study in HIV-infected individuals is planned.

RDEA427 and RDEA640 Are Novel NNRTI with Potent Anti-HIV Activity against NNRTI-resistant Viruses
RDEA427 and RDEA640 are superior to EFV against a panel of NNRTI-resistant viruses and are less affected by binding to serum proteins than EFV and TMC278. RDEA427 and RDEA640 also show a low potential for CYP induction and a large selectivity index. The in vitro characterization of these novel NNRTI shows strong potential for improved performance over current NNRTI and warrants evaluation in humans.

Resistance-selection Study in vitro and Favorable Human Pharmacokinetic Properties of RDEA427, a New HIV NNRTI
RDEA427 has shown potent in vitro activity against wild-type and NNRTI-resistant viruses. In a resistance-selection study, RDEA427 controlled K103N HIV-1 infection for >100 days, suggesting that RDEA427 may provide a high barrier to resistance. Favorable pharmacokinetics of RDEA427 following intravenous micro-dosing in healthy volunteers supports the development of RDEA427, and the long half-life may mitigate the risk of a missed dose.
 
Anti-viral Characterization in vitro of a Novel Maturation Inhibitor, MPC-9055
MPC-9055 is a potent anti-HIV agent with a broad range of action. It has a novel mechanism of action and targets the last step in Gag processing, cleavage of CA-SP1 to CA. MPC-9055 is also active against RT- and PI-resistant strains. Based upon this efficacy profile and novel mechanism of action, MPC-9055 is a promising new HIV therapeutic.

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CROI: Markers of Inflammation, Coagulation and Renal Function in HIV-infected Adults in SMART and in two Large Population-Based Studies, CARDIA and MESA: HIV+ have higher levels of inflammatory markers on and off HAART, "markers appear to predict mortality & disease progression in HIV"
Compared to participants from two population-based cohorts (CARDIA and MESA), HIV-infected individuals in SMART had higher levels of inflammatory markers (as measured by hsCRP and IL-6), coagulation and fibrinolysis activity (as measured by D-dimer) and impaired renal function (as measured by cystatin-C).

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CROI: No Association of Abacavir Use with Risk of Myocardial Infarction or Severe Cardiovascular Disease Events: Results from ACTG A5001
 In contrast to D:A:D and SMART, we did not find a significant association between recent ABC use and MI or severe CVD risk for ART-naïve patients randomized to an initial ABC regimen. Our results suggest the association with recent ABC use in other studies may be a marker for other factors not discerned in their analyses.

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CROI: Subgroup Analyses from STARTMRK, a Phase III Study of Raltegravir (RAL)-Based vs Efavirenz (EFV)-Based Combination Therapy in Treatment-Naive HIV-Infected Patients
In the STARTMRK trial of combination antiretroviral therapy in previously untreated patients, RAL with TDF/FTC demonstrated consistent virologic and immunologic efficacy relative to EFV with TDF/FTC across demographic and baseline prognostic factors, including:
 
Baseline plasma vRNA level >100,000 copies/mL: Both RAL and EFV demonstrated comparable efficacy in patients with high baseline viral loads (>100,000 copies/mL) compared to patients with lower viral loads
 
Baseline CD4 count ?50 cells/mm3
--Response rates for both RAL and EFV recipients were numerically slightly lower in patients with low baseline CD4 cells (?200 cells/mm3) compared to patients with higher CD4 cells
 
Demographic groups (including age, gender, region, and race)
 
Viral subtypes (comparing non-clade B as a group to clade B)

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CROI: Factors affecting virologic response to darunavir/ritonavir and lopinavir/ritonavir in treatment-naive HIV-1-infected patients in ARTEMIS at 96 weeks
In ARTEMIS at 96 weeks, significantly more treatment-naïve patients achieved HIV-1 RNA <50 copies/mL with once-daily DRV/r 800/100mg compared with LPV/r 800/200mg total daily dose, even after adjusting for baseline predictors of response (i.e. adherence, age, race and baseline HIV-1 RNA).
 
These results were also seen when patients who discontinued for adverse events or other reasons were excluded from the analysis (non-VF censored population).
 
Sub-optimal adherence to DRV/r did not compromise virologic response, whereas patients receiving LPV/r who had sub-optimal adherence were significantly more likely to fail therapy.
 
The efficacy benefit of DRV/r over LPV/r in the ARTEMIS trial was driven primarily by virologic endpoints. This efficacy benefit was not primarily caused by differences in discontinuations for adverse events or other reasons.

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CROI: Characterization of virologic failures in the randomized, controlled, Phase III ARTEMIS trial in treatment-naive patients (Week 96 analysis)
In this treatment-naïve ARTEMIS population, the VF rate was lower in patients receiving once-daily DRV/r 800/100mg compared with LPV/r 800/200mg total daily dose.
 
In this Week 96 resistance analysis, no major (primary) PI RAMs developed in VFs with an available genotype at baseline and endpoint. Almost all minor IAS-USA PI RAMs that developed were polymorphic.
 
All VFs with available phenotypes at baseline and endpoint remained susceptible at endpoint to all PIs, including the study PI used in the regimen.
 
These findings confirm the lack of development of major (primary) PI RAMs, and the preservation of phenotypic susceptibility to all PIs in ARTEMIS patients with VF.

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CROI: Emerging Patterns of Resistance to Integrase Inhibitors
Raltegravir (RAL) is the first licensed ARV that inhibits integration. Understanding resistance to this drug class is critical to maximizing the utility of the class in clinical practice, but data to date are still limited. Analysis of the phase 2 and 3 clinical trials of RAL has suggested the potential for several resistance pathways, each involving multiple mutations with different effects on susceptibility and replication capacity. This presentation will update and extend the analyses of integrase resistance from the clinical trials of RAL in both treatment-naive patients and patients with triple-class resistant HIV-1 infection.




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CROI: Assessment of Renal Findings of Abacavir/Lamivudine (ABC/3TC) Compared to Tenofovir/Emtricitabine (TDF/FTC) in Combination with QD Lopinavir/Ritonavir (LPV/r) Over 96 Weeks in the HEAT Study
Absolute differences in renal function as estimated by eGFR and eCrCl were small between ABC/3TC and TDF/FTC each coadministered with LPV/r over 96 weeks.
 
TDF/FTC-treated subjects were more likely to experience any renal adverse event compared to ABC/3TC-treated subjects.
 
Progression to CKD stage 3 (eGFR <60mL/min/1.732) occurred more often in TDF/FTC-treated subjects.
 
Routine renal monitoring can detect overt or antiretroviral-induced kidney disease earlier and should be considered in all patients commencing antiretroviral therapy.
ABC/3TC and TDF/FTC containing therapy similarly decreased inflammatory markers associated with CV risk in antiretroviral-naive patients.
 
Few CV events occurred in HEAT and event rate was similar between arms.
 
The declines in hsCRP, IL-6, and sVCAM-1 concentrations in the HEAT study do not support the hypothesis of an ABC-induced inflammatory response leading to increased CV risk.

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CROI: Similar Reductions in Markers of Inflammation and Endothelial Activation after Initiation of Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC) in the HEAT Study
ABC/3TC and TDF/FTC containing therapy similarly decreased inflammatory markers associated with CV risk in antiretroviral-naive patients.
 
Few CV events occurred in HEAT and event rate was similar between arms.
 
The declines in hsCRP, IL-6, and sVCAM-1 concentrations in the HEAT study do not support the hypothesis of an ABC-induced inflammatory response leading to increased CV risk.

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[John2038]

natap

CROI: Efficacy and Safety of Abacavir/Lamivudine Compared to Tenofovir/Emtricitabine in Combination with Once-Daily Lopinavir/Ritonavir through 48 Weeks in the HEAT Study
Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC) in the HEAT Study
ABC/3TC is comparable to TDF/FTC in virologic efficacy when combined with LPV/r through 48 weeks.
 
Both treatment regimens were well tolerated with few discontinuations due to adverse events in either arm.

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CROI: HIV-1 INFECTION IS ASSOCIATED WITH ACCELERATED VASCULAR AGING
The results of the present study demonstrate that endothelium-dependent vasodilation is impaired in HIV-1-seropositive treatment naive men compared with healthy men of similar age.
 
The degree of impairment in endothelial vasodilation in the HIV-1-seropositive men was similar to that of healthy men 25 years older, suggesting that HIV-1 infection is associated with accelerated vascular aging.
 
Diminished endothelial-dependent vasodilator function may contribute to the greater risk of cardiovascular disease and adverse vascular events in HIV-1-seropositive adults under the age of 50 years.
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CROI: SIMPLIFICATION WITH FIXED-DOSE TENOFOVIR-EMTRICITABINE OR ABACAVIRLAMIVUDINE IN ADULTS WITH SUPPRESSED HIV REPLICATION (THE STEAL STUDY): A RANDOMIZED, OPEN-LABEL, 96-WEEK, NON-INFERIORITY TRIAL
In this population, TDF-FTC and ABC-3TC had similar virological efficacy.
 
However, ABC-3TC was associated with more SNAEs (particularly cardiovascular disease) and lipid endpoints, and TDF-FTC caused more BMD loss.

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CROI: Neurocognitive (and neuropathy) Impairment Rate Remains High in Diverse US Cohort
In the general population the metabolics are associated with vascular disease and a broad concern that can affect many organ systems: the heart, kidney, diabetes, vascular system, and the brain.

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CROI: Antiretrovirals Have Not Banished Brain Injury in 7-Center US Imaging Study: brain damage persists despite HAART- inflammation and neuronal damage
Brain injury persists in antiretroviral-treated people with stable HIV infection, according to results of a seven-center, 268-person analysis by the US-based HIV Neuroimaging Consortium [1]. Among HIV-infected people without symptoms of neurologic disease, imaging showed diffuse inflammatory changes. Because the impact of potent antiretroviral therapy on the brain in people with stable HIV infection remains unknown, the HIV Neuroimaging Consortium undertook a study of 268 people with a lowest-ever (nadir) CD4 count below 200 who had been taking antiretroviral therapy for at least 1 year. The investigators also aimed to determine whether any benefits of antiretroviral therapy persist and whether brain pathology and cognitive impairment can develop in otherwise asymptomatic people. This prospective study excluded people taking illicit drugs and people with confounding neurologic, psychiatric, or medical disorders, including hepatic, renal, or diabetic disease.

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CROI: HCV Independently Adds to Hospital, Emergency Room, and Disability Days With HIV: days in hospital doubled
HIV-infected people with a positive hepatitis C virus (HCV) antibody test spend twice as many days in the hospital as HCV-seronegative people with HIV, according to results of a 3000-person analysis. HCV seropositivity also independently raised rates of emergency room (ER) visits and disability days. Benjamin Linas and colleagues scrutinized data from the ACTG Longitudinal Linked Randomized Trials (ALLRT) cohort to determine how HCV seropositivity affects health resource use in distinct CD4-count strata (under 100, 100-200, 201-350, and over 350) and to compare rates of hospitalization, ER use, and disability days in HIV-infected people with and without HCV antibodies. The ALLRT cohort includes antiretroviral-naive and experienced people who enrolled in randomized ACTG trials and agreed to prospective follow-up after the trial ended.
 
For this study, the investigators asked cohort members to recall over the past 4 months the number of (1) nights spent in the hospital, (2) ER visits made, (3) days spent in bed, and (4) days forced to cut back on work or daily activities. They defined disability days as the larger number of either days spent in bed or days with reduced work or activities. The analysis included 3082 ALLRT participants with at least one CD4 count. When predicting the impact of HCV on health resource use, Linas and coworkers factored in current CD4 count, current viral load, opportunistic infection history, age, gender, race, and history of injecting drug use.

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CROI: Suspending Antiretrovirals Has Fast Negative Impact on HDL Particle Concentrations: interruptions reduce HDL and this predicts risk for cardiovascular disease in SMART
Duprez concluded that total HDL particle concentration, and particularly small HDL particle concentration, predicted risk of cardiovascular disease in SMART. The study linked intermittent antiretroviral therapy to falling HDL particle quotients when compared with continuous therapy. Duprez called for further study of how long-term antiretroviral therapy affects HDL cholesterol and HDL particles.

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CROI: First Double-Blind HIV+ Trial of Ezetimibe Plus Statin Finds Falling LDL Cholesterol
Adding ezetimibe to a statin significantly lowered low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, total cholesterol, and apolipoprotein B (Apo B, the primary apolipoprotein component of LDL) after 12 weeks in a double-blind, placebo-controlled crossover trial [1]. Side effects were no more frequent or severe with ezetimibe than with placebo.
 
AIDS Clinical Trials Group (ACTG) investigators compared ezetimibe, which inhibits intestinal absorption of dietary and biliary cholesterol, and placebo in 44 people taking pravastatin, atorvastatin, or fluvastatin with a stable antiretroviral regimen. The investigators excluded anyone with diabetes or a history of coronary heart disease or congestive heart failure, or anyone who used anabolic steroids. Forty-four study participants were randomized to take 10 mg of ezetimibe daily or placebo for 12 weeks, then to take no drugs for 4 weeks, then to switch over to the alternative study assignment.

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CROI: Endothelial Function, Inflammatory Markers Do Not Change 24 Weeks After Switch to Atazanavir
Total cholesterol and triglycerides fell significantly when hyperlipidemic people switched from a boosted protease inhibitor (PI), usually lopinavir, to atazanavir/ritonavir [1]. But 24 weeks after the switch, endothelial function and cardiovascular inflammatory markers had not changed significantly in people who started atazanavir or people who stayed with their original PI. Robert Murphy and colleagues in the US, Argentina, and Italy did not speculate on the clinical implications of their findings. (from Jules: perhaps HIV causes endothelial dysfunction that may not be reversible by a switch to a more friendly lipid ART medication).
 
Murphy and coworkers randomized 50 people taking a stable ritonavir-boosted PI regimen to continue their drugs or to swap the PI for 300/100 mg of atazanavir/ritonavir once daily. Everyone had a viral load below 500 copies and a fasting low-density lipoprotein (LDL) cholesterol level above 130 mg/dL or triglycerides above 200 mg/dL. The study excluded anyone taking a nonnucleoside, anyone with cardiovascular disease or diabetes, or anyone who smoked more than one pack of cigarettes daily. However, 42% of study participants did smoke. The investigators also excluded anyone who began lipid-lowering therapy within 4 weeks and anyone who used systemic immunomodulators, insulin-sensitizing drugs, or many vitamin supplements.

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CROI: Two Inflammation Markers (hsCRP & IL-6) Predict Higher Risk of Opportunistic Disease in SMART
Two inflammation markers--high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) measured at study entry and during the trial--independently predicted a new opportunistic disease during the SMART treatment interruption study [1]. Not surprisingly, older age, clinical AIDS before SMART, latest CD4 count, and latest viral load also predicted a new opportunistic disease during the trial.
 
This case-control comparison involved 91 SMART enrollees diagnosed with a new opportunistic disease during the trial (the cases) and 273 matched SMART participants who did not have a new opportunistic disease during the study (the controls). SMART investigators measured four inflammatory markers (hsCRP, IL-6, amyloid A, and amyloid P) and two coagulation markers (D-dimer and prothrombin fragment 1+2) in samples collected at two points: at study entry and during follow-up (at the time of latest plasma sample before the opportunistic disease in cases and at a matched point in controls).

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CROI: Platelet Function & Heart Attacks in HIV+ & ART
This is the first study to show platelet dysfunction at multiple levels in HIV+ subjects with both clinical and HIV parameters associated. Further research into underlying mechanisms and examining the effect of ART is needed to determine how platelet dysfunction links to CVD in HIV+ patients.
 
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CROI: Pharmacokinetics and dose selection of etravirine in HIV-infected children between 6 and 17 years, inclusive
ETR administered at 4mg/kg and 5.2mg/kg bid following a meal provides comparable exposure in HIV-infected children (aged 6-17 years, inclusive) to 200mg bid in HIV-infected adults
 
ETR was generally safe and well tolerated
-- two subjects developed a transient rash of mild-to-moderate severity during Stage 1: no apparent association of rash with ETR exposure (AUC12h)
 
Given the general concern for underdosing of antiretrovirals in children7-9 and lack of any safety signal during Stage II, the selected target dose of ETR in children aged 6-17 years inclusive, is 5.2mg per kg bid
 
A Phase II trial (TMC125-C213; PIANO) to further determine pharmacokinetics, safety and efficacy over 48 weeks in treatment-experienced children is ongoing

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[John2038]

GeoVax Starts Injections for Phase 2a Human HIV/AIDS Vaccine Trial in USA

ATLANTA, Feb. 20 /PRNewswire-FirstCall/ -- GeoVax Labs, Inc. (OTC Bulletin Board: GOVX - News), an Atlanta-based, publicly traded biopharmaceutical company developing human vaccines for diseases caused by HIV-1 (Human Immunodeficiency Virus) and other infectious agents, announced the first injections in its Phase 2a Human Clinical Vaccine Trial for its candidate HIV/AIDS vaccine. The trial, designated HVTN 205, is being conducted by the HIV Vaccine Trials Network (HVTN). The HVTN, funded and supported by the National Institutes of Allergy and Infectious Diseases (NIAID), is the largest worldwide clinical trials network dedicated to the development and testing of HIV/AIDS vaccines. The HVTN has sponsored over 80 Phase 1 trials for the initial evaluation of safety and immunogenicity of candidate HIV/AIDS vaccines. The results of these trials have merited only five phase 2a trials since 1992. Progressing to Phase 2 is a significant step for GeoVax. The Company is pleased to report that the first injections for the Phase 2a trial were conducted at the HVTN network sites at the University of Alabama, Birmingham, and Vanderbilt University, Nashville.

The trial will include a total of 225 volunteers (150 vaccine recipients and 75 placebo recipients) and take place at 13 HVTN sites: 11 in North America and 2 in South America. Sites in the United States include Emory University, Atlanta; Harvard Medical School, Boston; Vanderbilt University, Nashville; University of Rochester; Fred Hutchinson Cancer Research Center, Seattle; the San Francisco Department of Public Health; University of Alabama, Birmingham and sites at Columbia University, Union Square, and the Bronx in New York City. In South America, participants are to be enrolled in Peru at sites in Iquitos and Miraflores (Lima).

"I am extremely pleased that our vaccine merited moving forward through the HVTN," said Harriet Robinson, Ph.D., developer of the vaccine and Senior V.P. of Research and Development at GeoVax. "This network provides a wide array of support for its clinical trials, from finances to statistical design and analysis; from community engagement to rigorous laboratory analysis. Working with the HVTN also affords us the input of the NIAID Prevention Science Research Committee, a committee with breadth of experience and knowledge in human vaccine development."

GeoVax's unique two component vaccine, a recombinant DNA and a recombinant modified vaccinia Ankara (MVA), is designed to stimulate both anti-HIV T cell and anti-HIV antibody immune responses. Stimulation of both T cells and antibodies differentiates the GeoVax vaccine from many other vaccine candidates. GeoVax's DNA and MVA vaccines are used in a prime-boost protocol in which priming is done with the DNA and boosting with the MVA. Both the DNA and MVA express the three major proteins of the AIDS virus: Gag, Pol, and Env, and produce non-infectious virus-like-particles. These particles contain proteins that mimic more than half of the components of the AIDS virus, but cannot cause AIDS. This multi-protein approach is designed to elicit a broad multi-target protective T cell response. The Env protein is designed to elicit a protective Ab response against the natural form of the virus envelope glycoprotein as well as protective T cells.

Dr. Paul Goepfert, principal Investigator of HVTN 205 and director of the University of Alabama trial site, said, "The road to an effective vaccine to prevent HIV infection is long and winding. It is vital to continue testing promising products. I am very pleased to aid in the further development of this important product in a phase 2 trial."

"For nearly 30 years since HIV/AIDS' discovery, researchers have been searching for a vaccine to combat its scourge," said Robert McNally, Ph.D., CEO and President of GeoVax Labs Inc. "Our Phase 1 trials found GeoVax's vaccines to be safe and immunogenic in humans. Good results from the Phase 2a human trial will build upon this foundation of safety and immunogenicity to support a Phase 2b efficacy trial."

In addition to the preventative vaccine entering Phase 2a, GeoVax also is working towards initiating human clinical trials testing its vaccines as potential therapies for people who are already infected with HIV. The goal of the therapeutic vaccination is to reduce the need of infected people for anti- viral drugs. Initial therapeutic trials will vaccinate infected people who are already on drugs to test the safety and immunogenicity of the vaccine in infected people. Therapeutic trials of a simian immunodeficiency virus (SIV) prototype of the GeoVax HIV vaccine in SIV infected primate animal models have held high promise that the GeoVax vaccine will be able to contribute to the control of HIV-1 in infected humans.

About GeoVax Labs, Inc.

GeoVax Labs, Inc. is a biotechnology company, established to develop, manufacture, license and commercialize human vaccines for diseases caused by HIV-1 (Human Immunodeficiency Virus) and other infectious agents. GeoVax's AIDS vaccine technology is the subject of 20 issued or filed patent applications. GeoVax AIDS vaccines are designed for use in uninfected people to prevent Acquired Immunodeficiency Disease (AIDS), caused by the virus known as HIV-1, should the person ever become infected. GeoVax AIDS vaccines also may be effective as therapeutics, treatment of people already infected with AIDS virus.

GeoVax's core AIDS vaccine technologies were developed by Dr. Harriet Robinson, Senior V.P. of Research and Development, through a collaboration of colleagues at Emory University's Vaccine Center, the National Institutes of Health (NIH), The Centers for Disease Control and Prevention (CDC) and GeoVax.

GeoVax AIDS vaccines have moved forward in human clinical trials conducted by the HIV Vaccine Trials Network (HVTN) based in Seattle, Washington. The HVTN, funded through a cooperative agreement with the National Institutes of Health (NIH), is the largest worldwide clinical trials program dedicated to the development and testing of AIDS vaccines. Preclinical work enabling evaluation of GeoVax DNA and MVA vaccines was funded and supported by NIAID, which provided additional support to GeoVax AIDS vaccine development program with a $15 million IPCAVD grant awarded in late 2007.

Safe Harbor Statement: All statements in this news release, not statements of historical fact, are forward-looking statements. These statements are based on expectations and assumptions on the date of this press release and are subject to numerous risks and uncertainties which could cause actual results to differ materially from those described in the forward-looking statements. Risks and uncertainties include, but are not limited to, whether: GeoVax can develop and manufacture these vaccines with the desired characteristics in a timely manner, GeoVax's vaccines will be safe for human use, GeoVax's vaccines will effectively prevent AIDS in humans, vaccines will receive regulatory approvals necessary to be licensed and marketed, GeoVax raises required capital to complete vaccine development, there is development of competitive products that may be more effective or easier to use than GeoVax's products, and other factors over which GeoVax has no control. GeoVax assumes no obligation to update these forward-looking statements, and does not intend to do so. Certain matters discussed in this news release are forward-looking statements involving certain risks and uncertainties including, without limitation, risks detailed in the Company's Securities and Exchange Commission filings and reports.

Source

[John2038]

After new high in China and Japan, now Russia

Russia Recorded More Than 50,000 New HIV Cases In 2008, Health Official Says

A total of 50,670 new HIV cases were reported in Russia in 2008, bringing the total number of registered HIV cases since 1987 to 467,016, Chief Sanitary Inspector Gennady Onishchenko announced Tuesday, RIA Novosti reports (RIA Novosti, 2/17). Of the new cases in 2008, 6,000 people already had progressed to AIDS, according to Onishchenko. He added that Russia's HIV incidence is 306 cases per 1,000 people (CIS General Newswire, 2/17). According to ITAR-TASS, Onishchenko said that the number of HIV cases was particularly high in some areas, including Moscow and St. Petersburg. The main route of transmission continues to be injection drug use, which accounted for 65% of all HIV cases, he said. Onishchenko added that more than 23 million people received HIV tests last year. In addition, an increasing number of people are accessing antiretroviral treatment, including pregnant women to prevent mother-to-child HIV transmission, according to Onishchenko (ITAR-TASS, 2/17).

According to Onishchenko, the government plans to implement a national project to add an additional 50,000 people to its antiretroviral treatment program. He added that funding pledges for HIV/AIDS treatment programs have been "confirmed" and that no funding will be cut because of the current economic situation (CIS General Newswire, 2/17).

Source

[John2038]

Important notice for people with impaired immune function about peanut products recalled for Salmonella
The Centers for Disease Control and Prevention (CDC) has been receiving reports of illnesses caused by a type of Salmonella called Salmonella Typhimurium, which have been traced to certain peanut products.

People with impaired immune systems, such as those with HIV/AIDS, are more likely to become severely ill from a Salmonella infection than are others. When severe infection occurs, Salmonella may spread from the intestines to the bloodstream and can even cause death unless properly treated.

Most persons infected with Salmonella develop diarrhea (sometimes bloody), vomiting, fever, and abdominal cramps within 12 to 72 hours after infection. Illness ranges from mild to severe. The illness usually lasts 4 to 7 days, and most people recover without treatment. However, infants, the elderly, and people with impaired immune systems are more likely to become severely ill from a Salmonella infection than are others.

If you have the symptoms listed above, see your health professional. Infection is usually diagnosed by culture of a stool sample. If your health professional determines you have the Salmonella infection, he or she will likely recommend that you increase your fluid intake to replace losses from diarrhea and, in some (but not all) instances, may also prescribe antibiotics to speed recovery. Your health professional can help you determine the right amount and type of fluid for your particular needs.

More information is available on the FDA web site as Frequently Asked Questions and Answers about the Recent Salmonella Outbreak: http://www.fda.gov/oc/opacom/hottopics/salmonellatyph/faq.htm

[John2038]

In South Africa - Free State, HIV drugs are no more delivered to new patients, and those currently treated are experiencing treatments shortages, leading to the development of resitances.
After the Mbeki policies in the early 2000s, here are the consequence 9 years later..

30 dying every day in the Free State - HIV Clinicians

Approximately 30 HIV positive people have died in the Free State every day following a moratorium the province placed on initiating any new patients on anti-retroviral (ARV) drugs, according to conservative figures from the Southern African HIV Clinicians Society.

Drugs have started trickling into the province this week following the lifting of an almost four month moratorium which had been placed on the initiation of newly diagnosed HIV patients since November.

The HIV Clinicians Society figures were based on the assumption that pregnant women and children were prioritized and not included as part of the moratorium.

It made a "conservative" projection that about 20 babies was infected during birth every month, of which half will die before they turn one year.

It is estimated that at least 15 000 people needing ARVs were placed on waiting lists, but it is unknown how many people were simply turned away during a four-month moratorium which saw people with HIV in need of ARVs sent home and others who had been on the drugs for years being told that the clinic had run out of stock.

The province has since lifted the moratorium, but it is still struggling to get the drugs to its 28 treatment sites with only a few patients being initiated since last week.

This week Free State premier Beatrice Marshoff failed to mention the ARV crisis in her State of the Province address. She reportedly later denied assertions that the province's health care system was in tatters.

Marshoff later told journalists that no-one was lying about the health situation in the Free State.

She said the provincial government could assure its citizens there was no crisis in health care and that the government would provide adequate health care.

Dr Yogan Pillay, Deputy Director General of Health in the national health department admitted this week that the province had "severe financial pressures".

Meanwhile Anglican Church Bishops have expressed their shock at the Free State health department's decision last year.

The Synod of Bishops of the Anglican Church of Southern Africa, meeting at Modderpoort in the Free State, said the impact on the lives of patients and on the work of health professionals would be enormous.

"Such deliberate action by the Department of Health is irresponsible," the statement said.

The church said it was "speaking up on behalf of those whose voice may not be heard".

"We wholeheartedly support the South African Constitution's affirmation that access to health care is a right of all citizens, and call on provincial and national government, in the name of God, to find a way to prevent this human catastrophe immediately.

"We assure those affected - patients, families, health workers and government - of our prayers and our support," the bishops' statement said.

Source

[John2038]

hivandhepatitis

Large Meta-analysis Indicates Antiretroviral Therapy Works as Well for Women as for Men
Since the early years of the AIDS epidemic, researchers and advocates have debated whether HIV positive women benefit as much as men from antiretroviral therapy. Some studies in the early HAART era suggested that women did not fare as well, but many believe this was a reflection of poorer access to care, differences in socioeconomic status, or other factors.

At the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last week in Montreal, Kimberly Struble and colleagues from the U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research presented results from a meta-analysis of efficacy outcomes among women in trials of antiretroviral therapy conducted over nearly a decade.

The researchers combed through datasets for registrational randomized controlled trials submitted to the FDA, looking for any gender differences in 48 week efficacy outcomes, defined as HIV RNA < 400 copies/mL, as well as differences in treatment effect size.

Studies were stratified by whether participants were antiretroviral treatment-naive or treatment-experienced. Efficacy analyses by antiretroviral class were also performed for nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, and CCR5 antagonists.

Results

    * The combined database included 17,826 HIV positive participants in 38 randomized controlled
      trials of 14 antiretroviral drugs.
    * There were no clinically or statistically significant gender differences in 48 week efficacy
      outcomes (assuming mean effect size difference between men and women were equal, the estimated
      95% confidence interval [CI] of equal mean effect size difference was -0.07, 0.09).
    * For treatment-naive study participants, the estimated 95%CI of equal mean effect size difference
      between men and women included zero (-0.1 to 0.09), indicating no differences.
    * For treatment-experienced patients, the estimated 95% CI also included zero (-0.095 to 0.16),
      again revealing no gender differences.
    * For all antiretroviral drug classes analyzed, the estimated 95% CI all included zero, or no
      differences:
        - NRTIs: -0.15 to 0.11;
        - NNRTIs: -0.29 to 0.35;
        - PIs: -0.08 to 0.13;
        - Fusion inhibitors: -0.50 to 0.37;
        - CCR5 antagonists: -0.46 to 0.50.

"Preliminary analyses of the FDA database are the most detailed review of gender-related antiretroviral efficacy data so far," the researchers stated.

"These analyses suggest no clinically or statistically significant gender differences in week 48 efficacy outcomes, regardless of treatment history or drug class," they continued.

"Such data could help healthcare providers and HIV-1-infected patients when considering different antiretroviral regimens," they concluded. "From scientific and regulatory perspectives, the cumulative data could help identify issues requiring additional investigation."

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HIV Positive People Can Modify Several Risk Factors that Increase Mortality
While effective antiretroviral therapy has dramatically reduced the risk of illness and death for people with HIV, positive individuals still have an elevated mortality rate relative to the HIV negative general population. Furthermore, as HIV positive people live longer, they are at increased risk for progressive conditions such as cardiovascular disease, liver disease, and non-AIDS-defining cancers.

As reported at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last week in Montreal, Colette Smith and colleagues with the D:A:D (Data Collection on Adverse events of Anti-HIV Drugs) study team sought to identify modifiable risk factors associated with specific causes of death.

In this analysis, more than 33,000 HIV positive patients from 11 cohorts in Europe, Australia, and the U.S. were followed from date of entry into the study until death or last follow-up, collectively contributing nearly 159,000 person-years (PY) of follow-up data. About three-quarters were men, 45% were white, 10% were black, the mean age was 39 years, 18% had a history of injection drug use, and about half were current (34%) or former (17%) smokers.

The researchers used Poisson regression to calculate adjusted rate ratios (RR) for the association between potentially modifiable risk factors and death after adjusting for other potential confounding factors.

The factors the investigators considered to be "modifiable" included body mass index (BMI), smoking, hepatitis C virus (HCV) and/or hepatitis B virus (HBV) coinfection, diabetes, hypertension, use of antiretroviral therapy, current CD4 cell count, and current HIV viral load.

Results

    During the follow-up period, there were 2192 total deaths (14 per 1000 PY across the entire
    period, but falling from 16 to 10 per 1000 PY since 2007).

    Underlying causes of death were:

        * AIDS: 32%;
        * Liver-related causes: 14%;
        * Non-AIDS-defining cancers: 12%;
        * Cardiovascular disease: 11%;
        * Bacterial infections: 9%;
        * Non-natural causes (e.g., accidents, drug overdose, violence, suicide): 9%.
        * Other causes: 13%.

    Significant non-modifiable risk factors were:

        * Male sex: 20% increase in mortality risk;
        * Older age: 22% increase per 5 years.

    HIV/AIDS-related risk factors linked to all-cause death were:

        * Lower current CD4 count (19% increase per 50 fewer cells/mm3);
        * Higher HIV viral load (56% increase if > 400 copies/mL);
        * HIV RNA < 10,000 copies/mL if untreated: 77% increase;
        * HIV RNA > 10,000 copies/mL if untreated: nearly a 4-fold increase;
        * Among patients on antiretroviral therapy, those with a detectable viral load still had a
          higher risk of death than those with fully suppressed HIV.

    Modifiable risk factors for all-cause death were:

        * Smoking: 20% increase in risk (15% for current, 30% for former);
        * Diabetes: 83% increase;
        * HCV coinfection: 45% increase;
        * HBV coinfection: 29% increase;
        * Hypertension: 53% increase;
        * Low BMI (< 18 kg/m2): 3-fold increase.

    The strength of association of modifiable risk factors with cause-specific death rates varied
    substantially, for example:

        * Smoking (current and former) was associated with cardiovascular disease and non-AIDS-defining
          cancers;
        * HBV and HCV coinfection were associated with liver-related deaths (about 80% of liver-related
          deaths were attributable to chronic viral hepatitis);
        * Hypertension was associated with liver-related and cardiovascular deaths.
        * Diabetes was a risk factor for all specific causes except non-AIDS-defining cancers.
        * Higher HIV viral was strongly associated with AIDS-related deaths, weakly linked to
          liver-related and cardiovascular disease, but not associated with non-AIDS-defining cancers.
        * Lower CD4 count was associated with a higher risk of death due to all specific causes, but
          was most pronounced for AIDS-related deaths.

"Multiple potentially modifiable risk factors for deaths in HIV-infected persons were identified," the D:A:D investigators concluded. "These factors must be addressed to further reduce mortality. Maintaining higher CD4 cell counts is likely to have the broadest effect on decrease in deaths."

These findings agree with those from the FRAM (Fat Redistribution and Metabolic Change in HIV Infection) study, also presented at the conference. In this cohort of 992 U.S. HIV patients, significant mortality risk factors were older age (61% increased risk per 10 years), low CD4 count (35% increase per 1 log decrease in CD4 cells), and current smoking (nearly a 3-fold increase).

Noting some of the more counterintuitive findings, she explained that the trend toward increased death associated with lower BMI was likely attributable to people losing weight as they get sicker. She did not have an explanation for the link between high blood pressure and liver-related deaths.

In a discussion after the presentation, some argued that these factors are not all necessarily modifiable in all cases. While hepatitis B can be prevented with a vaccine, for example, once a person is infected the virus may not be eradicated with antiviral treatment. Likewise, even state-of-the-art antiretroviral therapy does not always raise a person's CD4 count to a fully protective level.

In a press conference following the session, Smith noted that even in a population with widely available access to care, the most common cause of death was still AIDS, indicating that many people were not getting tested and treated in a timely manner.

The take-home message of the latest analysis, she said, is the important public health message: "You need to try as hard as you can to modify the modifiable risk factors."

More

Immune Deficiency Linked to Non-AIDS-defining Cancers with Infectious Causes
Over the past few years, evidence has accumulated that immune deficiency increased the risk for several types of cancer that are not traditionally classified as AIDS-defining (i.e., Kaposi's sarcoma, non-Hodgkin lymphoma, and cervical cancer). Further data along these lines were presented at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last week in Montreal.



Kaiser California

Michael Silverberg and colleagues reported rates of infection-related cancers at Kaiser Permanente health facilities in California. Like the 3 AIDS-defining cancers, several other malignancies are associated with infectious agents, and therefore might be expected to increase when the immune system is compromised. Anal cancer, for example, is caused by the same types of human papillomavirus (HPV) as cervical cancer, though only the latter is classified as opportunistic.

The investigators identified 18,890 adult HIV patients, pairing each one with 10 age-, sex-, and year-matched HIV negative Kaiser members. The HIV positive members contributed a total of 81,831 person-years (PY) of follow-up, while the 189,804 HIV negative control subjects contributed 971,675 PY. Cohort members were followed from first enrollment after January 1996 until the earliest non-AIDS-defining cancer diagnosis, last Kaiser enrollment, or December 2006. A large majority of the HIV positive patients were gay/bisexual men.

Cancers were classified as infection-related or infection-unrelated. Infection-related cancers included anal cancer, head and neck cancer (often linked to HPV, but also to non-infectious causes such as smoking), liver cancer (a possible consequence of chronic hepatitis B or C), and Hodgkin's lymphoma (associated with Epstein-Barr virus).

Incident (newly occurring) non-AIDS-defining cancers were identified from Kaiser Permanente cancer registries based on the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program. Age- and sex-adjusted rate ratios (RR) were estimated and compared between HIV positive and HIV negative participants. Changes in RRs over time were evaluated for the periods 1996-1999, 2000-2003, and 2004-2006.

Results

    * 482 non-AIDS-defining cancers were identified among the HIV positive patients, 220
      infection-related and 269 infection-unrelated (7 people had both).
    * 3065 non-AIDS-defining cancers were identified among the HIV negative participants, 398
      infection-related, and 2698 infection-unrelated (31 had both).
    * The rate of infection-related non-AIDS-defining cancers was 29.7 per 10,000 PY in the HIV
      positive group, compared with 4.4 per 10,000 PY in the HIV negative group (RR 6.8, or nearly 7
      times greater risk; P <0.001).
    * The rates of infection-unrelated non-AIDS-defining cancers were 36.4 for HIV positive group and
      30.6 for the HIV negative group (RR 1.2; P = 0.002).
    * The RR for infection-unrelated cancers was significant only for the most recent time period: 1.2
      in 1996-1999 (P = 0.26), 1.2 in 2000-2003 (P = 0.12), and 1.3 in 2004-2006 (P = 0.02) (P for
      trend = 0.85).
    * Looking at infection-related non-AIDS-defining cancers, significant rate differences between HIV
   positive and HIV negative participants were observed for anal cancer (RR 81.4, or 81% greater risk;
   P <0.001), Hodgkin's lymphoma (RR 17.4; P <0.001), and head and neck cancers (RR 2.1; P <0.001).
    * Looking at infection-unrelated cancers, HIV positive participants' rates were significantly higher
   for kidney cancer (RR 1.8; P = 0.045), lung cancer (RR 1.7; P = 0.004), and melanoma skin cancer
   (RR 1.7; P = 0.002).
    * However, HIV positive patients had a lower rate of prostate cancer (RR 0.7; P = 0.007).

The latter result agrees with a previous analysis that also found that a reduced prostate cancer rate in HIV positive men. But this study did not find an elevated risk of liver cancer in people with HIV, as others have]

"HIV positive persons have an elevated risk of non-AIDS-defining cancers, particularly infection-related, which comprised almost half of all the non-AIDS-defining cancers in this population," the investigators concluded.

They noted, however, that the risk of developing an infection-related non-AIDS-defining cancer has declined for HIV positive individuals since the advent of effective combination antiretroviral therapy, while remaining the same for HIV negative individuals, suggesting that treatment restores immune function and can protect against development of certain cancers.

EuroSIDA

A related analysis of the EuroSIDA cohort supported the Kaiser findings. Joanne Reekie and colleagues investigated whether current CD4 count was independently associated with risk of non-AIDS-defining cancers after accounting for traditional and other HIV-associated risk factors. The study included 12,865 EuroSIDA participants with a known CD4 count prior to enrollment, contributing a total of 75,234 PY of follow-up.

Results

    * A total of 317 non-AIDS-defining cancers were diagnosed in 309 patients during the follow-up
     period (58 anal, 24 lung, 60 hematological, 48 Hodgkin's lymphoma, 40 genitourinary, 55
     digestive, and 80   other), for an incidence rate of 4.2 per 1000 PY.
    * After adjusting for potential confounding factors, the excess risk of developing a
     non-AIDS-defining cancer, compared to participants with more than 500 cells/mm3, was:
        * CD4 count > 50 cells/mm3: 76% higher risk (RR 1.76; P = 0.0408);
        * 51-200 cells/mm3: 82% higher risk (RR 1.82; P = 0.0014);
        * 201-350 cell/mm3: 43% higher risk (RR 1.43).
        * 351-500/mm3: no significant difference (P = 0.89).
    * Each doubling of current CD4 count was associated with an 11% decrease in the risk of
      non-AIDS-defining cancers, including anal cancer (RR 0.83), hematological cancers (RR 0.94),
      genitourinary cancers (RR 0.87), and digestive cancers (RR 0.84).
    * Due to the small numbers of events, however, this finding only reached statistical significant
      for anal cancer (P = 0.0038) and digestive cancers (P = 0.0233).
    * In addition to CD4 count, other significant predictors of non-AIDS-defining cancer were older
      age, prior AIDS diagnosis, previous history of non-AIDS-defining cancer, time on antiretroviral
      therapy, and hepatitis B (but not hepatitis C) coinfection.

Based on these findings, the researchers concluded, "Immunosuppression was associated with an excess risk of [non-AIDS-defining cancers]."

"One possible explanation is enhanced oncogenic potential by pro-oncogenic viruses (e.g., human papillomavirus and anal cancer)," they hypothesized. "An infectious oncogenesis has only been established for a few [non-AIDS-defining cancers] linked with immunosuppression in this study and other mechanisms may also contribute. As the immunosuppression may be reversed by [combination antiretroviral therapy], HIV is a suitable candidate model for improving our understanding of how immunosuppression affects oncogenic transformation."

More

[John2038]

natap


CROI:  HIV Infection May Make the Brain 15 to 20 Years Older: HIV slows cerebral blood flow and stimulus response in MRI study
Older age and HIV infection both upset cerebral blood flow, regardless of viral load, current CD4 count, or lowest-ever (nadir) CD4 count, according to results of a brain scan comparison involving older and younger people with and without HIV. By these measures, the brain of an HIV-infected person may be up to 20 years older than the brain of a person without HIV.

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CROI: Framingham Risk Score Linked to Other Heart Risk Factors in HIV Cohort
An intermediate or high Framingham heart risk score predicted high internal carotid intima media thickness (IMT), high common carotid IMT, and detectable coronary artery calcium in 334 HIV-infected adults in the Nutrition for Healthy Living (NFHL) cohort. Liana Falcone and Tufts University colleagues proposed that the Framingham score is a useful "predictive instrument for cardiovascular risk stratification in the HIV-infected population." Meanwhile, other researchers are trying to devise a heart disease equation specifically for people with HIV.

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CROI: No Residual Raltegravir Activity After Resistance Emerges
A study of 4 people who stopped only raltegravir in a salvage regimen after emergence of integrase mutations found no evidence that the drug exerts residual activity after mutations evolve.
 
"Even if further observations will be useful to be certain" of this finding, Marc Wirden and Paris colleagues concluded, "it seems unnecessary to keep this drug in such a context. Moreover, the withdrawal of raltegravir avoids the risk of accumulating mutations for future compounds within this class."
 
The four patients were taking a raltegravir-containing regimen with a stable, detectable viral load for at least 2 months. Wirden and coworkers measured viral load and CD4 count at day 0 (the day patients stopped only raltegravir), then for up to 90 days as the patients continued the same regimen. A substantial viral load gain during this time would indicate that raltegravir had been exerting some antiviral activity after resistance mutations emerged. In the last month of raltegravir therapy, the hallmark integrase mutation N155H emerged in patients A, C, and D, while the classic Q148H mutation arose in patient B. Virus from all 4 patients also had evidence of other mutations with these signature mutations. Trough raltegravir concentrations were in the therapeutic range (from 118 to 268 ng/mL) when these people stopped raltegravir, then quickly became undetectable.
 
Follow-up continued for 28 days in patients A and C, for 90 days in patient B, and for 42 days in patient D. Variations in viral load during follow-up were minimal:
· Patient A: -0.04 log, +51 CD4s
· Patient B: -0.17 log, +25 CD4s
· Patient C: +0.19 log, -56 CD4s
· Patient D: -0.20 log, +252 CD4s
Wirden and colleagues noted that all viral load variations were well below a meaningful cutoff of 0.5 log.
 
Regardless of what other antiretrovirals people were taking with raltegravir, integrase mutations did not disappear during follow-up. Because of this finding, the investigators suggested, "the discussion remains open about impact [of these mutations] on replication capacity."

More
 
CROI: Effects of Aging on HIV Pathogenesis: aging is associated with higher t-cell activation in women than men, effects of menopause on inflammation and immune activation...."
"Aging is associated with higher levels of T cell activation in women Effects of menopause on inflammation and immune activation plays an important role in HIV pathogenesis"
 
"HIV infection results in CD4+ T cell depletion in GALT Progression is associated with T cell activation and tissue inflammation Partial T cell restoration occurs with HAART A threshold of CD4+ T cell restoration correlates with: Reduced immune activation in GALT Reduced inflammation in GALT Suppression of viral replication"

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CROI: Bone Loss at Baseline and Week 144 in Study 903 TDF vs d4T + EFV
The high prevalence of spine osteopenia/osteoporosis at baseline in this population suggests that BMD loss may be a consequence of HIV infection
 
Progression from normal/osteopenia to osteopenia/osteoporosis through 144 weeks was minimal and not significant between the TDF and d4T arms
 
No patient with spine osteoporosis at baseline or at week 144 developed bone fractures
 
No difference in the incidence of osteopenia and osteoporosis at the spine was observed between the TDF and d4T arms

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CROI: Safety and Efficacy of Raltegravir (RAL) in Pediatric HIV Infection. Preliminary Analysis From IMPAACT P1066
RAL in 6-18 yr old HIV infected children was generally well tolerated.
 
Preliminary data at 8 and 12 weeks shows viral suppression in a majority of participants:
-- 8 weeks: 50% <50 copies/ml; 77% <400 copies/ml
-- 12 weeks: 63% <50 copies/ml; 80% <400 copies/ml
-- CD4 increases for cohort I
 
Monitoring of safety and efficacy is continuing.
 
For Cohort IIA (ages >6-12 yrs), repeat PK and safety evaluations, at a uniform dose of 400 mg PO BID, regardless of weight, is ongoing.

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CROI: Telbivudine Has Activity against HIV
In our opinion the most likely explanation is that LdT has activity against HIV-1. We do not believe that ADV had an effect on the patient's HIV viral load because it has been shown that low dose ADV does not have any effect on HIV viral load. Given that re-challenge with LdT for 2 weeks resulted in suppression of the HIV viral load to 71 copies/mL, we believe that this is strong evidence that LdT is active against HIV-1. Until further trials have been done it should no longer be recommended as a treatment for chronic hepatitis B in HIV+ individuals who do not require treatment for their HIV.

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CROI: Abacavir Use is Not Associated with Lack of Virologic Response in ARV-treated HIV/HCV-Coinfected Patients Receiving PEG-IFN and Ribavirin
Among ARV-treated HIV/HCV-coinfected subjects, abacavir use was not associated with a decrease in early virologic response or SVR rates, particularly in those patients who received appropriate doses of PEG-IFN + RBV.

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CROI: Telbivudine Has No In Vitro Activity Against Laboratory and Clinical HIV-1, Including 5 Clades and Drug Resistant Clinical Isolates
This in vitro report confirms that telbivudine shows no in vitro antiviral effect against a broad range of wild-type and multi-drug resistant HIV isolates at IC50 values >600 µM, a value well above physiologically relevant concentrations and known to inhibit HBV activity in vitro (EC50 value = 200 nM). In contrast, entecavir activity against HIV was confirmed against drug sensitive and drug resistant clinical HIV-1 isolates. These results support further investigation in a clinical trial setting, of the efficacy and safety of telbivudine, for treatment of CHB in HIV-HBV co-infected patients who do not concurrently require anti-HIV treatment and for whom there are few available treatment options.

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CROI: Heart Disease Marker Rises in Women During 96 Weeks of Suppressive Efavirenz
High-sensitivity C-reactive protein (hsCRP), a cardiovascular risk marker, rose throughout 96 weeks of successful treatment with efavirenz (with or without abacavir) in AIDS Clinical Trials Group (ACTG) study A5095 [1]. The 96-week jump was statistically significant in women, but not in men.

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CROI: Liver Fibrosis Marker Rises in SMART Interrupters and Predicts Non-AIDS Deaths
suspending treatment "is particularly dangerous" in hepatitis virus-coinfected people if hyaluronic acid is high just before the antiretroviral holiday.....Among coinfected SMART interrupters with a study entry hyaluronic acid level above normal, cumulative risk of non-AIDS death came to 37.3% after 48 months, compared with 7.3% in noninterrupters who had either a normal or high baseline hyaluronic acid reading.... Coinfected people with elevated entry hyaluronic acid readings had significantly higher interleukin 6 (IL-6) and D-dimer levels than people with normal hyaluronic acid quotients at entry. An earlier SMART analysis tied elevated IL-6 and D-dimer to all-cause mortality in SMART, and interrupting antiretrovirals led to increases in both IL-6 and D-dimer

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CROI: Diverse Disease Markers Up in SMART Patients Regardless of Antiretroviral Therapy: inflammation markers linked to death, ART interruption, HIV, aging, & ART
Levels of hsCRP, IL-6, and cystatin-C did not differ significantly between SMART members taking versus not taking antiretrovirals.  Among 33-to-44-year-old SMART participants, D-dimer concentrations were 62% higher in SMART patients not taking antiretrovirals (P < 0.001). mong 45-to-76-year-old SMART patients, D-dimer levels were 63% higher among untreated people (P < 0.001). Both men and women in SMART had higher adjusted hsCRP concentrations than people of the same gender in CARDIA and MESA, but the differences were larger for men than for women. hsCRP level differences between SMART and the two control cohorts were even greater when the analysis excluded people with hepatitis C virus (HCV).

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CROI: Immune Activators Stay High Despite Long-Term HIV Suppression With Antiretrovirals: affects CD4 recovery
Levels of lipopolysaccharide (LPS) and sCD14, two immune activators, dropped significantly during antiretroviral therapy but did not return to normal levels after up to 11 years of treatment in a study by Reena Rajasuriar and Melbourne colleagues [1]. They also found that a higher pretreatment CD4 count and IL-7R-alpha haplotype GTA predicted CD4 gains exceeding 500 cells/mm(3). Because IL-7R-alpha polymorphisms could influence antiretroviral-induced CD4-cell recovery, Rajasuriar and coworkers examined the role of these genetic shifts, as well as gut microbial translocation and immune activation, on long-term CD4 gains in people taking a suppressive regimen. They included people who began treatment with a potent combination at a CD4 count under 500 whose viral load became undetectable within 6 months of starting therapy. Everyone had at least three CD4 counts in the first 12 months of therapy.

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[John2038]

Natap


CROI: Pharmacokinetics and Safety of Twice Daily Atazanavir 300 mg and Raltegravir 400 mg in Healthy Subjects
Compared to ATV 300 mg BID alone, ATV adjusted geometric mean Cmax, AUC and Cmin were 11%, 17% and 29% lower, respectively, upon coadministration with RAL; all of the individual ATV Cmin values were greater than the 10-fold protein binding adjusted EC90 for ATV against wild type HIV
 
RAL exposures were increased by approximately 40 - 55% when coadministered with ATV 300 mg BID; a similar trend was previously observed when RAL was concomitantly administered with ATV 400 mg QD and ATV/RTV 300/100 mg QD
 
ATV BID and RAL BID alone and when coadministered were generally safe and well-tolerated
 
RAL coadministration did not appear to affect ATV-associated hyperbilirubinemia
 
Mean QRS and PR interval increases were observed with ATV alone and remained elevated throughout coadministration with RAL; RAL did not appear to affect ATV-associated PR or QRS changes -- The clinical relevance of QRS interval increases with ATV BID is unclear and is being investigated further in an HIV-infected patient pilot safety and efficacy study

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CROI: Epidemic of Acute HCV Among MSM in Europe and New York City
 Acute HCV infection of HIV-infected MSM results in significant liver fibrosis. Treatment is highly successful when initiated in the acute phase, but may be less successful if initiated months later. Thus, it is crucial to detect HCV infection in the acute phase to allow successful treatment and to prevent further progression of the already significant liver fibrosis. We therefore recommend at least quarterly ALT and yearly HCV testing for all HIV-infected MSM. Promotion of safe sex and decreased drug use is also warranted.
 
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CROI: Neurocognitive Disorders Threaten HIV+
Here are several poster reports from CROI on neurocognitive disorders and function in HIV+ individuals. The first 2 posters report high prevalence (51% and 24%) of neurocognitive disorders despite using HAART. The 3rd study suggests cytokine dysfunction may persist in the brain despite HAART in patients with neurocognitive disorder. Another study reports CD4 nadir is associated with neurologic dysfunction despite HAART and this has been found in many studies CD4 nadir appears to predict neurologic dysfunction. A study from the CHARTER Study group found 41% of patients with undetectable HIV in the blood had HIV in the CSF when they used a sensitive assay (<2 copies/ml) and having these low levels was associated with cognitive impairment than patients with detectable HIV in both the blood and the CSF, the authors suggest this is because their HAART regimen was not effective enough in the CSF, didn't have enoiugh CSF penetration. The CHARTER group in an other study reported that substance abuse was not associated with cognitive impairment, the implication is that when HIV is found to be associated with neurocognitive disorders if the patient had a history of substance abuse it is the HIV at fault not the substance abuse.

High Prevalence (24%) of Mild Neurocognitive Disorders in HIV-infected Patients, ANRS CO3 Aquitaine Cohort
"For every 4 treated adults with well controlled HIV-infection, 1 had a mild cognitive disorder as compared to 6% in the French general population of 65 years or older"
For every 4 treated adults with well controlled HIV-infection, 1 had a mild cognitive disorder as compared to 6% in the French general population of 65 years or older. In addition to factors usually associated with mild neurocognitive disorders in the aging general population, advanced HIV infection and co-infection with hepatitis B may explain the high frequency in HIV population. A short battery of easy-to-administer tests could be used to explore mild neurocognitive disorders in HIV-infected patients.

High Frequency (51%) of Neurocognitive Disorders in Older HIV-infected Patients despite a Sustained Virological and Immunological Response on cART: The Sigma Study
Despite a sustained response to cART, neurocognitive disorders are more frequent in old HIV+ patients than in the general aging population, but are underdiagnosed by their physicians. In our patients, subcortical types of cognitive impairment remain more predominant than neocortical types. The respective role of HIV, ART, and co-morbidities is debated. Longitudinal studies are needed to assess the outcome of these disorders in aging and to determine their predictive factors.
 
"irrespective of HIV RNA control in CSF cytokine and chemokine CSF expression was not modified by ART. Both findings suggest a major role of pro-inflammatory cytokines in the pathogenetic mechanisms of HAND development in advanced HIV infected patients."
 
Intrathecal Immune Activation and Viral Changes in HIV-infected Naive Patients with Advanced Disease after Short-term HAART Introduction
HIV RNA decrease at a different rate in plasma and in CSF, which supports the hypothesis of compartmentalization of HIV replication in advanced disease. CSF HIV RNA levels did not seem to be primarily associated with impaired neurocognitive function. Conversely, pro-inflammatory cytokines levels were strictly associated to the development of cognitive disorders. Moreover, irrespective of HIV RNA control in CSF cytokine and chemokine CSF expression was not modified by ART. Both findings suggest a major role of pro-inflammatory cytokines in the pathogenetic mechanisms of HAND development in advanced HIV infected patients.
 
Cortical and Subcortical Volumes on Magnetic Resonance Imaging Associated with HIV History and Current Disease Status
"HIV severity and duration related to reduced cortical and hippocampal volumes, suggesting that patients who suffered prior severe immune dysfunction (low CD4 nadir) may eventually experience cortical and hippocampal changes even in the context of HAART. This is noteworthy, as these brain areas were not viewed as primary sites of HIV infection in the past, suggesting an evolution of cortical disturbances with chronic HIV infection that requires further investigation."

Cortical and Subcortical Volumes on Magnetic Resonance Imaging Associated with HIV History and Current Disease Status
Caudate volume was associated with current plasma viral load, as expected based on evidence from the pre-HAART. In contrast, HIV severity and duration related to reduced cortical and hippocampal volumes, suggesting that patients who suffered prior severe immune dysfunction may eventually experience cortical and hippocampal changes even in the context of HAART. This is noteworthy, as these brain areas were not viewed as primary sites of HIV infection in the past, suggesting an evolution of cortical disturbances with chronic HIV infection that requires further investigation.

Persistent HIV in the Central Nervous System during Treatment is Associated with Worse ART Penetration and Cognitive Impairment
"ART-treated individuals frequently (41%) have low levels of HIV in CSF which is associated with less penetrant ART. At least a quarter of these individuals appear to have HIV that persists solely within the central nervous system (detectable HIV in CSF but not in blood) and these individuals have much worse cognitive performance than those who appear to have a systemic source of HIV. We conclude that people living with HIV may have cognitive impairment as a result of ART that is incompletely effective in the nervous system. A more sensitive HIV assay may be needed to monitor CSF in treated individuals."
 ART-treated individuals frequently (41%) have low levels of HIV in CSF which is associated with less penetrant ART. At least a quarter of these individuals appear to have HIV that persists solely within the central nervous system (detectable HIV in CSF but not in blood) and these individuals have much worse cognitive performance than those who appear to have a systemic source of HIV. We conclude that people living with HIV may have cognitive impairment as a result of ART that is incompletely effective in the nervous system. A more sensitive HIV assay may be needed to monitor CSF in treated individuals.
 
Reduced Region-specific Corpus Callosum Volumes Correlate with Low-nadir CD4 and Decreased Cognition in HIV-infected Carriers of the ApoE4 Allele
HIV-seropositive individuals possessing at least one ApoE4 allele are more vulnerable to effects of low nadir CD4 count, which may contribute to region-specific corpus callosum atrophy and thereby to cognitive impairment. Early ART may be more vital for these patients than for those without the allele.

Substance Use and HIV Infection: Neurocognitive Effect, the CHARTER Cohort
Substance use was not associated with compromised neuropsychological function at baseline in this HIV+ cohort when important co-factors were considered. This suggests that historic substance use and acute stimulant use do not require special consideration in cross sectional analyses of neuropsychological function in neuro-AIDS research.
Substance use was not associated with compromised neuropsychological function at baseline in this HIV+ cohort when important co-factors were considered. The absence of relationship remained when substance use was determined by syndromic use, "casual" use, or urine toxicology, and did not vary by ARV status. This suggests that historic substance use and acute stimulant use do not require special consideration in cross sectional analyses of neuropsychological function in neuro-AIDS research.

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CROI: Immune Senescence, Activation, and Abnormal T Cell Homeostasis despite Effective HAART, a Hallmark of Early Aging in HIV Disease: "HIV-infected subjects (median 56 years) with good immune reconstitution and viral suppression had immune changes comparable to older (median 88 years) HIV-negative subjects"
HIV-infected subjects (median 56 years) with good immune reconstitution and viral suppression had immune changes comparable to older (median 88 years) HIV-negative subjects. Age-dependant changes in HIV-infected compared to young HIV-negative controls are more pronounced in CD8+ T cells, which exhibit higher immune activation and senescence levels and reduced naïve and central memory subsets. These findings have implications on the competency of adaptive immune system and its ability to combat infection
 
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CROI: High Prevalence of Hepatic Fibrosis and Steatosis in HIV/AIDS Patients without Chronic Viral Hepatitis but with Chronically Elevated Transaminases on ART: 35% without HCV or HBV had significant liver disease
Significant liver disease was seen in 35% of HIV-infected adults with chronic transaminase elevations while receiving ART. CT imaging and transient elastography can help identify such patients, but normal studies do not exclude significant pathologic abnormalities. Longitudinal follow-up of this cohort will better characterize the natural history of chronic transaminase elevations in this population.
 
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CROI: CCR5-tropic Resistance to Maraviroc is Uncommon Even Among Patients on Functional MVC Monotherapy or with Ongoing Low-level Replication
115/160 (72%) of patients receiving MVC with a wOBTSS >/= 2 were TLOVR<50 responders with a viral load <50 HIV-1 RNA copies/mL at Week 48.
 
Excluding non-R5 failures and those without matched MVC susceptibility data, R5 virologic failure occurred in 62/331 (19%) patients with MVC-resistant HIV-1 seen in 22/62 (35%) of these.
 
Functional monotherapy or a single active NRTI (wOBTSS<1) accounted for 16/22 (73%) MVC resistance-associated failures, and no MVC-resistant virus was found in patients with a wOBTSS of >/= 2 who failed MVC treatment with an R5 tropism result.
 
16/80 (20%) patients who received functional monotherapy or a single active NRTI experienced MVC resistance-associated R5 virologic failure, and 50/80 (63%) of these patients responded through Week 48.
 
The low incidence of MVC resistance in patients failing with virologic rebound or who never achieved viral suppression is consistent with a high barrier to resistance in these patients. Virologic failure in these patients is likely to be associated with other factors.

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[John2038]

Natap


CROI: Management of Treatment-Experienced Patients

Switching from Stable Lopinavir/Ritonavir (LPV/r)-Based to Raltegravir (RAL)-Based Combination Antiretroviral Therapy (ART) Resulted In a Superior Lipid Profile at Week 12 but Did Not Demonstrate Non-Inferior Virologic Efficacy at Week 24 (SWITCHMRK)
On the other hand, there are settings in which it might be safer to make RAL switches. The French ANRS 138 study randomized 170 patients with triple-class resistant HIV on an ENF-containing regimen for at least 3 months and with HIV RNA <400 c/ml to either stay on ENF (n=85) or substitute the ENF with RAL (n=84) [2]. Baseline patient characteristics were similar for both groups; it should be noted that this was a heavily pre-treated patient population with a median prior HAART and ENF exposure of 13.6 and 2.3 years, respectively. Through week 24 (ITT analysis), only 1 failure (HIV RNA >500 c/ml) occurred in each of the treatment arms and 89% of patients in both arms had HIV RNA <50 c/ml. Why such a big difference in outcome compared to SWITCHMRK? As stated previously, what is critical for RAL's efficacy seems to be its association with enough active drugs. For patients well suppressed on an ENF-containing regimen for a long period of time, it would be logical to assume that the other components of the regimen are substantially contributing to antiretroviral activity. Thus, substitution of active ENF with active RAL would be a safe and effective one-for-one switch.

96-Week Results from BENCHMRK 1&2, Phase III Studies of Raltegravir (RAL) in Patients (pts) Failing Antiretroviral Therapy (ART) with Triple-Class Resistant HIV 
There is a growing body of evidence that suggests there might be a connection between the use of abacavir (ABC) and cardiovascular disease (discussed at length in a CROI newsletter on cardiovascular and metabolic issues by my colleague Pablo Tebas), and the efficacy of ABC in patients with viral loads >100,000 c/ml has recently come into question. Nonetheless, because there is still considerable controversy surrounding this topic, studies are still being conducted in which ABC is part of the NRTI backbone. One such study was presented by David Cooper and colleagues, the Simplification with fixed-dose Tenofovir/Emtricitabine or Abacavir/Lamivudine (STEAL) study [4]. This switch study has also been nicely summarized at the NATAP website so I will not go into all the details. In short, patients with HIV RNA <50 c/ml were randomized to substitute the NRTIs in their ART regimen with either tenofovir/emtricitabine (TDF/FTC) (n=178) or ABC/lamivudine (3TC) (n=179), both as fixed dose combinations. Baseline characteristics were evenly matched except for smoking that was more prevalent among the patients switching to ABC/3TC (40%) than among those switching to TDF/FTC (29%). After 96 weeks of follow-up, the virologic efficacy and protection against death and progression to AIDS was similar for both treatment arms. However, even in this small number of patients followed for a relatively short period of time there was a trend for fewer ischemic cardiovascular events among the TDF/FTC-treated patients (1 vs. 7 events per 100 patient-years of follow up; HR 0.15 [95% CI 0.02, 1.15]; p=0.067). On the other hand, there was less bone loss as determined by hip T-scores among the ABC/3TC-treated patients (0.09 vs. -0.07; HR 0.16 [95% CI 0.08, 0.23]; p<0.0001). Thus, while these findings are not novel, they reinforce our perception that ABC is associated with a greater frequency of cardiovascular diseases while TDF is associated with disorders of bone metabolism.

SIMPLIFICATION WITH FIXED-DOSE TENOFOVIR-EMTRICITABINE OR ABACAVIRLAMIVUDINE IN ADULTS WITH SUPPRESSED HIV REPLICATION (THE STEAL STUDY): A RANDOMIZED, OPEN-LABEL, 96-WEEK, NON-INFERIORITY TRIAL
It is well-known that not all patients who start antiretroviral therapy have adequate immune restoration despite having a good virological response to antiretroviral therapy. The most recent update to the DHHS antiretroviral treatment guidelines for adults define immunologic failure on antiretroviral therapy as the inability to increase CD4+ cell counts by more than 25-50 cells/mm3 over the baseline in the first year of therapy despite having an undetectable viral load. This failure to have adequate immune reconstitution is critical as several studies have shown that such a discordant response is associated with an increased risk of opportunistic diseases, non-AIDS-related serious events, and mortality. In recognition of this, studies were begun almost a decade ago to determine if administration of IL-2, known to be associated with increases in CD4+ cell counts and especially of long-lived naïve and central memory cells, could also be associated with a lower rate of clinical complications.

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CROI: HIV Prevention at CROI 2009

HIV prevention has occupied an increasingly central place at CROI in recent years, with this year's conference no exception. Interesting and important observational and interventional studies were presented, relevant to a variety of settings and risk groups worldwide.

See the link below for more info on the following topics:

- Topical Microbicides
- Pre-Exposure Prophylaxis (PrEP)
- Antiretroviral Treatment for HIV Prevention
- Observational epidemiologic data relevant to HIV prevention
- PMTCT
- HIV Testing in High-Prevalence Settings

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[John2038]

ucla

Gene therapy shows promise as weapon against HIV

A new UCLA AIDS Institute study has found that gene therapy can be developed as a safe and active technique to combat HIV.
 
Researchers involved in this first-of-its-kind study found that cell-delivered gene transfer has the potential to be a once-only treatment that reduces viral load, preserves the immune system and avoids lifelong antiretroviral therapy. The study appears in the current online edition of the journal Nature Medicine.
 
Though modest, the results do show some promise that gene therapy can be developed as a potentially effective treatment for HIV, said lead investigator Dr. Ronald Mitsuyasu, professor of medicine and director of the Center for Clinical AIDS Research and Education (CARE) at the David Geffen School of Medicine at UCLA.
 
"It is the first randomized controlled study done with gene therapy in HIV," said Mitsuyasu, who is also an associate director of the UCLA AIDS Institute. "What we were able to demonstrate was that the patients who received the gene-modified cells had a somewhat better suppression of their HIV viral replication after discontinuing their highly active antiretroviral therapy (HAART) treatment, compared with the controls."
 
This was the first randomized, double-blind, placebo-controlled gene-transfer clinical trial and involved 74 HIV-positive adults.
The patients received their own blood stem cells, either untreated or modified to carry a molecule called OZ1, which prevents viral replication by targeting a key HIV gene. OZ1 was safe, causing no adverse effects over the course of the 100-week trial.
 
At the primary end-point, the difference in viral load between the OZ1 and placebo group at weeks seven and eight, after they had stopped HAART treatment, was not statistically significant. But other viral parameters did demonstrate better HIV suppression and improvement in the counts of CD4+ lymphocytes — the cell population that is depleted by HIV.
 
The technique still needs to be developed further and perfected, Mitsuyasu said.
 
"Part of the reason that we didn't see a larger effect is that the persistence of the anti-HIV gene in the patient's blood was not as long as we would have liked," he said. "We need to find better ways to get the genes into the patients and maintain them, which could include using different vectors to get the gene into the cells or conditioning the patients prior to gene transfer."
 
Still, the results indicate that gene therapy could eventually be a useful tool in the fight against AIDS, said study co-author Dr. Thomas C. Merigan, the George and Lucy Becker Professor of Medicine emeritus at the Stanford University School of Medicine. He agrees that more needs to be done to perfect it.
 
"But in the way we set up the trial with randomized placebo controls, we could dissect out that there was a positive effect in patients who had the gene successfully installed," Merigan said. "This could be a first step in developing a new method of controlling a chronic infectious disease."
 
This study was funded by Johnson and Johnson Research Pty Limited. Grants from the National Institutes of Health also helped support part of the research.
 
The UCLA AIDS Institute, established in 1992, is a multidisciplinary think tank drawing on the skills of top-flight researchers in the worldwide fight against HIV and AIDS, the first cases of which were reported in 1981 by UCLA physicians. Institute members include researchers in virology and immunology, genetics, cancer, neurology, ophthalmology, epidemiology, social sciences, public health, nursing and disease prevention. Their findings have led to advances in treating HIV, as well as other diseases, such as hepatitis B and C, influenza and cancer.

Source

[John2038]

sciencedaily

First Step Towards A World Reclassification Of Viruses

The atomic interpretation of the stressosome, with multiple copies of the scaffold protein RsbS colored red, and the sensor domain of RsbR in yellow and its corresponding scaffold domain in blue. The EM-derived molecular envelope, shown as a semi-transparent surface, is colored red for the core and blue for the sensory extensions. (Credit: Copyright Newcastle University)

Prof Dave Stuart, Director of Life Sciences at Diamond – the UK national synchrotron – and head of the Structural Biology Laboratory at Oxford's Wellcome Trust Centre for Human Genetics will unveil the structure of a biological protein from the vaccinia virus at the American Association for the Advancement of Science – AAAS- in Chicago. This is a significant step towards unlocking effective therapies to treat viruses.

The structure was solved at Diamond by Prof Stuart and his colleagues in December 2008 when they discovered that this complicated member of the poxvirus family is related to a large number of simpler viruses and shows the relevance of Darwinism to these, the simplest form of life.

Prof Stuart explains the significance of the new findings, "Viruses are by their very nature extremely hard to classify. They are much more common and diverse than any other form of life. On top of this, they evolve about 1 million times quicker than animals and we have no fossils to help us track their evolution back through history. Determining the structure of proteins is our best approximation to a fossil record and knowing more about virus families and the relationships between these families will help us to develop new, more effective, therapies".

The evolutionary path of human beings and animals fascinated Darwin and the quest for knowledge in this complex research area continues in the 21st century through the complex studies of many structural biologists across the world.

Prof Stuart continues, "With these latest results, we have been able to confirm our theories about the vaccinia virus at Diamond. This is a step towards a reclassification of the virus world, which can guide the way we think about therapies in the future. Currently, with viruses such as HIV, the therapies are targeting the replication machinery of the virus rather than their shells. If structural commonalities between viruses are known, these links can be used to create therapies that work on a family of viruses, as opposed to just one. With this approach, it is possible that we could be able to treat patients who are suffering from one of a number of viruses, in the same way that antibiotics are used to treat bacterial infections."

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aidsonline

HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review
Objective: To assess the efficacy of ritonavir-boosted protease inhibitor monotherapy.

Design and methods: Systematic review of all protease inhibitor-monotherapy studies published in peer-reviewed journals or presented at conferences to date. Data of randomized controlled trials were pooled to yield common odds ratios.

Results: Twenty-two protease inhibitor-monotherapy studies were identified. In the intent-to-treat analysis, 395 out of 582 (67.9%) patients had undetectable HIV-RNA at the end of follow-up. In the six randomized controlled trials (all lopinavir/ritonavir monotherapy), the risk of therapy failure was greater on monotherapy: 121 out of 364 (33.2%) patients on monotherapy against 64 out of 280 (22.9%) patients on HAART -pooled odds ratio 1.48 (95% confidence interval 1.02-2.13, P = 0.037). Regarding patients with successfully resuppressed HIV-RNA upon (re-)introducing nucleoside reverse transcriptase inhibitors (NRTIs) as nonfailures, the risk of therapy failure was comparable: 98 out of 364 (26.9%) against 64 out of 280 (22.9%) patients [odds ratio 1.05 (95% confidence interval 0.72-1.53, P = 0.81)].

Conclusion: The overall efficacy of ritonavir-boosted protease inhibitor monotherapy is inferior to HAART. The efficacy improves in patients started on monotherapy after suppressed HIV-RNA for at least 6 months. Ten percent of patients have viral rebound with HIV-RNA levels between 50 and 500 copies/ml. Possible explanations are lack of HIV suppression in particular cells or compartments, alternative resistance mechanisms, and nonadherence. Once proven that reintroduction of NRTIs, in patients with loss of viral suppression, is safe and effective, a broader use of simplification of HAART to protease inhibitor monotherapy might be justified. This review supports that the majority of patients with prolonged viral suppression on HAART can successfully be treated with protease inhibitor monotherapy. Arguments for this strategy are NRTI/NNRTI side effects, NRTI/NNRTI resistance, and costs.

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Efficacy and safety of etravirine (TMC125) in treatment-experienced HIV-1-infected patients: 48-week results of a phase IIb trial
Forty-eight-week results from a randomized, multicentre, part-blinded, phase IIb clinical trial assessing the efficacy and safety of 400 and 800 mg etravirine twice daily (phase IIb formulation) and optimized background regimen versus standard-of-care regimen are presented. Both etravirine doses demonstrated sustained virological suppression at 48 weeks and a favourable tolerability profile. Etravirine demonstrated higher efficacy than control, irrespective of the number of detectable nonnucleoside reverse transcriptase inhibitor-resistance-associated mutations at baseline or active background antiretrovirals.

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ascopubs

Highly Active Antiretroviral Therapy and the Incidence of Non–AIDS-Defining Cancers in People With HIV Infection
Purpose: The effect of highly active antiretroviral therapy (HAART) on the incidence of non–AIDS-defining cancers (NADCs) is unclear.

Methods: We have investigated the occurrence of NADCs in a prospective cohort of 11,112 HIV-positive individuals, with 71,687 patient-years of follow-up. Standardized incidence ratios (SIRs) were calculated using general population incidence data. We investigated the effect of calendar period, HIV parameters, and immunologic and treatment-related factors on the incidence of these cancers using univariate and multivariate analyses.

Results: The SIR for all NADCs was 1.96 (95% CI, 1.66 to 2.29). There was no significant excess in incidence in the pre-HAART era (1983 to 1995; SIR, 0.95; 95% CI, 0.58 to 1.47). However, the incidence increased in the early HAART period (1996 to 2001) and remains elevated in the most recent established HAART period (2002 to 2007; SIR, 2.05; 95% CI, 1.51 to 2.72, and SIR 2.49; 95% CI, 2.00 to 3.07, respectively). Multivariate analysis showed that use of HAART (hazard ratio HR = 1.64; 95% CI, 1.13 to 2.39) and a nadir CD4 count less than 200/µL (HR = 1.67; 95% CI, 1.10 to 2.54) were associated with an increased risk. Only the non-nucleoside reverse transcriptase inhibitors (NNRTIs) were associated with a significantly increased risk of NADCs (HR = 1.45; 95% CI, 1.01 to 2.08). Much of this association was attributable to an increased risk of Hodgkin's lymphoma with NNRTIs (HR = 2.20; 95% CI, 1.03 to 4.69).

Conclusion: Since the introduction of HAART, there has been a significantly increased risk of NADCs, which has now stabilized. A number of factors are associated with this increased risk, including HAART use. There may be an association between the use of NNRTIs and the development of Hodgkin's lymphoma.

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hivandhepatitis

Cancer Incidence in Clinical Trials of Raltegravir (Isentress)
The first-in-class HIV integrase inhibitor, raltegravir (Isentress), was approved by the U.S. Food and Drug Administration in October 2007.



During the drug's development, some clinical trials suggested that participants taking raltegravir had a higher rate of malignancies, though this was not confirmed in later studies.

In a poster presented at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) this month in Montreal, David Cooper and colleagues summarized the most recent and complete cancer rate data from 5 randomized, double-blind clinical trials of raltegravir and the open-label expanded access program (EAP-P023, also known as EARMRK). Data were collected through the end of August 2008.

The analysis included:

    * 96 week data from the Phase 3 trial protocols P018 and P019
     for treatment-experienced patients, better known as BENCHMRK 1 and 2;
     http://www.hivandhepatitis.com/recent/2008/072508_a.html
    * 48 week data from the Phase 3 treatment-naive study P021, better known as STARTMRK;
      http://www.hivandhepatitis.com/2008icr/icaac_idsa/docs/102808_b.html
    * 120 week data from Phase 2 trials P004 and 005.

In the randomized trials, a combined total of 1039 study participants were randomly assigned to receive raltegravir (total 1454 person-years [PY]), while 605 were assigned to comparator drugs (656 PY). The BENCHMRK protocols also included an open-label phase. In the EAP, 5438 patients enrolled through March 2008 received open-label raltegravir; they were required to report all serious adverse events, including cancers, whether or not they were thought to be drug-related.

The investigators used both a broad definition of cancer that included recurrences, worsening of pre-existing cancer, non-melanoma skin cancers, and carcinoma in situ, as well as a narrower definition that excluded these categories. A time-to-first-event analysis was used to estimate event rates per 100 PY. Relative risk (RR) was determined for double-blind data only. Cancer rates in the EAP were analyzed separately using a consistent time-to-first-event approach.

Results

    * In the double-blind trials, using the broad definition, 29 cancer cases
     occurred in the raltegravir arms (1.68 per 100 PY) versus 17 in the
     comparator arms (2.24 per 100 PY), for a RR of 0.75.

    * In the double-blind trials, using the narrower definition, there were 13 cancers
     in the raltegravir arms (0.75 per 100 PY) and 11 in the comparator
     arm (1.44 per 100 PY), for a RR of 0.52.

    * Looking at all clinical trial data combined -- both double-blind and open label --
     using the broad definition, there were 49 cancer cases (2.10 per 100 PY).

    * Looking at combined clinical trial data using the narrow definition,
     there were 22 cancers events (0.93 per 100 PY).

    * In the open-label EAP, using the broad definition,
     55 cancer cases were reported (2.48 per 100 PY).

    * In the EAP using the narrower definition, there were 32 cancers (1.44 per 100 PY).

    * A majority of cancers observed in raltegravir recipients were types
     recognized to occur more often in people with HIV/AIDS:

        - Kaposi's sarcoma: 12 cases;
        - Anal squamous cell carcinoma: 7 cases;
        - Skin squamous cell carcinoma: 7 cases;
        - Basal cell carcinoma: 7 cases;
        - B-cell lymphoma: 5 cases.

Based on these findings, the researchers stated, "cancer rates were slightly lower for raltegravir, but not significantly different from comparators."

Although the EAP included some 2200 additional person-years of follow-up in patients with more advanced HIV disease, cancer rates were similar to those seen in clinical trials.

"Data to date showed no difference in risk of cancer in HIV-infected patients receiving raltegravir vs other antiretroviral therapy," the investigators concluded.

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[John2038]

hivandhepatitis

HIV Can Remain in Semen despite Effective Antiretroviral Therapy
Effective antiretroviral therapy (ART) that suppresses HIV in the blood and semen dramatically reduces the risk of transmission. In 2008, the Swiss Federal Commission for HIV/AIDS sparked controversy when they stated that fully adherent HIV positive individuals on antiretroviral therapy who maintain an undetectable viral load for at least 6 months and have no concurrent sexually transmitted diseases (STDs) essentially cannot transmit HIV via sexual contact -- or at least via heterosexual vaginal intercourse.

Some researchers have suggested that universal treatment might be used as a prevention strategy, but this is not a completely reliable strategy since HIV can remain in semen despite undetectable plasma viral load.

Several studies presented at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) this month in Montreal shed further light on the relationship between HIV treatment and transmission.

Heterosexual Couples in Africa

Two studies looked at HIV transmission risk among heterosexual couples in Africa. Steven Reynolds from the National Institute of Allergy and Infectious Diseases (NIAID) presented findings from Rakai, a rural district in Uganda that produced some of the earliest data that antiretroviral treatment could reduce transmission.

The present analysis included stable serodiscordant heterosexual couples from the Rakai Community Cohort Study. Between 2004 and 2007, 205 serodiscordant couples were identified, and 12 HIV positive men and 8 women started free ART when they had a CD4 count < 250 cells/mm3 or WHO stage IV disease. Participants were followed for 12-18 months on average.

A total of 34 instances of HIV transmission occurred during 396 person-years (PY) of follow-up prior to ART initiation, an incidence rate of 8.6 per 100 PY. In contrast, no transmissions occurred during 25 PY of follow-up while on the positive partner was on ART. Prior to ART, the median viral load was about 44,000 copies/mL. After starting treatment, 79% achieved undetectable HIV viral load (< 40 copies/mL) at 6 months and 95% had at least 1 detectable measurement within the first 18 months.

No significant differences in sexual variables (e.g., number of partners, condom use, circumcision status, STDs) were observed between treated and untreated couples. The researchers concluded that, "ART reduced HIV transmission among discordant couples during the period ART was provided free in this rural treatment cohort."

Patrick Sullivan and colleagues conducted a similar but larger study of 2993 serodiscordant heterosexual couples in Kigali, Rwanda and Lusaka, Zambia followed from 2002 through 2008. HIV positive partners started ART when they had < 200 CD4 cells/mm3 or WHO stage III or IV disease. Negative partners were tested for HIV and received HIV risk reduction counseling every 3 months.

During a median follow-up period of 17 months, 175 new HIV infections occurred -- 171 from untreated partners (3.4% per 100 PY) and 4 from partners on ART(0.7% per 100 PY). Couples with the infected partner on ART were actually less likely to have risky sex (as determined by self-report and testing for semen in vaginal fluid) than untreated couples.

"Reduction in risk of HIV transmission was observed when HIV positive partners were on ART," the researchers concluded, adding that "the reduced risk was likely due to a combination of ART effects and lower risk behaviors." Sullivan noted that the transmission rate was 3-fold to 5-fold lower among couples receiving treatment.

HIV in Semen

Prameet Sheth presented data from a study comparing HIV positive men in Toronto, 25 of whom were just starting ART and 13 of whom had been on effective therapy for at least 4 years and had undetectable (< 50 copies/mL) plasma viral load.

In the newly treated group, plasma viral load became persistently undetectable in all cases by week 16. Most (70%) had undetectable (< 300 copies/mL) semen viral load by week 4, but some still had detectable HIV RNA in their semen at 24 weeks. A higher proportion (48%) had detectable semen viral load on at least 1 test after starting therapy -- usually isolated "blips" -- and 14% of the time HIV RNA was detectable in semen but undetectable in plasma.

Among the men on long-term ART, 31% had detectable semen HIV RNA. This was more likely in men with higher baseline semen viral load. But baseline plasma viral load, CD4 cell count, and herpes simplex virus status did not predict HIV shedding in semen.

"Although effective HAART often eliminated HIV RNA from the semen, isolated HIV semen shedding was common, even after extremely prolonged suppression of blood viral load," the researchers concluded. "Public health messages and policy must be tailored carefully to reflect this reality."

In a related study, Anne-Genevieve Marcelin and colleagues looked at 264 paired plasma and semen samples from 145 HIV positive men participating in an assisted reproduction program at the Pitie-Salpetriere Hospital in Paris that used "sperm washing" to enable conception without putting HIV negative female partners at risk. HIV RNA was measured in seminal fluid after sperm cells were removed by centrifugation.

In 85% of sample pairs, HIV RNA was undetectable in both plasma (< 40 copies/mL) and semen (< 200 copies/mL), while in 3.4% of pairs it was detectable in both. In 8.7% of sample pairs, however, HIV RNA was undetectable in semen despite being detectable in plasma, while in 2.7% of pairs (coming from 4.8% of the men), HIV was detectable in semen but not plasma; in all the latter cases, the men were on stable ART and had fully suppressed plasma HIV RNA for at least 6 months. Here too, detectable semen viral load often occurred as transient "blips."

"These results show that 5% of patients had detectable HIV-1 RNA in semen although they had concomitantly undetectable HIV-1 RNA in blood while they were under HAART," the researchers concluded. "These results should be taken into account in public health messages. Indeed, while effective antiretroviral therapy is likely to substantially reduce HIV transmission at a population level, residual HIV RNA shedding can occur."

Cell-free Virus

Finally, David Butler from the University of California at San Diego presented data showing that HIV may be free-floating in seminal fluid, not only as genetic material in infected semen lymphocytes.

Butler and colleagues studied 4 previously serodiscordant male-male couples in which the negative partner was recently infected. In all 4 cases, the newly infected individual's HIV was closely related to cell-free HIV RNA, but not cell-associated HIV DNA, from the positive partner.

"Recipients' blood HIV RNA sequences clustered completely and with 100% bootstrap support with their respective sources' [cell-free RNA] sequences and separately from [cell-associated DNA] sequences in all cases," they reported.

The investigators also found 6 amino acids "signature" sequences that were associated with transmission, which might provide potential targets for a preventive HIV vaccine.

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medicalnewstoday

About 42% Of Pregnant Women In Swaziland Are Living With HIV, Report Says
About 42% of pregnant women in Swaziland are HIV-positive, an increase of 3% since last year, according to a government report that was released on Friday, the AP/Google.com reports. According to the report, the increase likely is because more women's lives are being prolonged through improved access to antiretroviral drugs. About 185,000 people in Swaziland -- which has a population of one million and the highest HIV/AIDS prevalence rate worldwide -- are living with HIV. About 30,000 people have access to antiretrovirals in the country, and average life expectancy is 37 years.

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Organised Crime Gang Targets HIV/AIDS Patients In Internet Scam
The Medicines and Healthcare products Regulatory Agency (MHRA) is warning people to be aware of internet sites claiming to have a medical device that cures HIV/Aids among other ailments.

The company, Savec Health Systems Ltd, claimed to be able to supply the machine and associated medicine to the public with payment made via credit card, Paypal or money transfer.

Savec Health Systems also claimed to have a list of doctors who say they have used this device successfully on patients and they quote endorsement by four UK medical clinics.

Along with The Department of Health, Social Services and Public Safety (Northern Ireland), and the Police, the MHRA have investigated this case and believe the probability of any such device existing is extremely low.

MHRA Director of Policy, Mr Shaun Gallagher said, "We have contacted one of the clinics referred to in a testimonial on the Savec Health Systems website and they have no knowledge of the product. The Northern Ireland Authorities are contacting the other three clinics."

"It would be extremely doubtful that any machine of this kind would have any value in the treatment of HIV/Aids," he said. "But all of the evidence suggests that the product does not even exist and that this is simply a scam, being run through an organised crime gang, to take money from vulnerable people."

The website has been closed by the authorities but the MHRA is urging anyone who has had dealings with this company to come forward, and for the public to remain vigilant, reporting any similar scams they may come across on the net.

Notes

1. The MHRA is the government agency responsible for ensuring that medicines and medical devices work, and are acceptably safe. No product is risk-free. Underpinning all our work lie robust and fact-based judgements to ensure that the benefits to patients and the public justify the risks. We keep watch over medicines and devices, and take any necessary action to protect the public promptly if there is a problem. We encourage everyone - the public and healthcare professionals as well as the industry - to tell us about any problems with a medicine or medical device, so that we can investigate and take any necessary action.

2. MHRA

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payvand

18,000 Iranians HIV positive
An estimated 18,000 of the country's 70 million population are infected with the human immunodeficiency virus (HIV), the pathogen that causes AIDS, secretary of the state Welfare Organization's committee of AIDS control and prevention said on Sunday.

There is about 80,000 AIDS cases in Iran, Majid Reza-Zadeh said.

He described "injecting drug use" as the main means of AIDS transmission, lamenting the fact that in some parts of the country, "HIV is typically transmitted through sexual behaviors".

Referring to the increasing numbers of AIDS sufferers all around the world, Reza-Zadeh stressed the need for accelerating HIV prevention global efforts especially those targeted at youth.

AIDS (Acquired Immune Deficiency Syndrome), which is now a pandemic, is a very serious disease that stops the body from defending itself against infections, and usually causes death.

In 2007, an estimated 33.2 million people lived with the disease worldwide, and it killed an estimated 2.1 million people, including 330,000 children. Over three-quarters of these deaths occurred in sub-Saharan Africa.

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Boston Globe

Panacos mulls sale
Panacos Pharmaceuticals Inc., which is trying to develop HIV drugs, said it is cutting more than more than half its workforce and is considering selling the company.

Specifically, the Watertown biotechnology company said it will close its Gaithersburg, Md. office on Friday and reduce its workforce to 4 employees, down from 11. The layoffs include Jane Pritchett Henderson, the company's chief financial officer, and Graham P. Allaway, the firm's chief operating officer and co-founder.

In addition, Panacos said it hired Oppenheimer & Co. to advise the company on "strategic alternatives," including selling its HIV drug development programs or the entire company. HIV is the virus associated with AIDS.

Unless it strikes a deal soon, Panacos warned it may not be able to continue funding the firm's operations beyond the second quarter.

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bizjournals

Panacos Pharma shutters Gaithersburg office
Panacos Pharmaceuticals Inc. is shutting down its longtime Gaithersburg location to cut costs as it considers putting itself up for sale.

After a round of layoffs that included some Gaithersburg employees late last year, the then-33-employee company, based in Watertown, Mass., said it will shrink down to four people by the end of this week. Included in this latest round of departures this week is Graham Allaway, Panacos’ local chief operating officer who founded the Gaithersburg biotech that merged into Panacos in March 2005.

He joins three other major executives who are leaving the company this month, including the chief financial officer and chief medical officer.

Panacos also said it has hired Oppenheimer & Co. Inc. to help come up with strategic options, including the potential sale of the company or pieces of its HIV development portfolio. The company already sold its lead HIV treatment line, called bevirimat, to Myriad Pharmaceuticals Inc. last month in a $7 million deal.

If it doesn’t find buyers or partners soon, Panacos (NASDAQ: PANC) said it may not be able to survive past the second quarter of this year.

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[John2038]

natap

New HIV Drug Candidates in Pre-Clinical Development

There is yet little exciting news in this front but there were several pre-clinical HIV drug candidates reported at CROI. CMX157 is being developed by former GSK virologist Randall Lanier down the road in Durham, NC where he is trying to develop a more potent and safer tenofovir, he presented this first last Summer at the Resistance Workshop in Spain. At this time the most promising and timely help for patients with HIV drug resistance who need new therapies may come from PRO140 and perhaps Bevirimat, as well the Tanox monoclonal antibody drug Ibalizumab appears to have survived and has a new study on clinical trials.gov. PRO140 is an entry inhibitor and data from subcutaneous injection in patients was presented at CROI, and this drug appears potent and is moving ahead in studies in patients. Bevirimat , the maturation inhibitor, was recently sold to Myriad for $7 million from Panacos. Myriad told me they are planning a new bevirimat study to start soon, as well they have their own maturation inhibitors, and Panacos also has further bak in evelopment stages a second generation maturation inhibitor program. As well, both Myriad and Panacos have additional HIV drugs, I recall Panacos has an ora fusion inhibitor, all these are several years back in develoment.
 
TNX-355 survives Tanox: new Phase 2 Dose-Finding StudyStudy
TaiMed Biologics Inc. will conduct clinical trials of TNX-355 -- also known as Ibalizumab -- from a location on the West Loop near the former Tanox ... www.natap.org/2009/HIV/012809_01.htm


Hexadecyloxypropyl Tenofovir Associates Directly with HIV and Subsequently Inhibits Viral Replication in Untreated Cells

Background: CMX157 is a lipid conjugate of tenofovir (TFV). Compared to TFV, CMX157 is >300 times more potent against wild-type and NRTI-resistant HIV in vitro; it effectively penetrates isolated human peripheral blood mononuclear cells (PBMC), producing >30-fold higher intracellular levels of the active anabolite, TFV-diphosphate (TFV-PP). Since CMX157 has a lipid side chain and HIV has a lipid bilayer, it was postulated that CMX157 associates directly with virions. To test this hypothesis, purified HIV was incubated with CMX157 or TFV followed by quantification of virus-associated drug and determination of the tissue culture infectious dose (TCID50).
 
Methods: Concentrated HIV-1IIIB was incubated with 500 nM CMX157 or TFV for 2 hours, pelleted to remove unbound compound and lysed with 70% methanol. Supernatants were analyzed in triplicate using LC/MS/MS. Analytes were separated by gradient, reverse phase, ion-paring chromatography and detected by positive ion electrospray; separate viral aliquots were used to determine TCID50 by XTT, RT, and p24 assays. To assess the effect of exposure time, concentrated HIV-1IIIB was incubated with 500 nM CMX157 for 1, 15, 30, 60, and 120 minutes prior to TCID50. To determine the effect of drug dose, TCID50 was determined following a 15 minute incubation of virus with eight concentrations of CMX157 ranging from 0.039 to 125 nM. HDP-acyclovir was evaluated in parallel as a control.
 
Results: Analysis of purified HIV pellets following incubation with 500 nM drug showed ≈30,000 molecules of CMX157 were associated with each virion versus ≈100 molecules/virion for TFV. Incubation of HIV for 1 to 15 minutes with concentrations of CMX157down to 3.9 nM resulted in 3-4 fold decreases in TCID50. No inhibition of HIV replication was observed following incubation with TFV or the lipid control bearing the same alkyl modification as CMX157, HDP-acyclovir.
 
Conclusions: Overall, these results indicate that CMX157 associates directly with HIV and that this association enhances its antiviral activity in vitro. The most likely mechanism is direct targeting of CMX157 to the cell being infected; this has implications for treatment and prevention of HIV infection. Once inside the cell, CMX157 is presumably converted to TFV-PP which inhibits HIV replication via chain termination. CMX157 could have advantages over TFV via this mechanism of cell targeting as any HIV virion exposed to drug would carry CMX157 into any compartment or cell type it subsequently enters.


β-D-3'-Azido-2,6-diamino-2',3'-dideoxypurine Is a Potent Inhibitor of HIV-1 and Is Bioconverted Intracellularly to both AZD-TP and Its Guanosine-5'-triphosphate Form
 
Background: New antiviral nucleosides that are potent and safe are urgently needed. Recently, we showed that b-D-3'-azido-2',3'-dideoxyguanosine (AZG) is a potent and selective inhibitor of HIV-1 with a superior resistance profile compared to AZT. This discovery led to the synthesis and evaluation of 3'-azido-2,6-diamino-2',3'-dideoxypurine (AZD) and a 5'-monophosphate (MP) pro-drug of AZD.
 
Methods: We used a multi-disciplinary approach including medicinal chemistry, molecular virology, rational drug design, biochemistry, cellular pharmacology, HPLC-MS/MS, and enzyme kinetics to uncover the molecular mechanisms of anti-HIV-1 activity for AZD and its MP pro-drug.
 
Results: AZD was considerably more potent against HIV-1 in human peripheral blood mononuclear cells (PBMC) (EC50 = 0.07 mM) than previously reported in MT-4 cells (EC50 = 2 μM). Incubation of AZD in PBMC for 4 hours and subsequent HPLC-MS/MS analysis revealed low levels of AZD-DP and AZD-TP, but surprisingly high levels of AZG-DP and AZG-TP (ratio of AZD-TP to AZG-TP 1:167). The AZD-MP pro-drug showed greater potency (EC50 = 0.0031 mM) against HIV-1 in PBMC than AZD. This pro-drug increased the intracellular levels of AZD-TP in PBMC approximately 250-fold compared to the levels achieved with AZD and resulted in a reversal of the ratio of AZD-TP to AZG-TP (73:1). Computational evaluation of AZD paired with either T or C in a DNA duplex bound to HIV-1 reverse transcriptase (RT) indicated that AZD behaves like an A-analog rather than a G-analog.
 
Conclusions: AZD and its pro-drug can deliver both AZD-TP and AZG-TP intracellularly, each of which can inhibit HIV-1 RT. The combined delivery of chain-terminating 3'-azidopurine nucleotide analogs with different incorporation profiles (as A- vs G-analog) may improve the resistance profile of AZD. The potency and intracellular delivery of AZD-TP were substantially increased by phosphate pro-drugs of AZD.


Investigational New Drug-directed Development of IQP-0410, a Safe and Highly Potent Dual-acting Nonnucleoside Pyrimidinedione for the Therapy of HIV-1 Infection
 
Background: Drug cocktails combining NRTI and NNRTI and PI are the first-line treatment for HIV infection. The primary problems associated with anti-HIV therapy continue to be drug toxicity, drug-drug interactions, patient compliance with prescribed treatment regimens, and the appearance of drug-resistant viruses.
 
Methods: ImQuest Pharmaceuticals is developing IQP-0410, a highly potent nonnucleoside pyrimidinedione inhibitor of both HIV-1 and HIV-2. A comprehensive program of standard investigational new drug (IND)-enabling good laboratory practices (GLP) studies has been performed in order to establish the acute and multiple dose toxicity, toxico-kinetics, genotoxicity, and safety pharmacology profile of IQP-0410.
 
Results: Oral dosage of IQP-0410 administered via gavage, up to a maximum feasible dose level of 1000 mg/kg, was well tolerated in beagle dogs. There were no test article-related findings noted during the evaluation of in-life data, clinical pathology or necropsy data. Histopathology evaluation of selected tissues revealed no IQP-0410-related microscopic findings. Preliminary pharmacokinetics studies of IQP-0410 in dogs following oral administration demonstrated significant plasma concentrations of IQP-0410 at 24 hours on day 6, with an average of 37 ng/mL remaining. Cmax values for Day 1 ranged from 52 to 113 ng/mL and from 71 to 165 ng/mL on day 7 and the calculated EC95 value for IQP-0410 was 1 ng/mL. Thus the effective concentration of IQP-0410 was exceeded by 30- to 50-fold at 24 hours, indicating once per day dosage. Metabolic stability assays showed a high degree of liver microsome metabolism reaction phenotyping in human liver microsomes indicated that CYP3A4 is the major enzyme responsible for the metabolism of IQP-0410. Safety pharmacology studies (in vitro effects of IQP-0410 on the hERG channel current, neuropharmacological profile determination and pulmonary assessment in mice) showed no signs of pharmacological or toxicological activity. All genotoxicology testing of IQP-0410-including the Ames, Mouse Lymphoma, Bone Marrow Micronucleus, and CHO Chromosome Abnormality tests-were negative.
 
Conclusions: This favorable pre-clinical profile suggests that IQP-0410 will be an important addition to the currently available primary therapeutic regimens used to treat HIV. In addition, the activity of IQP-0410 against multi-drug resistant virus strains indicates a significant potential for use in salvage therapy.


Antiviral Active against Different Subtypes in vitro and Resistance Profile of 2 New HIV-1 Protease Inhibitors: CRS-074 and CRS-075
 
Background: CRS-074 and CRS-075 are 2 new PI with EC50 values of 0.5 and 50.0 nM, respectively. The aims of this study are to characterize the phenotypic and enzymatic antiretroviral activity against wild-type viruses from different HIV-1 subtypes, to investigate the resistance profile against protease inhibitor resistant (PIr) HIV-1 strains from different subtypes, and to describe in vitro selection of HIV-1 variants having increased resistance do CRS-074 and CRS-075.
 
Methods: Phenotyping assays were performed using a MT-4 cell-based MTT viability assay. A panel of 19 HIV-1 recombinant viruses was generated: 12 viruses from subtypes B and F carrying PIr mutations, and 7 others PI-susceptible, from subtypes B, C, and F. Recombinant HIV-1 protease from subtypes B, C, and F were expressed and its activity determined using a fluorogenic substrate. Selection experiments were performed in vitro by passaging HIV-1 strain NL4-3 into MT-4 cells, in the presence of increasing concentrations of CRS-074 or CRS-075. Viral RNA was extracted from selected viruses and the cDNA subjected to sequencing and viral load determination by quantitative polymerase chain reaction (q-PCR).
 
Results: Both drugs presented the same EC50 for different subtypes wild-type viruses (B, C, and F). The EC50 values of CRS-074 against resistant viruses varied from 1.0- to 510.0-fold higher than the EC50 for reference virus. For the CRS-075 these EC50 values varied from 0.2 to 64.1; while ritonavir (used as a reference drug) exhibited values from 1.2- to 666.7-fold. The Ki values obtained for CRS-074 (0.02 to 0.07 nM) and for CRS-075 (0.9 to 2.2 nM) were subtype independent. After 43 days, a viral variant carrying the mutation E34G was selected for the CRS-074. No mutations were found from the viruses under selective pressure of CRS-075, after 53 days in culture.
 
Conclusions: CRS-074 is one of most potent PI ever described (EC50 = 0.5 nM). Although CRS-074 presented high relative values of EC50 against resistant viruses, the absolute value of EC50 reached is still very low when compared to other PI against susceptible viruses. CRS-075 has an EC50 value comparable to the Food and Drug Administration-approved PI, moreover, CRS-075 highly effectiveness against resistant viruses demonstrated its potential as a future drug for second line therapy. Both drugs were highly active against the different HIV-1 subtypes circulating in Brazil.


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[John2038]

natap

A Single-dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of OBP-601, a Novel NRTI, in Healthy Subjects
--Festinavir was safe and well tolerated
--Festinavir plasma pharmacokinetics demonstrated dose-proportional relationship across the dose range studied in healthy men
--At doses ranging from 100 to 900 mg given once a day, the plasma concentration of Festinavir remained above the IC90 through the dosing period (24 h); QD dosing is anticipated
--Phase 1b to further evaluate safety, tolerability, PK, and antiviral activity of Festinavir is ongoing

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CMX157 Conjugate of tenofovir, prodrug: Hexadecyloxypropyl Tenofovir Associates Directly with HIV and Subsequently Inhibits Viral Replication in Untreated Cells



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Inhibitors of the RNase H Activity of Reverse Transcriptase as an Approach to New HIV-1 Antiretroviral Agents: Merck program
A novel series of HIV-1 RNase H inhibitors has been developed. A prototype inhibitor was shown to bind to two manganese ions in the RNase H active site of full length RT by X-ray crystallography. Systematic structure-activity studies around the core structure identified substituents which improved potency and selectivity in biochemical assays and antiviral activity in cell culture. An optimal compound from this work, inhibitor 5, showed good potency and selectivity in biochemical assays (RT RNase H IC50 = 0.045 uM, RT Polymerase IC50 = 13 uM; Integrase Strand Transfer IC50 = 24 uM) and antiviral effects in cell culture (IC50 = 0.19 uM) with a 17-fold window with respect to cytotoxicity (CC50 = 3.3 uM).

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Summary from CROI for Hepatitis Coinfection - What are the challenges and how can we improve outcome of Hepatitis coinfection in HIV-Infected Patients?
• HIV/HBV coinfected patients receiving a tenofovir-containing regimen are most likely to become undetectable for HBV-replication (>98%)
• In the few HIV/HBV coinfected patients with ongoing HBV replication despite prolonged tenofovir therapy no clear HBV relevant mutation has been described so far. The development of polymorphisms not associated with HBV resistance however, has been observed
• A first case report suggests anti-HIV activity of telbivudine which however has not been confirmed in comprehensive in vitro studies. Close monitoring of telbivudine treated HIV/HBV patients not on HAART is warranted
• First cohort data suggests that higher HCV viral load levels may have a significant negative impact on overall survival and liver disease related death
• Although these findings need to be confirmed clinicians should pay attention to HCV viral load in the setting of HIV/HCV coinfection
• In a subset of patients with HIV/HCV coinfection successful HAART is accompanied by an improved HCV specific T-cell response which may lead to lower HCV viral load levels
• Early virological response (negative HCV-RNA at week 12) is associated with the best treatment outcome under peg-IFN/RBV therapy

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High HCV Is Associated with an Increased Risk for Mortality in HIV/HCV-co-infected Individuals
Background: The influence of hepatitis C virus (HCV) RNA level and HCV genotype on HIV or HCV disease progression is still unknown. These factors were investigated in HIV/HCV-co-infected individuals from the EuroSIDA cohort
 
Methods: Serum HCV RNA level and HCV genotyping was determined in all HCV antibody-positive samples from the EuroSIDA cohort. Poisson regression analyses were used to investigate progression to death from any cause or from liver-related disease and compared between HCV-viremic (low <500,000 IU/mL and high =500,000 IU/mL) and aviremic patients (HCV RNA <615 IU/ml) and comparing genotypes 1-4. Models were adjusted for data source (analysis from central sample repository or data from clinical site), gender, HIV-transmission category, region of Europe, HBV-co-infection, race, prior AIDS diagnosis, age, CD4 at genotype testing, date recruited to EuroSIDA, type of ART, and date of HCV genotype testing.
 
Results: HCV viral load was determined in 1952 HIV/HCV antibody-positive subjects. 1537 patients (78.7%) showed detectable HCV RNA >615 IU/mL; of these, 821 (53.1%) had an HCV RNA =500,000 IU/mL. Incidence rates (per 100 person-years of follow-up) and adjusted incidence rate ratios for death and liver-related death are shown in the table. Compared to patients with low HCV RNA, viremic patients had a similar incidence of death and liver-related death while patients with high HCV RNA had a significantly increased incidence of death and liver-related death after adjustment (see slides below). Of the 1537 HCV RNA-positive patients, 800 (52.0%), 53 (3.4%), 466 (30.3%), and 218 (14.2%) were genotypes 1-4, respectively. The figure shows the adjusted IRR for death and liver-related death. After adjustment, genotypes 2 and 3 had a lower incidence of death, statistically significant for genotype 3. A similar pattern was seen for liver-related death, although it did not reach statistical significance, possibly due to limited power.

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A Pilot Study to Determine the Effect on Dyslipidemia of the Addition of Tenofovir to Stable ART in HIV-infected Subjects: Results from A5206 Study Team v
The addition of TDF to existing virologically-suppressed ART regimens improved lipid parameters, supporting an independent lipid-lowering effect of TDF.
 
The mechanism of the lipid-lowering effect and potential rebound effect of increased TG with discontinuation of TDF warrants further study.

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[John2038]

natap


Single Dose Tenofovir Disoproxil Fumarate (TDF) with and without Emtricitabine (FTC) in HIV-1 Infected Pregnant Women and Their Infants: Pharmacokinetics (PK) and Safety
No significant maternal or infant adverse events were observed with the administration of 900 mg of TFV to HIV-infected pregnant women and 4 mg/kg TDF oral suspension to their infants.
 
Single dose TDF administration results in CB/M ratios of approximately 65% regardless of maternal dose.
 
There was a trend to lower AUC (<38%) and Cmax (<62%) in women delivering by VD (n=9) compared to CS (n=6) but sample size was small resulting in limited power.
 
TFV Cmax increased by 83% compared to 600 mg dosing but AUC was similar.
 
TFV exposures were lower in infants suggesting either altered absorption or more rapid clearance.
 
Single dose TDF did not result in detection of the K65R mutation in the 8 women who were assessed for resistance. However, the remaining 8 women and all of the infants had undetectable levels of viremia that precluded resistance testing.

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Cardiovascular complications 16th CROI - written by Pablo Tebas, MD University of Pennsylvania
A few studies suggest that HIV infection per se is associated with an increased risk of cardiovascular disease. These studies used surrogate markers of atherosclerosis, like coronary artery calcium (OR = 2.7 for worse calcium scores among HIV positive individuals, after adjusting for traditional risk factors)13, and arterial elasticity (individuals with untreated HIV infection had lower levels of eleasticity than HIV negative individuals after adjusting for traditional risk factors)14
 
The ACTG study presented a small study (17 patients, ACTG study # A5206) showing that tenofovir (TFV) has lipid lowering properties independent of its anti HIV properties, maybe explaining some of the results seen in studies like Gilead 903 and switch studies that have showed improvements in lipids when individuals start tenofovir compared to other nucleoside analogs. In this ACTG study, the addition of TDF to existing virologically-suppressed ART regimens improved lipid parameters -LDL-C (-12%), TC (-16%), non-HDL-C (-16%). The intervention had little effect on triglycerides. The mechanism/s by which tenofovir has these lipid lowering effects is not clear15.
 
The results of ACTG protocol A5209 were also presented, showing that Ezetimibe (Zetia) was well tolerated as an add on drug to 44 patients receiving a statin for managing their cholesterol, with a clinical safety profile similar to that of placebo, and that adding ezetimibe to ongoing statin therapy resulted in significant reductions in LDL-C (-14%), TC (-19%), non-HDL-C (-23%), and Apo B (-9%)16.

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[John2038]

natap


Back to Basics: the science at CROI focuses on the tough questions that remain in HIV pathogenesis

Is replication completely stopped by ART?
 
As the Bernard Fields lecturer in virology, Bob Siliciano opened the 16th CROI with a discussion of HIV persistence. Siliciano (abstr. #16) began by reviewing the decay of plasma viremia upon the initiation of therapy: 1) the rapid initial decay that is thought to reflect the interruption of viral infection and production by activated cells of short lifespan that produce most of the plasma virus, which is also short-lived, 2) a second slower phase of decay which was thought to originate in long-lived cells such as macrophages, but is not apparent when antiretroviral therapy (ART) includes an integrase inhibitor, perhaps due to the efficacy of this new class of drug in both resting and activated cells, and 3) the slow or negligible decay of infection in persistently infected resting CD4 T cells.

...

The effect of ART on persistent HIV

Maldarelli and colleagues at the NCI performed an additional intensification study to probe the ability of ART to affect low-level viremia (abstr. 423b). As they have with lopinavir/ritonavir, atazanavir/ritonavir, and efavirenz, they conducted a trial of treatment intensification with raltegravir in patients with plasma HIV-1 RNA <50 copies/mL but residual viremia =1 copies/mL. Five patients added raltegravir (RAL) 400 mg twice daily to their therapy for a 30-day intensification period. The level of residual viremia before intensification (median, 1.9 copies/mL plasma) was similar to that found in prior studies of patients on standard combination therapy. Overall, the median plasma HIV-1 RNA level during RAL intensification (3.2 copies/mL) was not different from the median pre-intensification level (p = 0.72), but ranged from 0.1 copies/ml to 10 copies/ml.
 
No significant decreases in HIV-1 RNA levels were observed during drug intensification in individual patient analyses. So short-term intensification (ie. 30 days) with a new (to the patient) and potent RT inhibitor, protease inhibitor, or integrase inhibitor does not affect low-level viremia. It seems unlikely that drug compartment issues could explain the lack of effect of drugs of three different classes. In small published and unpublished studies, my research group has also seen no such effect using an entry inhibitor (enfuvirtide). Therefore, the cells from which this viremia emanates must have a half-life of much longer than 30 days.

...

Where and how does HIV persist

Wightman and colleagues (abstr. 416) measured the effect of ART on HIV DNA persistence within naïve CD4 T cells that had recently left the thymus, and distinguished by the surface marker CD31. It has been previously established that most latently, persistently infected CD4 cells are within the memory subset, but infection of naïve cells may occur. 10 patients were followed after ART initiation over 18 months. HIV DNA within cell populations was measured by real time PCR, adjusting for cell equivalents by the parallel quantitation of CCR5.
 
All patients sustained HIV RNA <50 copies/mL within 6 months. CD4+ cells increased overall, with naive cells increasing by 8% and the memory population decreasing by 12%. The percentage of CD31+ naive cells did not change, consistent with both a thymic and peripheral contribution to the naive CD4 T cell increase. As expected, HIV DNA content was higher in memory CD4 T cells than in CD31+ or CD31- naive cells. However, after ART HIV DNA declined significantly in memory cells but was stable in naïve cells. The authors concluded that "infected" naive CD31+ or CD31- CD4 T cells represent a very stable reservoir on ART. However, as mentioned above, the presence of HIV DNA is not equivalent to the presence of latent, replication-competent HIV. It remains to be proven if naïve cells are a more stable site of persistent HIV infection.

...

A new strategy to purge persistent HIV

Gisslen and colleagues (abstr. 88) presented provocative findings suggesting the IV immunoglobulin therapy could reduce the frequency of latent HIV-1 infection. Like many great ideas in medicine, this trial was sparked by a clinical observation: a patient on ART was treated with IV Ig for an autoimmune disease, stopped ART, and remained aviremic for several months. The idea was that the mild immune and complement activation induced by IV Ig might ignite replication of latent HIV, and its clearance.
 
9 subjects on ART were treated with 30 gm IV Ig for 5 days. Highly purified resting memory CD4+ T cells were isolated and activated, and replication-competent HIV-1 was quantified. Replication-competent HIV-1 was detected in resting T cells in 7 of the 9 subjects. IVIG was said to decrease the frequency of resting CD4 cell infection by more than 68% during the study period (8 to 12 weeks) in 5 of 9 subjects. The investigators also observed a transitory increase in plasma HIV-1 RNA using a sensitive assay (LOD 2 copies/ml), and in increase in serum IL-7 levels.
 
This study was provocative and interesting, especially given the safety record of IV Ig. However, the frequency of resting cell infection appeared to vary over a range of 50 to 0.1 per million in the patients studied, and the quantitative measurements of infection could not be explained by the presenter. It was not clear how many replicate cultures were studied, and what quantitative change in viral recovery led to the conclusion that resting cell infection had decreased three-fold. These findings would need to be clarified, but if shown to be credible the further testing and validation of this pilot study might be worthwhile.


Overall, these presentations at CROI offered an exciting and detailed new picture of persistent HIV infection in patients on ART. The picture requires further clarification, as by some measures current ART has achieved its functional limit, but by others improvements in antiviral activity, either in hidden cells or hidden anatomic compartments, might improve its effectiveness. It appears to be more and more practical to achieve and maintain full suppression of HIV viremia in more and more people across the globe. But further advances in therapy that might achieve eradication of persistent HIV infection remains an elusive goal.


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[John2038]

liebertonline

Raltegravir and Etravirine Are Active against HIV Type 1 Group O
The activity of raltegravir and etravirine was assessed in vitro in HIV-1 group O isolates. Despite the presence of some natural polymorphisms associated with resistance to raltegravir (V72I, L74I, S153A, V201I, and T206S) and etravirine (G190A), both drugs showed significant antiviral activity. Subsequently, the clinical benefit was shown in an HIV-1 group O-infected individual in whom enfuvirtide was replaced by raltegravir. Therefore, individuals infected with HIV-1 group O might benefit from raltegravir and/or etravirine therapy.

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ingentaconnect

Hazardous drinking is associated with an elevated aspartate aminotransferase to platelet ratio index in an urban HIV-infected clinical cohort

Objectives:
The aim of the study was to determine the relationship between alcohol consumption and liver fibrosis as assessed by aspartate aminotransferase to platelet ratio index (APRI) in HIV-infected adults and to explore the relative contributions of alcohol and hepatitis C virus (HCV) to APRI among HIV/HCV-coinfected adults. Methods

We performed a cross-sectional analysis of data from an observational clinical cohort. Alcohol consumption was categorized according to National Institute on Alcohol Abuse and Alcoholism guidelines. We defined significant liver disease as APRI>1.5, and used multinomial logistic regression to identify correlates of increased APRI. Results

Among 1358 participants, 10.4% reported hazardous drinking. It was found that 11.6% had APRI>1.5, indicating liver fibrosis. Hazardous drinking was associated with increased APRI [adjusted relative risk ratio (RRR) 2.30; 95% confidence interval (CI) 1.26-4.17]. Other factors associated with increased APRI were male gender, viral hepatitis, and HIV transmission category of injecting drug use. Among coinfected individuals, 18.3% had APRI>1.5, and hazardous drinking was not associated with APRI. Among non-HCV-infected individuals, 5.3% had APRI>1.5 and hazardous drinking was associated with increased APRI (adjusted RRR 3.72; 95% CI 1.40-9.87).

Conclusions:
Hazardous drinking is an important modifiable risk factor for liver fibrosis, particularly among non-HCV-infected patients. Clinicians and researchers must address alcohol use as the burden of liver disease increases among HIV-positive individuals.

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Effect of nucleoside reverse transcriptase inhibitors on CD4 T-cell recovery in HIV-1-infected individuals receiving long-term fully suppressive combination antiretroviral therapy

Objective:
The aim of the study was to determine the effect of nucleoside reverse transcriptase inhibitors (NRTIs) on CD4 recovery in HIV-1-infected individuals receiving long-term suppressive combination antiretroviral therapy (cART). Methods

A retrospective cohort study was carried out. The mean time-weighted CD4 change from baseline was determined at weeks 48, 96 and 144: its associations with exposure to NRTIs were assessed using linear regression. Results

One hundred and five patients were included. Their median baseline CD4 count was 225 (interquartile range 91-362)?cells/µL. A trend of greater CD4 change from baseline was observed for individuals who at baseline had CD4 counts >200?cells/µL (138 vs. 113, 176 vs. 134 and 204 vs. 173?cells/µL), or were =40 years old (136 vs. 118, 182 vs. 150, 208 vs. 174) at weeks 48, 96 and 144, respectively; however, all P-values were >0.05. Lower CD4 increases were observed in patients exposed to didanosine (ddI) or a combination of ddI and stavudine, although the difference was not statistically significant. For patients that commenced cART with CD4 count =200?cells/µL, a trend towards a CD4 count response <250?cells/µL at weeks 48, 96 and 144 was observed in patients receiving zidovudine.

Conclusion:
Exposure to different NRTIs in initial cART was not significantly associated with variable rises in CD4 cell count. However, these findings need to be confirmed in larger studies.

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aidsmap

Swiss court accepts that criminal HIV exposure is only 'hypothetical' on successful treatment, quashes conviction
In the first ruling of its kind in the world, the Geneva Court of Justice has quashed an 18 month prison sentence given to a 34 year-old HIV-positive African migrant who was convicted of HIV exposure by a lower court in December 2008, after accepting expert testimony from Professor Bernard Hirschel – one of the authors of the Swiss Federal Commission for HIV / AIDS consensus statement on the effect of treatment on transmission – that the risk of sexual HIV transmission during unprotected sex on successful treatment is 1 in 100,000.

The case began in Lausanne in 2007, when a court sentenced the HIV-positive man, originally from the Democratic Republic of Congo, to a suspended 28-month sentence for having unprotected sex without disclosing his HIV status to a female complainant. Although the woman was not infected, Article 231 of the Swiss Penal Code allows prosecutions against HIV-positive individuals for having unprotected sex, with or without disclosure. Individuals can also be prosecuted under Article 122, for “an attempt to engender grievous bodily harm”.

Deborah Glejser of Swiss civil society organisation, Groupe SIDA Geneve, told aidsmap that although the law allows for prosecutions for unprotected sex even when disclosure has taken place, in practice, prosecutions for HIV exposure only take place when there is no disclosure, and that a suspended sentence is the norm.

A second complaint last year led to the man standing trial again in Geneva in November 2008. According to a report in The Geneva Tribune, an expert medical witness had testified that although treatment greatly reduces the risk of transmission, there remained a residual risk.

Although the man's lawyer, Nicole Riedle, had entered the statement by the Swiss Federal Commission for HIV / AIDS into evidence, and Geneva's deputy public prosecutor, Yves Bertossa, had wanted to suspend the hearing in order to consult with them, the lower Geneva court declined to accept any further evidence. Since this was the man’s second conviction, he was sentenced to 18 months in prison in December 2008.

In January, Mr Bertossa told the Geneva Court of Justice that he was persuaded by the Swiss Federal Commission for HIV / AIDS that the risk of transmission for an HIV-positive individual on successful treatment was less than 1 in 100,000 and that under the circumstances he wanted to drop the charges.

On Monday, the Geneva Court of Justice acquitted the man, who was freed after spending almost three months in prison.

Significantly, it was Geneva’s deputy public prosecutor, Yves Bertossa, who called for the appeal. He told Le Temps that despite the fact that there is a still some debate regarding the residual risks of transmission in people on successful treatment this should not influence justice: "One shouldn't convict people for hypothetical risks,” he said.

Professor Hirschel told aidsmap that he was very pleased with the outcome. It was, he said, the main reason that he and his colleagues were motivated to issue their January 2008 statement.

Deborah Glejser added that Monday’s ruling suggests that in Switzerland effectively treated HIV-positive individuals should no longer be prosecuted for having unprotected sex. Having already been contacted by advocates from around the world, she hoped that this ruling will have consequences for other jurisdictions that have HIV exposure laws.

Last May, a five member US Court of Appeals for the Armed Forces panel discussed the effect of treatment on transmission following the appeal of an HIV-positive soldier who had previously pleaded guilty to HIV exposure following unprotected sex with two women without disclosing his HIV status. Although the majority did not agree, and did not allow the accused soldier’s guilty plea to be set aside, two members of the panel found the medical expert’s testimony – that it was highly unlikely that the soldier could have infected either women because of his low viral load – valid enough to question HIV exposure laws.

And last July, a Canadian court explored the Swiss statement following a submission from Clato Mabior’s defence team that at the time he had unprotected sex with six women without disclosing his HIV status to them, he did not believe he was infectious. Although expert testimony concluded that Mr Mabior may have been uninfectious for some of the time, this was not enough to convince the judge, who noted that neither the CDC nor WHO/UNAIDS agreed with the Swiss, and that the crimes of which Mr Mabior was accused took place prior to their being any public statement on the effect of treatment on transmission.

Following Monday’s ruling, however, Geneva’s deputy public prosecutor, Yves Bertossa, believes it is only a matter of time before other jurisdictions realise that prosecutions for HIV exposure should not take place when the accused is on successful antiretroviral therapy. He told Radio Lac: “There are some medical advances which can change the law. I think that in other [parts of Switzerland] or in other countries, the same conclusions should apply to their laws.”

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HIV doesn't increase risk of melanoma, but immune suppression associated with risk of rarer skin cancers
HIV-related immune suppression does not increase the risk of melanoma, one of the most common types of skin cancer, American investigators report in the January 23rd edition of AIDS. However, they did find that AIDS patients had a higher risk of developing two rare skin cancers, Merkel cell carcinoma and appendageal carcinomas. The investigators believe that their results “suggest a need for guidelines aimed at the prevention and early detection of skin cancers in HIV-infected individuals.”

HIV-positive individuals with suppressed immune systems have an increased risk of developing cancer. The most important cancers seen in people with HIV are related to infections, for example Kaposi’s sarcoma (due to HHV-8), non-Hodgkin’s lymphoma (due to Epstein-Barr virus) and anogenital cancers (caused by certain strains of human papilloma virus).

Infection-related cancers also occur more often in organ recipients who have been treated with immunosuppressive drugs. Increased rates of skin cancer, most notably melanoma have also been observed in this group of individuals. Aggressive melanomas have also been reported in people with HIV. Increased exposure to UV radiation from the sun and immune suppression have been suggested as possible causes. Furthermore, there is also some evidence that people with HIV have an increased prevalence of rarer skin cancers, such as Merkel cell carcinoma and appendageal carcinomas.

To gain a better understanding of the risk of skin cancer amongst HIV-positive patients who had been diagnosed with AIDS, US researchers designed a study that compared the risk for AIDS patients of three cancers (melanoma, Merkel cell carcinoma and appendageal carcinomas) with the risk for the general population.

Their study population was derived from the HIV/AIDS Cancer Match study that links HIV and general cancer registry databases in nine US states. Just under 400,00 HIV-positive patients diagnosed with AIDS between 1980 and 2004 were included in the analysis. The investigators checked these databases for cases of cancer of the skin in the five years before and the five years after AIDS was diagnosed.

Results showed that patients with AIDS had a 30% increase in the risk of developing melanoma. This increased risk did not reach statistical significance. Nor did the risk of melanoma increase over time as a patient’s immune system weakened and CD4 cell count declined, suggesting to the investigators that the modest elevation in risk of this cancer they observed was not related to immune deficiency.

White gay and other men who have sex with men were the group most likely to develop melanoma (odds ratio, 1.7, 95% CI 1.2-2.4 vs. other groups). Exposure to UV radiation was identified as an independent risk factor for melanoma (p = 0.0005).

The investigators suggest that the modest increase in the risk of melanoma seen in gay and other men who have sex with men with AIDS was most likely due to “recreational sun exposure or the use [of] tanning beds.” They also suggest that the increased surveillance of this population for Kaposi’s sarcoma could have increased the detection rate of early melanoma lesions.

However, patients with AIDS were significantly more likely to be diagnosed with both Merkel cell carcinoma (standardised incidence ratio [SIR] = 11, 95% CI 6.3-17) and appendageal carcinomas (SIR = 4.2, 95% CI 2.5-6.7). Both these cancers were, however, rare (17 cases each of Merkel cell carcinoma and appendageal carcinomas compared to 292 cases of melanoma).

Gay and other men who have sex with men had a higher risk of appendageal carcinomas than other groups (SIR = 6.8, 95% CI 3.6-12). As with melanoma, the risk of this cancer was associated with increased levels of exposure to UV light.

Risk of appendageal carcinoma also increased with increasing time (p = 0.03), suggesting an association with immune suppression.

The greatly increased risk of Merkel cell carcinoma in people with AIDS suggested to the investigators that “immunological mechanisms” were an important risk factor. They note “Merkel cell carcinoma risk is also elevated among immunosuppressed transplant recipients.”

The investigators conclude, “the greatly increased risk of Merkel cell carcinoma and appendageal carcinomas…among people with AIDS points to immunosuppression as a major risk factor for these cancers.”

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pattayadailynews

PATTAYA - HIV POSITIVE ROBBER HAD UNSAFE SEX WITH MORE THAN 20 WOMEN VICTIMS
At 2.00 am on 25th February 2009, Miss Tarunya Setawaree from U-dorn Thani informed Pattaya Deputy Investigator, Pol.Lt. Somchai Chaikananukul, that she had found a snatcher who robbed her on the 9th January 2009, hanging around in Soi 9, Pattaya Second Rroad. A police team was despatched to investigate.

At the scene, Miss Tarunya indentified Mr. Sirichat Tanomsook, residing at 1/4 Moo. 8, Maichieng, Cha Wang, Nokornsrithamamrat. Police arrested him immediately.

The suspect, who was taken totally by surprise, said he had suffering from the final stages of HIV/Aids and he needed money to pay for his treatment.

After checking his record, police found he had a long history of robbery. He speaks very good English because he used to work in a boat trip service and on several occasions had pretended to be a Prince from the Middle East to impress many women in Pattaya, including bar girls and high society women..

He confessed that most of the time he had sex with his victims without using condoms and robbed them after having sex. Many of these women had reported their cases to the police.

According to Tanomsook more than 20 victims have had sex with him without knowing he was HIVpositive.

He has been charged with robbery.



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nasdaq

FDA Says Ranbaxy Falsified Some Drug Application Data
WASHINGTON -(Dow Jones)- The Food and Drug Administration said Wednesday that a manufacturing plant owned by Ranbaxy Laboratories Ltd. (500359.BY) falsified data and test results in approved and pending drug applications.

The agency said it was halting the review of drug applications made at Ranbaxy's Paonta Sahib plant in India.

Last September, the FDA banned Ranbaxy from importing more than 30 generic drugs into the U.S. because of serious manufacturing violations it found at two company plants in India, including Paonta Sahib. Such drugs include generic versions of the popular cholesterol-lowering drug Zocor and the heartburn treatment Zantac.

The FDA said it hasn't identified any health problems with drugs made at the Paonta Sahib site and said consumers shouldn't stop taking medications made by Ranbaxy. "To date the FDA has no evidence that these drugs do not meet their quality specifications," the agency said in a statement.

Ranbaxy, based in India and among the world's biggest generic-drug makers, is facing investigations by the U.S. Justice Department and the FDA into whether it manufactured substandard generic drugs, including allegations that it made weak or adulterated HIV drugs given to thousands of AIDS patients in Africa.

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[John2038]

natap

Lopinavir/ritonavir+Tenofovir/Emtricitabine Is Superior to Nevirapine+Tenofovir/Emtricitabine for Women with prior Exposure to Single-dose Nevirapine: A5208 ("OCTANE")

At entry, median values were as follows: age 31 years, CD4 139 cells/mm3, HIV-1 RNA 5.15 log10 copies/mL, time since last sdNVP use 17 months, and duration of follow-up 73 weeks.
 
All women recalled sdNVP use; 73% had written documentation that sdNVP was provided. Significantly more women in the NVP arm (31, or 26%) than the LPV/r arm (10, or 8%) reached the primary endpoint (p = 0.0007). Of these, 36 had virologic failure (27 in NVP, 9 in LPV/r arm); 5 died without preceding virologic failure (4 in NVP, 1 in LPV/r arm). None of the 5 deaths were reported to be treatment-related. The difference between the NVP and LPV/r arms appeared to decrease with increasing time between last sdNVP exposure and ART initiation. Among women starting ART 6 to <12 months after sdNVP, 15 (37%) and 1 (3%) in the NVP and LPV/r arms, respectively, reached the primary endpoint, vs 12 (26%) and 6 (12%) when last sdNVP exposure was 12 to < 24 months prior, and 4 (12%) and 3 (10%) when last sdNVP exposure was =2 years prior. Baseline genotypes, run retrospectively in 239 women, showed NVP resistance in 33 (14%; K103N in 28 of 33); of these 33, 11 of 15 (73%) in the NVP arm reached the primary endpoint vs 1 of 18 (6%) in the LPV/r arm. Among the 206 women without baseline NVP resistance, 18% (NVP arm) vs 9% (LPV/r arm) reached the primary endpoint. More women (15, 12%) discontinued NVP due to adverse events than LPV/r (1, 1%).





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No Association of Abacavir (ABC) Use with Risk of Myocardial Infarction (MI) or Severe Cardiovascular Disease Events (SCVD): Results from ACTG A5001/ALLRT
In contrast to D:A:D and SMART, we did not find a significant association between recent ABC use and MI or SCVD risk for ART-naïve pts randomized to an initial ABC regimen. Our results suggest the association with recent ABC use in other studies may be a marker for other factors not discerned in their analyses.

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Progression of High-grade Anal Intraepithelial Neoplasia to Invasive Anal Cancer among HIV+ Men Who Have Sex with Men
Both intra-anal and peri-anal HGAIN have potential to progress to invasive anal cancer. Carefully controlled clinical trials are needed to evaluate screening and treatment of HGAIN in HIV+ MSM to prevent anal cancer.

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Prevalence of Cervical Cancer Screening Among HIV-Infected Women in the United States: 23% Did Not Receive Pap tests within last year
HIV care providers should ensure that annual Pap tests are performed for women of all ages who have low CD4 cell counts or receive gynecologic care elsewhere. Integrating HIV and gynecologic care and educating clinicians about Pap screening recommendations for HIV-infected women may increase screening among this population.

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Serious Fatal and Non-fatal Non-AIDS-defining Illnesses in Europe: most common no-AIDS events malignancies/CVD/liver in EuroSida
Non-AIDS-defining illnesses were more common than AIDS-defining illnesses in the combination ART era, have considerable mortality, and should be routinely reported in clinical trials and observational studies. The risk factor profile for non-AIDS-defining illnesses was diverse with multiple potentially modifiable immunodeficiency and lifestyle-related risk factors. Evidence on the influence of modifying these factors on the risk of non-AIDS-defining illness is an important but unmet research need.




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Causes of Death in Patients Treated with ART (IDUs vs non-IDUs), 1996 to 2006: Collaborative Analysis of 13 Cohort Studies
To achieve further declines in mortality rates among patients treated with ART, causes of non-AIDS death must be addressed. Such causes are of particular importance in patients infected via IDU.



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Relationship between Current Level of Immunodeficiency and Non-AIDS-defining Malignancies, EuroSida: "Immunosuppression ...current CD4 count....was associated with an excess risk of NADM"
Immunosuppression was associated with an excess risk of NADM. One possible explanation is enhanced oncogenic potential by pro-oncogenic viruses (e.g., human papillomavirus and anal cancer). An infectious oncogenesis has only been established for a few of NADM linked with immunosuppression in this study and other mechanisms may also contribute. As the immunosuppression may be reversed by cART, HIV is a suitable candidate model for improving our understanding of how immunosuppression affects oncogenic transformation.



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Infection-related Non-AIDS-defining Cancer Risk in HIV-infected and -uninfected Persons: Increased Rates in HIV+ vs HIV-negatives in Kaiser
HIV+ persons have an elevated risk of non-AIDS-defining cancers, particularly infection-related which comprised almost half of all the non-AIDS-defining cancers in this population. The increased risk of non-AIDS-defining cancers in HIV+ persons has not changed much during the ART era.



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New HIV Agents

GS 9350
Gilead Sciences obviously has incredible motivation to develop an alternative booster to RTV. The Gilead integrase inhibitor, elvitegravir, has to be given with RTV boosting. Elvitegravir has fallen behind in development compared to raltegravir, which is already approved and there has been some reluctance to studying the elvitegravir in treatment naïve patients if it has to be given with low dose RTV. At 16th CROI Brian Kearney from Gilead presented the first human data on their pharmacologic or pharmacokinetic enhancer (PKE) GS 9350[1]. The presentation was remarkably well organized, answering one by one many of the questions one would have about an alternative non-RTV PKE and addressing some of the drawbacks to RTV listed above.
..

SPI 452

Sequoia Pharmaceuticals also presented data on a non-RTV PKE[2]. This drug also does not have anti-HIV activity in vitro and is a potent preferential inhibitor of CYP3A in human liver microsomes. First in human studies demonstrated that SPI 452 had a long half life and the compound had the ability to substantially increase saquinavir concentrations with a single dose of each drug.
 
In a second study, single doses of the protease inhibitors darunavir or atazanavir or PI placebo were given, followed by washout and then 15 day dosing of one of 3 once daily doses of SPI 452 (50, 100, 200 mg) plus a SPI 452 placebo arm. On days 15 and 16 the protease inhibitors were dosed again. Boosting of either DRV or ATV was substantial and appeared similar to the boosting effect seen with 100 mg of RTV though no RTV control arm was included in the study. The boosting effect lasted even one day after the PKE was stopped (Day 16). SPI 452 appeared to be fairly well tolerated though there were GI side effects recorded and differences with PCB were not displayed. The changes in triglycerides and LDL cholesterol were not significant over 14 days compared to placebo. As yet his compound has not been formulated as a tablet, though formulation work is ongoing.
..

PRO-140 subcutaneous Infusion
 
PRO-140 is a humanized monoclonal antibody to human CCR5 that has previously been shown with single dose IV infusions to lower HIV RNA substantially in patients who have R5 virus by the standard tropism assay.[3] The highest dose decreased plasma HIV RNA by a mean of 1.83 log10 copies/mL and was generally well tolerated. However IV infusion would be cumbersome and more feasible means of administration are being explored. At 16th CROI Melanie Thompson presented new data with PRO 140 administered for up to 3 doses by subcutaneous infusion (that's right infusion, not injection)[4]. Three dosing schemes were tried 1) 162 mg SQ weekly on day 1, 8 and 15, 2) 324 mg SQ on day 1 and 15 and 3) 324 mg SQ weekly on day 1, 8 and 15 and an arm with weekly placebo infusions. The highest dose given weekly produced a mean peak reduction in VL of 1.65 log10 and an antiretroviral effect of a mean 1 log10 decrease persisted for 2 weeks following the last infusion. Side effects were minimal with short lived infusion site reactions in a minority of patients. The investigators hope that given the long half-life of this humanized monoclonal that perhaps an initial loading dose would allow for a twice weekly infusion dosing regimen.
 
Realistically though PRO-140 will still have at least 2 disadvantages. Firstly it is still a CCR5 inhibitor and therefore will only be useful in about 50% of patients who are highly treatment experienced and its mode of administration might restrict its use to this group, i.e. advanced patients. Secondly the patients will still need to have an assay result to show if they indeed have R5 virus. An oral R5 inhibitor has already been approved in the US and the uptake of maraviroc has been slow.
..

Where are the Maturation Inhibitors?
 
HIV-1 maturation inhibitors were going to be the next new agents that worked by a novel mechanism. These agents bind to the gag protein and prevent proteolytic cleavage of the gag poly-protein in a mechanism distinct from protease inhibitors. Bevirimat, which is the first agent in this class, has been in Phase IIa development (short term studies to demonstrate proof of principle and obtain initial dose ranging information)[5]. However recent data suggest that a substantial subset of subtype B variants and perhaps the majority of subtype C variants have intrinsic resistance to bevirimat based on gag polymorphisms around the bevirimat binding site[6]. Panacos stopped development of Bevirimat and this agent was picked up by Myriad Pharmaceuticals who plan to continue development. There were no new data on bevirimat at CROI but Myriad did have some preliminary data on other maturation inhibitors. Their inhibitor that is farthest along, MPC-9055, also bind to gag poly-protein at the capsid-SP1 cleavage site. This agent is active in vitro at nanomolar concentrations[7] and had activity across multiple HIV-1 sub-types including sub-type C (2 variants), which may indicate that this drug will be active against variants with gag polymorphism that reduced bevirimat activity, though such variants were not directly tested. A single point mutation at codon 364 (which is at the cleavage site) results in resistance and this mutation was selected for in vitro. This mutation also conferred resistance to bevirimat[8]. A single dose study in HIV uninfected volunteers demonstrated that it was orally bioavailable with a long half life[9]. There appeared to be some mild GI side effects with this single dose. How the concentrations achieved related to the inhibitory concentrations for the virus were not clearly defined. In summary development of maturation inhibitors continues to move forward but given development time lines it will be several years before these agents reach late stage clinical development if indeed they can pass the phase IIB hurdle of activity and safety with dosing greater than 7-14 days.

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Resistance Report

1. Resistance to Protease Inhibitors
Oral Session 18 contained a number of presentations relating to fundamental mechanisms of drug resistance. First, in Abstract 65LB, Celia Schiffer and colleagues documented that protease inhibitors (PIs) could potentially be designed that would interact with the active sites of the HIV-1 protease (PR) in such fashion as to preclude the development of drug resistance. This work was initiated on the basis of crystal structure analysis of HIV-1 PR and its ability to bind to specific protease inhibitors. The results indicated that a number of inhibitors could bind to PR notwithstanding the presence of a number of classical mutations that are associated with resistance to many other members of the PI family of drugs. Results were confirmed on the basis of phenotyping analysis to demonstrate that many of these inhibitors possessed high level potency against a panel of resistant viruses. These results validate approaches based on efforts to specifically design novel PIs that are able to fit within the substrate envelope of PR and give hope that more robust PIs will be developed in the future that will less susceptible to problems of resistance.
..

2. Resistance to NRTIs/NtRTIs
In Abstract 66LB, E. Lansdon et al, working at Gilead Sciences, have performed further work on a novel nucleotide analogue termed GS-9148-disphosphate. This molecule has a unique resistance profile and can continue to be active against viruses possessing a number of classical NRTI resistance mutations including M184V, K65R, L74V and several thymidine analogue mutations (TAMs). Co-crystallization of this molecule together with covalently tethered double-stranded DNA documented that it bound in a highly specific way to RT, such that conformational changes ensued that resulted in closing of the fingers' domain. The authors believe that this constitutes firm evidence of a unique mechanism of action of GS-9148 and helps to explain why only one mutation associated with drug resistance, i.e. the multidrug resistance Q151M substitution, was unique in being able to confer a moderate level of resistance against this compound. Further studies are underway in regard to the clinical development of GS-9148 and/or derivative molecules that will hopefully prove to be non-toxic and fully efficacious in regard to blockage of HIV replication.
..

3. Resistance to Integrase Strand Transfer Inhibitors (INSTIs)
Abstract 69 by S. Fransen and colleagues was on the topic of mutations within the integrase (IN) gene that help to define resistance against Raltagravir (Ral). These investigators studied individuals who had failed therapy with Ral and have created a series of site-directed mutants containing mutations at position 143, 148, 155, either alone or in combination with other secondary IN-related resistance mutations. Thus, these investigators created combinations of mutations that may appear early in the multiple pathways that are associated with resistance to integrase inhibitors alongside mutations of a more secondary nature that have been shown to both augment viral replication fitness, when coupled with primary mutations, as well as increase overall levels of drug resistance to integrase strand transfer inhibitors (INSTIs). In general, the results of the studies now show that the mutations at positions 143 and 148 may have less of an effect on viral replication and cause higher levels of drug resistance against Ral than do mutations at position 155.
..

4. Resistance to entry inhibitors
Session 32 at CROI included issues of drug resistance and treatment responsiveness as well as lectures on the transmission of HIV drug resistance and development of assays that might predict responsiveness to CCR5 antagonists. These topics will be dealt with by other reporters who were present at the conference.
..

5. Resistance to Bevirimat
Several abstracts dealt with the topic of resistance to this novel first-of-class maturation inhibitor. In one of them (Salzwedel et al, Abstract 635), it was demonstrated that subtype-specific polymorphisms at or near the CA-SP1 junction may determine responsiveness to this compound. Should it turn out that not all HIV subtypes can respond equally well to bevirimat, this might complicate its future use in therapy. A second abstract by NA Margot et al (Abstract 637) suggested that many patients who have not yet received bevirimat may be unable to respond to it in ideal fashion due to polymorphisms in SP1 and the capsid junction.
 
6. Studies in Developing Countries
Abstract 656 was by C. Hoffman et al reporting on the development of resistance to antiretroviral drugs in South African patients receiving antiretroviral therapy. Not surprisingly, these individuals received treatment with ZDV/3TC/EFV and had a preponderance of M184V mutations in the aftermath of treatment failure. NNRTI resistance was also reported in this group as were the presence of TAMs. Patients with HIV viremia had a preponderance of NNRTI mutations. Clearly, patients who fail a regimen of ZDV/3TC/EFV with multiple mutations as noted above will be limited in regard to a number of future second or third line therapeutic options.
..

7. The Use of Ultrasensitive Procedures including Pyrosequencing for Analysis of HIV Drug Resistance
Session 42 was a themed oral discussion of abstracts that were also presented as posters in session 119 on the topic of novel technologies to better understand HIV drug resistance. In particular, pyrosequencing, also referred to as �g454�h sequencing, provides ultra-sensitive analyses that can detect the presence of minority viral populations including specific mutations that may be present in the total viral population at frequencies <1%. In contrast, population-based sequencing which is the classic technique employed by most diagnostic labs will only detect species that are present at a level of 20% or more of the total viral population. An important question to now ask is whether the advent of such techniques as pyrosequencing will render more traditional procedures obsolete.

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[John2038]

aegis

Mylan's Matrix Receives WHO Approval for First Generic, Heat-Stable Version of HIV Protease Inhibitor: Provides first affordable protease inhibitor for patients in developing countries
PITTSBURGH, Feb. 25 /PRNewswire-FirstCall/ -- Mylan Inc. (NASDAQ:MYL) today announced that Matrix Laboratories Limited, its India-based subsidiary in which it holds a 71.5% controlling interest, received the first and only World Health Organization (WHO) approval for Lopinavir/Ritonavir Tablets, 200 mg/50 mg. Matrix's version of this product is heat-stable and affordable, making it practical for distribution and use in warm climates.

Lopinavir/Ritonavir Tablets are the generic version of Abbott Laboratories' Kaletra(R) Tablets, the brand marketed in the U.S. and Europe, and Alluvia Tablets, the brand marketed in the developing world. It is used in combination with other medications to control HIV infection and is included in the antiretroviral (ARV) class of drugs known as HIV protease inhibitors.

Mylan Vice Chairman and CEO Robert J. Coury said: "Mylan and Matrix are committed to our growing and high quality ARV franchise. Our goal is to provide HIV treatments to patients around the world -- especially in developing countries. With Matrix's heat-stable and affordable version of Lopinavir/Ritonavir, patients in remote parts of developing nations now have access to this important medicine."

A WHO approval indicates that a drug meets international safety, efficacy and manufacturing quality standards. With such status, Matrix can sell the treatment in most countries outside the United States and Europe.

Matrix's wide range of ARV products includes active pharmaceutical ingredients (API) and first- and second-line finished doses; patients use second-line therapies if and when they develop resistance to initially prescribed treatments. The company's emphasis on producing affordable products has allowed it to drive down the average annual cost per patient of effective therapies. Approximately 30% of HIV/AIDS patients in the developing world depend on Matrix's ARV products.

Mylan Inc., which provides products to customers in more than 140 countries and territories, ranks among the leading diversified generic and specialty pharmaceutical companies in the world. The company maintains one of the industry's broadest - and highest quality - product portfolios, supported by a robust product pipeline; owns a controlling interest in the world's third largest active pharmaceutical ingredient manufacturer; and operates a specialty business focused on respiratory and allergy therapies. For more information, please visit www.mylan.com.

CONTACT: Media: Michael Laffin or Investors: Dan Crookshank, +1-724-514-1813, both of Mylan Inc.

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HIV quickly evolving among large groups - study
LONDON, Feb 25 (Reuters) - The AIDS virus is quickly adapting across large groups of people to avoid triggering the human immune system, posing another challenge in the search for a potential vaccine, researchers said on Wednesday.

Scientists know the human immunodeficiency virus, or HIV, constantly mutates within individual people to find ways to attack cells.

But the study published in the journal Nature suggests changes that help the virus do this are increasingly passed on in the wider population.

"What was previously clear is the virus could evolve within each infected person but that doesn't really matter from a vaccine perspective if the virus at the population level is staying the same," said Philip Goulder, an immunologist at Oxford University who led the study.

"The implication is that once we have found an effective vaccine, it would likely need to be changed to keep pace with the rapidly evolving virus."

There is no cure for AIDS and 33 million people globally are infected with HIV. Cocktails of drugs can control the virus and keep patients healthy. AIDS has killed more than 25 million people since the early 1980s, mostly in sub-Saharan Africa.

Researchers are trying to find vaccines that either prevent infection or would control the virus so that patients are less likely to transmit it -- a so-called therapeutic vaccine.

"The process of the virus adapting is happening before our eyes at quite a speed, and it is something we need to take into account when making our vaccines," Goulder said.

HIV attacks the immune system, the body's natural defences. Like other viruses, it cannot replicate on its own but must hijack a cell and turn it into a virus factory.

HIV must evade several genes to do this, including an immunity gene called HLA.

The team, which included researchers from Australia and Japan, analysed the genetic sequences of HIV and versions of HLA genes known to control the virus in 2,800 people.

Some people have a version of the gene that is more protective. In the study, the researchers found that mutations that allow HIV to evade immune responses directed by HLA were more common in people with the protective variant of the gene.

This was strong evidence for HIV adaptation to the human immune system among the wider population, Goulder added in a telephone interview.

This means the so-called escape mutation is circulating in more and more people and accumulating in the wider population of those infected with HIV, he said.

"We saw similar effects in every mutation that we looked at," Goulder said. "This shows that HIV is extremely adept at adapting to the immune responses in human populations that are most effective at containing the virus." (Editing by Will Dunham and Jon Boyle)

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abstract published in nature
The rapid and extensive spread of the human immunodeficiency virus (HIV) epidemic provides a rare opportunity to witness host–pathogen co-evolution involving humans. A focal point is the interaction between genes encoding human leukocyte antigen (HLA) and those encoding HIV proteins. HLA molecules present fragments (epitopes) of HIV proteins on the surface of infected cells to enable immune recognition and killing by CD8+ T cells; particular HLA molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, are more likely to mediate successful control of HIV infection1. Mutation within these epitopes can allow viral escape from CD8+ T-cell recognition. Here we analysed viral sequences and HLA alleles from >2,800 subjects, drawn from 9 distinct study cohorts spanning 5 continents. Initial analysis of the HLA-B*51-restricted epitope, TAFTIPSI (reverse transcriptase residues 128–135), showed a strong correlation between the frequency of the escape mutation I135X and HLA-B*51 prevalence in the 9 study cohorts (P = 0.0001). Extending these analyses to incorporate other well-defined CD8+ T-cell epitopes, including those restricted by HLA-B*57 and HLA-B*27, showed that the frequency of these epitope variants (n = 14) was consistently correlated with the prevalence of the restricting HLA allele in the different cohorts (together, P < 0.0001), demonstrating strong evidence of HIV adaptation to HLA at a population level. This process of viral adaptation may dismantle the well-established HLA associations with control of HIV infection that are linked to the availability of key epitopes, and highlights the challenge for a vaccine to keep pace with the changing immunological landscape presented by HIV.

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medicalnewstoday

Bioject Enters Into A Collaborative Research Agreement With IAVI For The Delivery Of An HIV Vaccine Candidate
Bioject Medical Technologies Inc. (OTCBB: BJCT), a leading developer of needle-free injection therapy systems, today announced that it has entered into an agreement with the International AIDS Vaccine Initiative (IAVI) to supply its unique Needle-Free Injection Therapy (NFIT) system, the Biojector® 2000, for the delivery of a DNA-based HIV vaccine candidate that is currently under development. The new agreement extends through December 2009.

IAVI and the St. Stephen's AIDS Trust at the Chelsea and Westminster Hospital have initiated a Phase I clinical trial in London, UK to test a prime-boost combination of two HIV vaccine candidates. One of the vaccine candidates, a DNA-based vaccine called ADVAX, will be administered using the Biojector® 2000.

"We welcome this collaboration with Bioject to assess the value of their needle-free device for the delivery of this DNA HIV vaccine candidate," said Dr. Pat Fast, Chief Medical Officer at IAVI. "It is essential that we enhance immune responses against HIV, which may be achieved by optimizing vaccine design, but also by evaluating alternative vaccine delivery methods."

The trial in London includes ADVAX to prime the immune system prior to the administration of an MVA-based HIV vaccine candidate called TBC-M4. In a previous Phase I trial, TBC-M4 generated modest immune responses in all volunteers who received the highest dose. The rationale for combining TBC-M4 with ADVAX is to improve immune activation. Previous Phase I studies with different DNA and MVA-based HIV vaccines in combination have shown that this prime-boost regimen was safe and well tolerated, and also able to generate enhanced immune responses when compared with the responses generated by either vaccine alone. Furthermore, DNA-based vaccine candidates such as ADVAX may offer value economically, since these vaccines are relatively inexpensive and easy to manufacture, two characteristics that make them particularly appealing for use in the developing world.

ADVAX will be administered with the Biojector® 2000 needle-free injection system. "Needle-free injection of a DNA vaccine can provide enhanced immune responses compared with administration by needle and syringe," said Dr. Richard Stout, Executive Vice President and Chief Medical Officer of Bioject. "We are quite pleased that IAVI has decided to utilize Bioject's B2000 system in order to explore the potential benefits over needle and syringe," commented Dr. Stout.

The development of a safe and effective AIDS vaccine is one of the greatest priorities in global health R&D. Today, 33 million people worldwide are living with HIV and 7,500 are newly infected every day. It is vital to have both short-term and long-term solutions to this problem. Treatment must reach those who are infected, and proven prevention tools need to be made available to those who need it. At the same time, greater investment is needed to develop new and better tools to improve control and prevention of HIV infection. An AIDS vaccine offers the best hope for achieving this and to realize a world without AIDS.

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GSK Should Allow Generic Competition For HIV/AIDS Drugs To Address Innovation, Access Problems In Developing Countries, Opinion Piece Says
GlaxoSmithKline's recent announcement that it plans to reduce drug prices in some low-income countries and share information on patented drugs is "welcome" but not a "radical departure from standard fare," Tido von Schoen-Angerer -- director of Medecins Sans Frontieres' Campaign for Access to Essential Medicines -- writes in an opinion piece in London's Guardian. According to von Schoen-Angerer, GSK should employ the "tried and tested way to drive prices down -- competition with multiple generic manufacturers, thanks to which the first generation of AIDS treatments has seen a price drop of close to 99% in the past decade."

According to von Schoen-Angerer, the "price-cut pledge is restricted to 'the 50 least developed countries,' excluding those nations where burgeoning middle classes live side by side with millions who cannot afford medicines." He adds that this situation -- such as the one occurring in China, where GSK's patent "allows the company to charge prohibitive costs for the AIDS drug lamivudine" -- is "not one that can be wished away: as patients across the world start to develop resistance to existing drugs, they will need access to newer, more expensive medicines. The price of AIDS treatment is set to skyrocket."

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sciencedaily

Vaccine Research Targets HIV In The Slower, Early Stage Of Infection
New research at Oregon Health & Science University's Vaccine and Gene Therapy Institute suggests vaccines that specifically target HIV in the initial stages of infection before it becomes a rapidly replicating, system-wide infection - may be a successful approach in limiting the spread of the disease.

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iol

Gates donates funds for HIV gels
Washington - A foundation backed by Microsoft billionaire Bill Gates has donated $100-million to research into vaginal gels and other products which could help dramatically cut HIV-infection rates.

The Bill and Melinda Gates Foundation made the donation to the Maryland-based International Partnership for Microbicides (IPM) after clinical trails of one product posted "encouraging results", the IPM said.

Although an effective microbicide does not yet exist, health policy makers have high hopes that the gels, creams or films - which block or kill pathogens - will soon be ready for widespread use.

"Safe and effective microbicides have the potential to save millions of lives by giving women an HIV prevention option that they can initiate and control," a IPM statement said.

Last month, the US National Institutes of Health reported that a phase two clinical trial had shown microbicide candidate PRO2000 to be 30-percent more effective in preventing HIV than other products.

IPM said it would use the money to further clinical trials. "IPM will bring pioneering HIV prevention technologies into 10 new clinical studies this year, including long-acting vaginal gels and vaginal rings that could provide sustained protection for up to a month."

According to World Health Organisation estimates, more than 33 million people were living with HIV at the end of 2007. In the same year more than two million people died of Aids and 2.5 million more became infected with HIV. Two thirds of infections are in sub-Saharan Africa.

But the apparent success of PRO2000 has prompted new-found hope that effective microbicides are more than a pipe dream.

PRO2000 is based on the same anti-retroviral medicines that have proved successful in treating millions of HIV sufferers around the world.

The results of a phase three clinical trial of PRO2000 involving 9 400 women in Africa is expected in August.

On Tuesday the British government also announced it would donated around $30-million to IPM, part of a $320-million disease prevention program by the country's Department for International Development. - AFP

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businesswire

Aethlon Medical Announces Cytomegalovirus (CMV) Research Program
SAN DIEGO--(BUSINESS WIRE)--Aethlon Medical, Inc. (OTCBB:AEMD) announced today it has initiated a research program to test the capabilities of the Aethlon Hemopurifier® to identify and capture Cytomegalovirus (CMV). The Hemopurifier® is a first-in-class medical device that assists the immune response in combating infectious disease through real-time therapeutic filtration of infectious viruses and immunosuppressive proteins from the entire circulatory system. Safety of the Hemopurifier® has been demonstrated in multi-site human studies, with robust viral load reductions observed in enrolled Hepatitis-C (HCV) infected patients. Safety and efficacy data resulting from the first use of the Hemopurifier® in an individual infected with Human Immunodeficiency Virus (HIV) is forthcoming.

The market opportunity to extend the value of the Hemopurifier® into CMV care is significant. CMV is a common virus found throughout all geographic locations and socioeconomic groups. In the United States, between 50% and 80% of all adults are infected with CMV by 40 years of age. In general, CMV remains latent in the body unless activated by suppression of the immune system. In such cases, CMV becomes a major cause of disease and death in immune compromised individuals, including recipients of both organ and stem-cell transplants, patients undergoing hemodialysis, patients with cancer, patients receiving immunosuppressive drugs, and HIV infected individuals, of which CMV is considered an AIDS-defining infection.

“Our CMV research programs will study both the therapeutic and diagnostic potential of our Hemopurifier®,” stated Aethlon Chairman and CEO, Jim Joyce. “While CMV represents an exciting new market opportunity, our immediate goals remain the establishment of a GMP manufacturing relationship and the hopeful demonstration that our Hemopurifier® is able to reduce viral load in both HCV and HIV infected individuals, which likely would be the first such accomplishment by a single therapeutic candidate,” concluded Joyce.

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[John2038]

vietnamnet

A physician spends 23 years help poor patients
VietNamNet Bridge - Over 23 years, she always helps poor patients who catch social diseases such as drug addiction, tuberculosis, leprosy and mental illness. Particularly, she spends 13 years to take care HIV/AIDS patients.



She has been a friend, a mother and fulcrum for people living with deadly disease. She is physician Tran Thi Xuan Hong (photo), head of the Health Center of Xuan Khanh ward, Ninh Kieu district, Can Tho city.

“In 1995, there were three people infected with HIV/AIDS. Then everyone thinks that HIV/AIDS is death. However, I did not discriminate that” she said and added “From that to now, I have helped over 170 HIV-infected people, major of them are poor. Many patients are in the last phase, lie in dank house and they catch diarrhoead for a long time and their body is ulcerated.”

Ms. Hong said that sentiment of people with HIV/AIDS is very complicated and even some respond to her help. However, her pride is not only hurt but she always takes care and encourages them. Discrimination of the community and society is always her big worry. She has witnessed that children of people with HIV are such discriminated that they cannot sell lottery ticket because buyers are afraid of being infected with HIV through the ticket.

Not only take care people with HIV/AIDS, over past ten years she has taken care 15 drug users and helped them re-integrate into the community.

“When they detoxify, I also spend time to keep an eye on and encourage them. I am afraid that they are feeble and relapse. This is also a pleasure to solace me,” she said.

She is now managing 79 people with HIV/AIDS, 19 of them become full-blown AIDS, 98 drug users, 53 with tuberculosis, 76 with metal illness and 3 with leprosy.

In addition, she voluntarily joins a group of doctors to establish Hope House to take care AIDS patients.

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foundationcenter

Gates Foundation Awards $100 Million to Help Women Prevent HIV Infection
The International Partnership for Microbicides in Silver Spring, Maryland, has announced a $100 million grant from the Bill & Melinda Gates Foundation for its work to develop microbicides that give women in developing countries the power to protect themselves against HIV infection. The UK Department for International Development has pledged an additional $28.5 million.

This is the Gates Foundation's second grant, and DFID's third, to IPM, a nonprofit product-development partnership working to accelerate the development and availability of safe, effective topical products called microbicides that have the potential to prevent HIV transmission during sexual intercourse. The announcement follows the encouraging results last month of the National Institutes of Health Microbicide Trials Network's clinical trial of a microbicide candidate, PRO2000, which showed the product was 30 percent more effective than any other in the study at preventing HIV.

Around seven thousand new cases of HIV infection and almost six thousand AIDS-related deaths occur each day. Increasingly, women and young girls bear the burden of the epidemic, and in sub-Saharan Africa, young women are more than three times as likely to be infected as young men. But IPM's microbicide research could result in "an HIV prevention method that would put the power to prevent HIV in the hands of women, who often are unable to insist on abstinence or condoms," said Dr. Tachi Yamada, president of the Gates Foundation's global health program.

"Safe and effective microbicides have the potential to save millions of lives by giving women an HIV prevention option that they can initiate and control," said Dr. Zeda Rosenberg, CEO of IPM. "Taken together, these grants by two of IPM's longstanding donors will provide additional momentum to deliver on this promise."

“International Partnership for Microbicides Receives US $130 Million From UK Government and the Gates Foundation.”

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pharmatimes

Use of HIV drug Prezista expanded in the UK
Treatment-naïve patients in the UK can now get access to Johnson & Johnson unit Tibotec Pharmaceutical’s HIV drug Prezista, after regulators expanded the drug’s approved uses.

Specifically, patients who have not received prior HIV therapy can now take Prezista (darunavir) 800mg with a low-dose ritonavir as part of combination therapy, offering healthcare professionals an additional option for managing the disease.

Therapy for treatment-naïve patients consists of two 400mg Prezista pills taken in a once-daily regimen, thereby offering patients greater convenience, the company says, which should in turn help to encourage better adherence and boost treatment outcomes.

In addition, Tibotec has launched a new 600mg tablet for treatment-experienced patients with HIV, which replaces the 300mg tablet and reduced the pill burden from four a day to two.

Prezista was first launched for highly treatment-experienced adults with HIV in February 2007, and subsequently won two additional marketing authorisations within two years to expand its licence to treatment-experienced adults in November 2008 and treatment-naive adults earlier this year.

“The relatively short approval timeline since Prezista's original launch demonstrates the European Commission’s confidence in [the drug’s] safety and efficacy in all adults with HIV,” a company spokesperson told PharmaTimes UK News.

Comparable price, better efficacy
In addition, the spokesperson said pricing for the treatment-naïve dose of Prezista is comparable to Abbott’s rival drug Kaletra (lopinavir) plus ritonavir, but stressed that the Prezista/ritonavir combination provides the “added benefit of superiority” over the Kaletra-based regimen, as demonstrated by findings of the ARTEMIS trial. At 96 weeks in the study, significantly more patients in the darunavir/r arm reached an undetectable viral load (<50 copies/mL) versus those taking the lopinavir/r combination.

“We welcome Prezista’s availability as an effective, once-daily option for adults who have never taken HIV medication before,” commented Mark Nelson, Consultant Physician and Deputy Director of HIV Research at Chelsea and Westminster Hospital, London, UK. “It has made a significant contribution in the care of treatment-experienced adults with HIV for the last two years, and this is an important treatment development for patients,” he added.

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[John2038]

natap

Clinical Pharmacology at CROI 2009: Pharmacoenhancement, Pharmacogenetics, Drug Interactions and the Pharmacotherapy of HIV Infection
The 16th CROI had many abstracts related to clinical pharmacology. In this report I will highlight those I think are of broad interest or might benefit from some expert clarification. I will discuss abstracts in four broad categories: pharmacoenhancement, pharmacogenetics, drug interactions and the pharmacotherapy of HIV infection.

I. Pharmacoenhancement
Clearly, the pharmacologic highlight of the 16th CROI were two abstracts describing the basic and ongoing clinical development of drugs that are intended to only inhibit CYP enzymes and thus be used clinically as booster for other PIs as is presently the use of RTV.
..

II. Pharmacokinetics and Pharmacogenetics
CROI has provided an important venue for information related to the contribution of naturally occurring genetic variability to the variability seen in the PK of ARVs among patients and the variability seen in the response (pharmacodynamics, PD) to ARV therapy. I'll highlight some of the abstracts that presented PK information with clinical implications.
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III. Drug Interactions
The study of interactions among ARV drugs, and among ARVs and other commonly used drugs remains an area of considerable study. Primarily, these interactions arise because of the concomitant use of drugs that are substrates, inhibitors and inducers of drug metabolizing enzymes, especially those of the cytochrome P450 system (CYP), and drug transporters.
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IV. Pharmacotherapy of HIV Infection
In this final category I will discuss abstracts that present information relevant to improving the safe and effective use of drugs in the treatment of HIV infection. I will primarily focus on abstracts that present pharmacologic information - that is pharmacokinetic, pharmacodynamic or pharmacogenetic data and the implications of those data to increase the likelihood of the desired response to drug therapy and minimize the risk of adverse drug effects.
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Pharmacology at the 2009 Conference on Retroviruses and Opportunistic Infections
The 16th CROI was notable for the small number of pharmacology presentations. However among the presentations several were of considerable potential importance. In his Bernard Fields Lecture during the Opening Session, Bob Silicaino reviewed his landmark work on viral persistence and latent reservoirs (summarized in the natap report by David Margolis), and connected this to his current investigations defining drug potency. Early phase studies of possible alternatives to ritonavir as a pharmacokinetic enhancer were presented by scientists from both Gilead Sciences and Sequoia Pharmaceuticals. Finally a novel means of measuring intracellular concentrations of nucleoside reverse transcription inhibitor was presented by Charles Flexner and colleagues. While none of these presentations will permit clinicians new tools or agents immediately, all have great potential impact for the development of new antiretroviral agents and an enhanced understanding of how to optimally utilize current and future therapies in the treatment of HIV infection.
 
Non-Ritonavir Pharmacokinetic Enhancers
Initially developed as a protease inhibitor in the early 1990s, ritonavir's use to the field of antiretroviral therapeutics is in the enhancement (or boosting) of other PIs. Ritonavir (RTV) has complex pharmacologic activity that results in the elevation of coadministered PI levels. This has resulted in the enhanced therapeutic potency of the coadministered PI, a notable reduction in the development of PI-associated resistance mutations, and greater ease of dosing. These favorable attributes are achieved by several actions of RTV including enhanced oral bioavailability, slowing of coadministered drug metabolism, and reduction of drug (efflux) transport from target cells. These actions are mediated through RTV's inhibition of the predominant drug metabolizing enzyme, CYP3A4, and xenobiotic transporter, P-glycoprotein (P-gp) located in critical tissue compartments of the gut, liver and lymphocytes. However RTV's inhibitory activity is not limited to CYP3A4 or P-gp, but rather extends to other drug metabolizing enzymes and cellular transport mechanisms, leading to complex and often unpredictable drug-drug interactions. Further the pharmacologic effects of RTV are not limited to enzyme and transporter inhibition, but also include induction of many of these same drug metabolizing enzymes and cellular transporters. The generalized effect of RTV on other enzyme and transporter systems is one aspect that has prompted investigation of alternative approaches to enhance PI drug exposures.
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Defining Antiretroviral Potency - The Role of Dose Dependency
The Bernard Fields Lecture was given by Bob Silicaino from Johns Hopkins University School of Medicine. Summarizing more than a decade of sentinel work on viral persistence (see natap report by David Margolis), Silicaino followed this discussion with work that currently involves his laboratory and collaborators. Attempting to better define and delineate concepts that assess antiretroviral potency he described an approach that adds dose-dependent antiviral response to the more traditional measures of IC50 and the inhibitory quotient. This approach was first published in 2008 (Shen, Nature Medicine).
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Measurement of Intracellular NRTI Levels
From the time of their development it has been appreciated that the active moiety of nucleoside reverse transcription inhibitors is the intracellular tri-phosphate (TP). The ability to measure NRTI-TP during the past several years has lead to a more complete understanding of intracellular pharmacokinetics and pharmacodynamics. Indeed the dosing schedules of several approved agents have been revised based on determination of the intracellular half-life of the TP. These measurements have been time consuming, expensive, required large volumes of blood and limited in the level of TP detection. Charles Flexner in collaboration with investigators from York, UK and GlaxoSmithKline (abstract 704) reported on the use of a novel technique to quantify NRTI-TP. Using Accelerator Mass Spectrometry (AMS), radio-labeled NRTI, in this instance 14carbon-labeled zidovudine, the investigators established that the method is capable of detecting levels of ZDV-TP to 10-21, considerably more sensitive than current measures. The application of AMS is potentially substantial for both currently available and investigational agents allowing determination of intracellular metabolites in numerous tissue compartments and cellular subsets. One can envision use of such techniques in the development programs of microbicides or in the development of agents used for pre-exposure prophylaxis.

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Cervicovaginal Shedding of HIV-1 Is Related to Genital Tract Inflammation Independent of Changes in Vaginal Microbiota
The pro-inflammatory cytokines IL-1b and IL-8 are associated with higher cervicovaginal HIV-1 RNA concentrations, an association which persists after controlling for plasma viral load and vaginal microbial co-factors. This association suggests that there may be additional, non-infectious causes of inflammation that increase cervicovaginal HIV-1 shedding.

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Forty-Fold Elevated Risk for Lymphoepithelial Carcinoma of Salivary Gland Among People with AIDS in the United States
Persons with HIV/AIDS have more than a 40-fold increased risk of LEC of the salivary gland. An increased risk for squamous cell carcinomas of both salivary gland and nasopharynx is also apparent. The magnitude of elevated risk for LEC of the salivary gland suggests an underlying viral etiology. The marked increase in risk for LEC of the salivary gland is in striking contrast to the modest increase in the risk for LEC of the nasopharynx. Our data are consistent with the hypothesis that LES promotes salivary gland cancers in the HIV-infected population.

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Update on Kidney Disease in HIV Infection: CROI 2009
The growing relevance of non-AIDS conditions was again evident in this year's program, which included abstract sessions devoted to cardiovascular, hepatic, bone, and kidney disease, and concluded with a clinical symposium on non-AIDS complications. Interested clinicians are encouraged to refer to Lynda Szczech's presentation for a review of practical considerations in the management of acute and chronic kidney disease in the aging HIV population [abstract 180]. (from Jules: as the author's of this paper say at this year's CROI there was increased attention to so-called non-AIDS conditions, although they are tied to HIV in I think several ways. From looking at all the studies confirming non-AIDS events and deaths it appears evident that the ages of patients in the stays is young, in their 40s on average, which speaks volumes but is not said in a loud way. It appears that HIV plays a role in leading to premature aging of T-cells, upon initial infection HIV gets into various organs including the kidney, the heart, vascular system, the brain, the CNS, and more. HIV appears to cause immune activation and inflammation. So, although researchers are paying attention to increased morbidity and mortality due to non-AIDS researchers are not discussing understanding these underlying preocesses in such a way as to try to better understand it so we could perhaps address it and intervene, and slow aging and the development of non-AIDS events and death.
 
Kidney Disease and Non-AIDS Morbidity
Investigators from several large cohort studies described the important contribution of non-AIDS conditions such as kidney disease to morbidity and mortality. Only half of all deaths in the ART Cohort Collaboration were considered AIDS-related [abstract 708]. While non-AIDS malignancy and infections were the most common causes of non-AIDS mortality, liver, cardiovascular, and renal disease were also important contributors. Death from renal disease was associated with advanced immunodeficiency, although it is unclear whether this reflects increased frequency and severity of kidney disease, in particular HIV-associated nephropathy (HIVAN), or a tendency to withhold dialysis in patients with advanced AIDS and severe comorbid disease.
 
The EuroSIDA investigators also reported more morbidity related to serious non-AIDS conditions than AIDS-defining illnesses [abstract 707]. The most common non-AIDS conditions were malignancy, cardiovascular disease, and liver failure, but end-stage renal disease was also an important contributor to morbidity in this cohort. The development of end-stage renal disease is of particular relevance in this largely Caucasian European cohort at relatively low risk for progressive kidney disease.
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Chronic Kidney Disease in HIV
Andy Choi and colleagues described an accelerated loss of kidney function among HIV-positive patients enrolled in the UCSF SCOPE Cohort, compared to general population estimates [abstract 38]. Over a median followup of 2.7 years, the decline in estimated glomerular filtration rate (eGFR) was -2.6mL/min/1.73m2 per year, a figure comparable to the rate of decline observed in many patients with established kidney disease. Of note, chronic kidney disease and traditional risk factors, such as hypertension and hyperlipidemia, were relatively common. Older age, female gender, diabetes, and hyperlipidemia were associated with eGFR decline, while HIV-related factors did not predict the rate of decline. In particular, there was no relationship between eGFR decline and the use of ART, although the study was not powered to look at the impact of specific drugs or drug classes. In a subgroup of 82 patients who initiated ART during the study period, the decline in eGFR was slower after the initiation of ART, suggesting a beneficial effect of virologic suppression. At the same time, a separate subgroup analysis revealed that patients who achieved virologic suppression on ART had more rapid eGFR decline than elite controllers. It is not clear whether this difference reflects a balance of benefit and harm associated with ART, or whether there are other unmeasured differences between these two populations that may impact kidney disease progression.
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Acute Renal Failure and Nucleoside Toxicity
In a prospective cohort study from Boston, Shikha Garg and colleagues reported a higher incidence of acute renal failure among patients with HIV-hepatitis C co-infection compared to patients with hepatitis C alone [abstract 822]. More than one-third of co-infected patients developed at least one episode of acute renal failure during the 7-year study period, for an incidence of 8.7 cases/100 person-years. Previous studies have demonstrated a similar increase in the incidence of acute renal failure among patients with HIV-hepatitis C co-infection compared to those with HIV alone, although the relative contribution of each viral infection is not known. Decompensated cirrhosis and cocaine use were also independently associated with acute renal failure, suggesting that factors associated with acquisition and complications of viral infection are important contributors to the risk of acute renal failure in this population.
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Kidney Disease and ART in Resource-Limited Settings
With expanding access to ART in sub-Saharan Africa and other resource-poor regions, it is increasingly important to develop simple, inexpensive, and sensitive methods for the prevention and early recognition of ART toxicity. It is reassuring that the widespread introduction of tenofovir-containing ART in Zambia has been associated with low rates of severe renal insufficiency (creatinine clearance < 50 mL/min) comparable to that observed with alternative NRTI [abstract 142]. Longitudinal data from ART-naïve patients in Kenya suggest that baseline kidney function may predict progression of HIV disease and identify patients who would benefit from earlier initiation of ART [abstract 741], providing another potential rationale for the routine assessment of kidney function in this population. In a retrospective cohort of 8,737 patients with a CD4 above 200 enrolled in the USAID-AMPATH Partnership, a striking proportion of patients (almost 20%) had an estimated creatinine clearance below 60mL/min. Lower creatinine clearance was associated with more rapid progression to WHO stage 3-4 disease, CD4 below 200, and death. Data on progression of kidney disease were not reported.
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Impairment in Kidney Tubular Function in Patients Receiving Tenofovir Is Associated with Higher Plasma Tenofovir Levels
Plasma levels of TDF are increased in patients experiencing abnormal kidney tubular function on treatment. These results confirm the potential specific toxicity of TDF on the kidney tubular epithelium, as other nucleoside monophosphates (adefovir and cidofovir). Studies assessing the efficacy and safety of lower doses of TDF are warranted, and this information could be helpful for hepatitis B mono-infected patients as well.

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HIV & HAART Interruption Increase Inflammation and Disease
Higher levels of IL-6 and hs-CRP were independently associated with development of an opportunistic disease. Although reverse causality may have influenced this association, the fact that baseline levels also predicted opportunistic disease events makes it less likely. Use of these biomarkers could provide additional prognostic information for predicting risk of development of opportunistic disease.

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Weekly and Biweekly Subcutaneous PRO 140 Demonstrates Potent, Sustained Antiviral Activity: 2-week study





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[John2038]

sciencedaily

Antibiotic Combination Defeats Extensively Drug-resistant TB

A combination of two FDA-approved drugs, already approved for fighting other bacterial infections, shows potential for treating extensively drug resistant tuberculosis (XDR-TB), the most deadly form of the infection. This finding is reported by scientists from Albert Einstein College of Medicine of Yeshiva University in the February 27 issue of Science.



In the Science paper, Einstein researchers and collaborators at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, describe a two-drug combination that inhibited both the growth of susceptible laboratory strains and 13 XDR-TB strains isolated from TB patients in laboratory culture medium. The drugs truly work in tandem: one of them (clavulanate) inhibits a bacterial enzyme, β-lactamase, which normally shields TB bacteria from the other antibiotic (meropenem, a member of the β-lactam class of antibiotics).

The idea of inhibiting β-lactamase to make β-lactam antibiotics effective isn't new ─ which is why β-lactamase inhibitors, such as clavulanate, already exist. The strategy finally proved effective against XDR-TB because Einstein researchers conducted a detailed, methodical investigation of the β-lactamase enzyme to find the ideal combination of β-lactamase inhibitor and β-lactam antibiotic. β-lactam antibiotics include penicillin, the first antibiotic discovered and one of the safest.

Amoxicillin/clavulanic acid and meropenem have excellent safety profiles and are FDA-approved for adult and pediatric use.

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[John2038]

aegis


The case for starting HIV therapy early gets stronger

People living with HIV who had a CD4 count above 500 and who waited to start therapy had a 36 percent higher risk of death than those who started highly active antiretroviral therapy.

The data [see below] presented earlier this month in Montreal at the 16th Conference on Retroviruses and Opportunistic Infections provided further evidence for the movement toward earlier initiation of therapy.

The analysis was the second installment of an unusual collaboration between all 22 HIV research cohorts in North America that followed patients between 1996 and 2006. In the study of patients with 350 to 500 CD4 cells researchers found that those who deferred therapy had a 70 percent greater risk of death than those who started therapy.

The new study in those with higher CD4 counts involved 9,174 patients and 25,337 person-years of follow up. Some 2,620 (29 percent) initiated HAART above 500 while the majority (6,553, 71 percent) deferred to some later point.

"Our finding suggests that therapy earlier in HIV infection could significantly prolong survival," said lead author Mari Kitahata, a researcher at the University of Washington. Neither baseline CD4 count nor viral load were predictors of mortality; increasing age was the only significant predictor of death.

In Europe, the When to Start Consortium examined 15 cohort studies and reached similar conclusions at lower CD4 ranges but not at the higher ones. Lead author Jonathan Sterne, from the University of Bristol in the United Kingdom, said, "Delaying to below 250 was clearly associated with increased rates of AIDS and death. We found that starting above 350 was beneficial to deferring ... but we didn't find benefit from starting above approximately 400."

He added, "Starting above 350, the absolute rates of mortality and absolute rates of death and dying are actually relatively low. So, the higher you put your threshold, the smaller the absolute benefit becomes." In other words, the costs may outweigh the benefits.

Kitahata pointed to emerging data that the ongoing inflammation of untreated HIV infection contributes to risk of heart disease, diabetes, and likely premature aging. "These help to understand why HIV is persistently creating defects in the immune system," she said.

She added that the collaboration is beginning to analyze these and other clinical events in the cohort datasets.

"We would like the message to be, the earlier you come into care, the better we can care for you," Kitahata said. Vaccinations are more effective and comorbidities often are easier to treat and resolve, she said.

"All of the data seems to be pushing in the same direction - studies on immune activation, cardiovascular disease, malignancies - it's all snowballing in favor of earlier therapy," said Johns Hopkins University infectious disease expert John Bartlett.

He also believes that an earlier start to treatment will have a public health benefit by reducing viral load and the number of new infections.

Conference chairman John Mellors, University of Pittsburgh, said concern over the toxicities of therapies had moved the field "toward the precipice" of serious HIV disease before initiating therapy. "Now I sense that we are moving away from that to higher and higher CD4 starting points," he said.

Very early treatment

Researchers have been tantalized by the possibility that treating HIV infection during the first few weeks after exposure might allow the immune system to better control the virus and significantly change the course of disease.

New evidence from an ongoing cohort study at the Academic Medical Center in Amsterdam teased at that possibility but did not conclusively answer the question.

The study looked at 102 patients who had detectable virus in their blood but were negative or indeterminate on tests for antibodies to HIV. Antibodies generally develop one to three months after initial infection, so these patients were within that three-month window.

Patients were randomized to receive no treatment (47) or temporary HAART for six or 15 months (55) before stopping. The patients continue to be followed and this analysis was for the five-year period March 2003 to February 2008.

About half of the first group (23 of the 47) who did not initially start treatment would later do so because of falling CD4 count and rising viral load. Some 10 patients who received early HAART and then an interruption would later restart therapy for the same reasons. Those in the untreated group went an average of 126 weeks before starting HAART, while those in the treated group restarted therapy after an average of 181 weeks off of treatment.

"Early treatment prolonged time off treatment by more than a year," said researcher Radjin Steingrover. Just how close to the point of infection these patients started therapy is unclear. "We only have data from the time of seroconversion to the start of treatment, on average that was three weeks," Steingrover said.

The most intriguing fact is that "five patients (about 10 percent) have an extreme amount of viral control after treatment and interruption, they may very well be long-term non-progressors," said Steingrover. "Several of them have [viral load] less than the limit of detection over a couple of years."

Study of individual patients suggests that starting therapy closer to the point of infection has the greatest impact on bolstering the immune response and affecting the long-term course of HIV infection.

The window for intervention likely is only a few weeks long, perhaps only a few days. This makes it difficult to study the phenomena, and nearly impossible to envision very early intervention as a major treatment strategy. However, insights from studying very early intervention may provide insights to developing a vaccine that helps patients better control the virus.

Source

data


Initiating rather than Deferring HAART at a CD4+ Count >500 Cells/mm3  Is Associated with Improved Survival

Background:  The optimal time to initiate HAART for asymptomatic HIV-infected individuals is uncertain. Emerging data about the benefits of earlier ART, such as improved response to therapy and preservation of immune function, suggest that initiating HAART earlier in the course of HIV disease may improve outcomes. Prior studies have been limited by insufficient size, follow-up, and methods to compare survival for patients who initiate HAART with those who defer treatment from the same CD4 cell count level.

Methods:  In a Canadian and US collaboration of observational cohorts, we examined all participants with a CD4 count >500 cells/mm3 between 1996 and 2006 who were free of clinical AIDS and ART-naïve. We compared the relative hazard (RH) of death for patients who initiated HAART at a CD4 count >500 with those who deferred using an inverse-probability weighted Cox proportional hazards analysis stratified by cohort and calendar-year, and adjusted for demographic and clinical characteristics. Patients who deferred HAART at a CD4 count >500 whose CD4 count fell to <350 without initiating HAART were censored at that time regardless of whether they subsequently started HAART.

Results:  The analysis currently includes 9174 patients who contribute 25,337 person-years of follow up; 2620 (29%) initiated HAART at a CD4 count >500 and the remaining 6553 (71%) deferred. The proportion of patients initiating HAART at a CD4 count >500 by year peaked in 1997 to 1998 (16%) and declined <10% by 2003; median (IQR) CD4 count at initiation was 674 (579 to 831), and 196 patients died. Among patients who deferred, median (IQR) CD4 count for the 602 who initiated HAART between 350 and 500 was 435 (397 to 472), and 271 died. Patients who deferred treatment at a CD4 count >500 had significantly higher risk of mortality than those who initiated HAART (RH 1.4, 95%CI 1.1 to 1.7; p = 0.008). Increasing age (RH 1.5 95%CI 1.4 to 1.7; p <0.001), but neither baseline HIV-1 RNA nor CD4 count (within range >500) were independent predictors of mortality.

Conclusions:  In this large North American cohort collaboration, we found 36% higher risk of death for patients who deferred rather than initiated HAART at a CD4 count >500. We adjusted for several prognostic variables, but the decision to start treatment may involve additional factors that could confound these results. Our findings support the initiation of HAART earlier in the course of HIV disease than currently recommended.

Source

[John2038]

aidsonline

Protease inhibitor levels in hair strongly predict virologic response to treatment

Objective: Antiretroviral (ARV) therapies fail when behavioral or biologic factors lead to inadequate medication exposure. The currently available methods to assess ARV exposure are limited. Levels of ARVs in hair reflect plasma concentrations over weeks to months, and may provide a novel method for predicting therapeutic responses.

Design/methods: The Women's Interagency HIV Study, a prospective cohort of HIV-infected women, provided the basis for developing and assessing methods to measure commonly prescribed protease inhibitors (lopinavir/ritonavir and atazanavir) in small hair samples. We examined the association between hair protease inhibitor levels and initial virologic responses to therapy in multivariate logistic regression models.

Results: ARV concentrations in hair were strongly and independently associated with treatment response for 224 women starting a new protease inhibitor-based regimen. For participants initiating lopinavir/ritonavir, the odds ratio (OR) for virologic suppression was 39.8 [95% confidence interval (CI) = 2.8-564] for those with lopinavir hair levels in the top tertile (>1.9 ng/mg) compared to the bottom (=0.41 ng/mg) when controlling for self-reported adherence, age, race, starting viral load and CD4 cell count, and prior experience with protease inhibitors. For women starting atazanavir, the adjusted OR for virologic success was 7.7 (95% CI = 2.0-29.7) for those with hair concentrations in the top tertile (>3.4 ng/mg) compared to the lowest (=1.2 ng/mg).

Conclusion: Protease inhibitor levels in small hair samples were the strongest independent predictor of virologic success in a diverse group of HIV-infected adults. This non-invasive method for determining ARV exposure may have particular relevance for the epidemic in resource-poor settings due to the ease of collecting and storing hair.

Source


aegis

Breaking news: Obama names AIDS policy chief
President Obama today (Thursday, February 26) announced the appointment of an openly gay man with deep connections in the AIDS service community to head the White House Office of National AIDS Policy.

Jeffrey Crowley, a former officer at the National Association of People with AIDS and a current research scholar at the Georgetown University Health Policy Institute, will head up the Obama administration's efforts to address the HIV/AIDS epidemic. The position will also now be linked to efforts to help all people with disabilities - an expansion applauded by AIDS activists.

"It's exactly the kind of integration that folks in HIV community have been talking about for a while," said Earnest Hopkins, federal policy official for the San Francisco AIDS Foundation. Hopkins said the choice of Crowley for the position is "really good news."

"He's a good friend, he's smart, he goes very deep, as far as his knowledge base," said Hopkins. "He's been one of the external consultants to all the national AIDS folks who do AIDS work day to day. He's really an expert. We can be pretty assured the administration is going to support something that is supporting the needs of people with HIV."

Crowley, a former Peace Corps worker, earned a master's in public health from Johns Hopkins University and served as deputy executive director for programs at NAPWA. While at NAPWA, he helped with both the National HIV Testing Day campaign and the Ryan White National Youth Conference.

A spokesperson for the White House said Crowley starts work today.

In announcing Crowley's appointment, the White House also made clear that, despite some confusion over a recent executive order projected, the Office of National AIDS Policy "is part of the executive office of the President's Domestic Policy Council."

A February 5 executive order indicated that the position of AIDS policy coordinator - the head of the Office of National AIDS Policy - was to be struck from the membership of the White House Domestic Policy Council.

Carl Schmid, director of federal affairs for the AIDS Institute, said he hopes Crowley will be able to get to work immediately on developing a national AIDS strategy - a strategy that Obama said would be a goal for his first year in office.

"We'll hope he makes sure that gets off the ground, and we hope he'll be able to make sure there are increases for HIV prevention and Ryan White in the president's budget," Schmid said. The White House is releasing today a summary of its federal budget for FY 2010, but details are not expected until April.

Schmid said he hopes Crowley will also be able to advocate for directing some money from the stimulus package to go to HIV work. A specific earmark for some $400 million to go to HIV prevention efforts was lost after some Republicans claimed it amounted to spending millions of dollars on condoms.

Source


aidsmap

Recent infection, high viral load and STIs mean higher risk of onward HIV transmission for gay men

Recent HIV infection, sexually transmitted infections, and a higher blood viral load are associated with a higher risk of onward HIV transmission in gay men, according to research conducted in Brighton and presented to the recent Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal.

The researchers used phylogenetic, clinical and epidemiological data to model the transmission of HIV. Use of HIV treatment was associated with a significantly reduced risk of HIV transmission, but they found that many cases of transmission originated in men whose HIV had not been diagnosed. Furthermore, the investigators found two possible cases of HIV transmission involving individuals who apparently had an undetectable viral load.

There continue to be large numbers of new HIV infections in gay and other men who have sex with men. Such transmissions are continuing despite the availability of effective HIV treatment that not only improves the health of the individual but can, buy lowering viral load, also reduce the risk of HIV transmission.

Recent infection with HIV and untreated sexually transmitted infections are thought to be factors associated with an increased risk of HIV transmission. There is also some evidence to suggest that a substantial number of HIV infections originate in patients whose HIV is undiagnosed.

Studies in heterosexuals have shown the association between higher viral load and an increased risk of transmission and the disproportionate contribution that recently infected individuals make to the continued spread of HIV. Evidence from heterosexual couples has also demonstrated that HIV treatment can reduce the risk of HIV transmissions. However, researchers have been cautious about applying these findings to gay men.

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[John2038]

aidsmap

Poorer responses to lipid-lowering drugs in people with HIV
People with HIV had poorer responses to lipid-lowering drugs than the HIV-negative population, but these responses varied according to antiretroviral regimen and lipid-lowering drug, according to a major review of patients receiving treatment through California’s Kaiser Permanente managed care system in the San Francisco area. The findings were published in Annals of Internal Medicine.

The study is the largest and most rigorous comparison to date of the effects of lipid-lowering treatments in people with HIV and the general population.

Cholesterol and triglyceride levels may be altered in untreated people with HIV due to effects of HIV infection (lowered levels of `good` HDL cholesterol and elevated triglyceride levels) or effects of some antiretroviral drugs, particularly all the protease inhibitors apart from atazanavir (elevated levels of `bad` LDL cholesterol and triglycerides, normalisation of HDL cholesterol).

..

Reductions in triglyceride levels as a result of gemfibrozil treatment were significantly smaller in HIV-positive people (44.2% vs 59.3%, p<0.001), but when responses were analysed according to antiretroviral drug class, people taking non-nucleoside reverse transcriptase inhibitors (NNRTIs) showed a similar triglyceride reduction to that seen in HIV-negative people.

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Treatment intensification does not eliminate HIV in reservoir sites
HIV continues to be released in small amounts from "reservoir" sites in the body despite suppressive antiretroviral therapy, and adding more drugs has not succeeded in eradicating the virus, researchers reported at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal last month.

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esciencenews

Largest study compares cholesterol treatment in HIV patients and patients without HIV
A new study in the online issue of Annals of Internal Medicine has found that cholesterol medications can work well among certain HIV patients at risk for cardiovascular disease. Though HIV patients are at higher risk for cardiovascular disease in part due to lipid abnormalities that can occur with the use of certain antiretroviral therapies, researchers now have evidence that cholesterol medications work very well in this population.

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Researchers unveil new monkey model for HIV
Scientists have succeeded in infecting pig-tailed macaque monkeys with a human version of the virus that has until now been impossible to study directly in animals. The new strain of HIV has already been used to demonstrate one method for preventing infection and, with a little tweaking, could be a valuable model for vetting vaccine candidates.


A pig-tailed macaque

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newkerala

New type of vaccination may provide instant immunity against diseases
Washington, March 3 : Scripps research scientists say that a new vaccination method they have developed may be used to provide instantaneous protection against diseases caused by viruses and bacteria, cancers, and even virulent toxins.

Professor Carlos Barbas, III, says that tests on mice suggest that the vaccination method called covalent immunization can overcome a major drawback of vaccinations - the lag time of days, or even weeks, that it normally takes for immunity to build against a pathogen.

He revealed that his team tested the vaccination method on mice with either melanoma or colon cancer.

Describing the study in the Proceedings of the National Academy of Sciences (PNAS), the researcher said that the mice were injected with chemicals specifically designed to trigger a programmable and "universal" immune reaction.

They developed other chemicals, "adapter" molecules," that recognized the specific cancer cells.

The researchers said that after being injected into the mice, the adapter molecules self-assembled with the antibodies to create covalent antibody-adapter complexes.

"The antibodies in our vaccine are designed to circulate inertly until they receive instructions from tailor-made small molecules to become active against a specific target," Barbas says.

"The advantage of this method is that it opens up the possibility of having antibodies primed and ready to go in the time it takes to receive an injection or swallow a pill. This would apply whether the target is a cancer cell, flu virus, or a toxin like anthrax that soldiers or even civilian populations might have to face during a bioterrorism attack," adds the researcher.

Barbas revealed that only those mice that had received both the vaccine and the adapter compound generated an immediate immune attack on the cancer cells, which led to significant inhibition of tumour growth.

This is the first time that any research team have successfully designed and tested such a covalent vaccine.

"Our approach differs from the traditional vaccine approach in the sense that when we design an antibody-adapter compound we know exactly what that compound will react with," Barbas says.

"The importance of this is best exemplified with HIV. In current vaccines, many antibodies are generated against HIV, but most are not able to target the active part of the virus," the researcher adds.

He is currently planning future studies so that his team may apply their covalent vaccination approach to HIV, cancer, and infectious diseases for which no vaccines currently exist.

"We believe that chemistry-based vaccine approaches have been underexplored and may provide opportunities to make inroads into intractable areas of vaccinology," Barbas says.

Source


hivandhepatitis

Lopinavir/ritonavir (Kaletra) Monotherapy May Be Hazardous for Patients with a History of Low CD4 Cell Counts
Given the side effects, inconvenience, and cost of combination antiretroviral therapy, researchers have explored various strategies for simplifying treatment, including monotherapy using a single boosted protease inhibitor (PI).

Monotherapy using nucleoside reverse transcriptase inhibitors (NRTIs) prior to the HAART era led to drug resistance and poor outcomes. More recent studies of monotherapy using lopinavir/ritonavir (Kaletra) or ritonavir-boosted atazanavir (Reyataz) have produced promising results in some patients who achieved viral suppression (HIV RNA < 50 copies/mL) prior to regimen simplification.

But maintenance monotherapy may not produce adequate viral suppression in people with a history of severe immune system impairment and may not reach all body "compartments," according to a study presented at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last month in Montreal.

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NNRTI Microbicide UC781 Appears Safe for Rectal Use
Microbicides are being studied in large trials as a means of preventing transmission of HIV to women during vaginal intercourse, but there is also an urgent need to test these products for rectal safety, since any approved product will inevitably be used for anal sex by both heterosexual and homosexual couples.

In a poster at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last month in Montreal, Peter Anton from the University of California at Los Angeles and colleagues presented the first data from a Phase 1 trial evaluating at the acceptability and rectal safety of a microbicide gel containing UC781, an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI).

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natap

Preferential Bone Demineralization at the Hip in Treated HIV+ Males: Another Example of Premature Aging?
 In both younger and older treated HIV+ males, more bone mineral density loss occurs at the total hip than at the lumbosacral spine. This differs from the pattern of bone mineral density loss observed in age-matched controls wherein the bone mineral density is similar at the total hip and the lumbosacral regions in both younger and older subjects.. Significantly, the extent of bone mineral density loss at the hip in younger HIV+ males is greater than in older controls. This preferential loss of hip bone mineral density, occurring much earlier in this population, may predict an increased risk of morbidity and fragility fractures.
 
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Changes in Bone Turnover, OPG/RANKL, and Inflammation with ART Initiation: A Comparison of Tenofovir- and Non-Tenofovir-Containing Regimens
Prior to ART initiation, bone resorption activity was high among young, untreated HIV-infected patients.
 
After 6-12 months of ART initiation, bone turnover increased markedly.
 
Changes in bone turnover were not associated with systemic concentrations of OPG or RANKL or changes in these markers.
 
Advanced HIV disease was associated with greater increases in bone resorption with ART initiation.
 
Tenofovir use, PI use and higher baseline TNFalpha activity were independently associated with increases in osteocalcin with ART initiation.
 
The acceleration of bone turnover with high levels of bone resorption may account for the decreases in bone mineral density with ART initiation observed in previous studies.

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aidsonline

HSV suppression reduces seminal HIV-1 levels in HIV-1/HSV-2 co-infected men who have sex with men
Objectives: Suppressive herpes simplex virus (HSV) therapy can decrease plasma, cervical, and rectal HIV-1 levels in HIV-1/HSV-2 co-infected persons. We evaluated the effect of HSV-2 suppression on seminal HIV-1 levels.

Design: Twenty antiretroviral therapy (ART)-naive HIV-1/HSV-2 men who have sex with men (MSM) in Lima, Peru, with CD4 >200 cells/µl randomly received valacyclovir 500 mg twice daily or placebo for 8 weeks, then the alternative regimen for 8 weeks after a 2-week washout. Peripheral blood and semen specimens were collected weekly. Anogenital swab specimens for HSV DNA were self-collected daily and during clinic visits.

Methods: HIV-1 RNA was quantified in seminal and blood plasma by TaqMan real-time polymerase chain reaction (RT-PCR) or Roche Amplicor Monitor assays. HSV and seminal cytomegalovirus (CMV) were quantified by RT-PCR. Linear mixed models examined differences within participants by treatment arm.

Results: Median CD4 cell count of participants was 424 cells/µl. HIV-1 was detected in 71% of 231 semen specimens. HSV was detected from 29 and 4.4% of swabs on placebo and valacyclovir, respectively (P < 0.001). Valacyclovir significantly reduced the proportion of days with detectable seminal HIV-1 (63% during valacyclovir vs. 78% during placebo; P = 0.04). Seminal HIV-1 quantity was 0.25 log10 copies/ml lower [95% confidence interval (CI) -0.40 to -0.10; P = 0.001] during the valacyclovir arm compared with placebo, a 44% reduction. CD4 cell count (P = 0.32) and seminal cellular CMV quantity (P = 0.68) did not predict seminal plasma HIV-1 level.

Conclusions: Suppressive valacyclovir reduced seminal HIV-1 levels in HIV-1/HSV-2 co-infected MSM not receiving ART. The significance of this finding will be evaluated in a trial with HIV-1 transmission as the outcome.

Source


Depletion of CD4+ T Cells in Semen During HIV Infection and Their Restoration Following Antiretroviral Therapy
Background: Information concerning the effects of HIV-1 infection, disease progression, and antiretroviral therapy (ART) on male genital white blood cell (WBC) profiles could provide important insight into genital immune defense in HIV-infected men and seminal HIV transmission mechanisms.

Objective: To compare concentrations of WBC populations in semen from HIV-1-seronegative (HIV-) and HIV-1-seropositive (HIV+) men and determine whether HIV disease stage and ART are associated with alterations in seminal WBC profiles.

Subjects and Methods: Subjects were 102 HIV- men, 98 ART-naive (ART-) HIV+ men, and 22 HIV+ men on dual nucleoside ART, before and 6 months after addition of indinavir. Seminal WBCs, macrophages (MØ), and T-lymphocyte subpopulations were enumerated by immunohistology technique.

Results: Seminal CD4+ and CD8+ T-cell populations were severely depleted in most ART- HIV+ men regardless of peripheral blood CD4+ cell count. Seminal MØ counts were reduced by 50%. HIV+ men on dual nucleoside ART had significantly higher seminal MØ, CD4+, and CD8+ T-cell counts than ART- HIV+ men; addition of indinavir led to a dramatic (>25-fold, P < 0.001) increase in seminal CD4+ T-cell counts which paralleled an increase in blood CD4+ cell counts. Two outlier ART- HIV+ men with notably elevated seminal WBC profiles (>20 × 106 WBCs/mL) and infectious cell-associated HIV in semen are described.

Conclusions: HIV infection severely depletes CD4+ T cells in the male genital tract as it does at other mucosal sites. This provides evidence that ART- HIV+ men have depressed T cell-dependent genital immune defense functions and are vulnerable to other genital infections that could promote HIV transmission. Seminal CD4+ T-cell counts rebounded after treatment with a viral-suppressing ART regimen, indicating that ART may reverse HIV-associated genital immunosuppression. The relative abundance of seminal MØ in HIV+ men suggests that these cells may be predominant HIV host cells in the male genital tract and vectors of HIV transmission. A subgroup of HIV+ men with exceptionally elevated seminal MØ and CD4+ T-cell counts and HIV titers may be highly infectious and contribute disproportionately to HIV transmission.

Source

[John2038]

natap

Evidence of persistent low-level viremia in long-term HAART-suppressed individuals

Results

Ultra-sensitive Plasma HIV-1 RNA Levels
A total of 1606 TMA assays were performed on 438 specimens in 180 HAART-suppressed subjects (median 3 replicates per specimen). In the first year of viral suppression, plasma RNA levels declined at a rate of -0.25 S/Co per month (p=0.001), but after month 12 there was no evidence for a continued decline (p=0.383) (Figure 2).
 
HIV-1 antibody levels
A total of 189 LS-EIA's were performed on 98/180 HAART- suppressed subjects. In the first year of viral suppression, HIV antibody levels declined at a rate of - 0.10 SOD per month (p=0.054), but after month 12 there was no evidence for a continued decline (p=0.988) (Figure 3).
 
Conclusions
Residual viremia is commonly observed in long-term HAART-suppressed patients, and appears to remain stable after 1 year of viral load suppression
 
There is an initial decline in HIV antibody levels that occurs shortly after suppression of plasma viral load. HIV antibody levels subsequently stabilize during long-term HAART, suggesting a steady-state relationship between virus and the host.





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Osteopenia and Osteoporosis in HIV-infected Patients Are Associated with Reduced Frequency of Central Memory CD8+CD127+ T Cells: T-cell activation/senescence associated with bone loss
Our data show lower mean frequency of central memory CD8+CD127+ in HIV+ patients with bone metabolism disorders, independently of demographic, HIV and HAART conditions. Given that the loss of CD127 in HIV/AIDS has been related to enhanced T cell activation/senescence, accelerated turnover and reduced function, our data suggest immune hyper-activation and T cell exhaustion as a pathogenetic pathway of HIV-related bone perturbations. Furthermore, our findings identify CD8+CD127+ as a novel feature of the HIV-associated bone metabolism disorders

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Brain Damage, Comorbidities and Early Death Threaten HIV+
High rates of comordities and deaths due to these comorboidities, and at early ages, were reported at CROI. This is not surprising. Reported at CROI were increased rates of certain cancers, kidney disease, liver disease/failure, bone disease, and cardiovascular disease, all exacerbated by aging, and these comorbidities occurred in the studies at average ages of patients in their 40s. Also at CROI were a series of studies of cognitive function, neuropathy, and the brain all suggesting finding high rates of cognitive impairment & neuropathy, and the rates remain high, they have not gone down despite HAART. There were 2 studies both with links to them below, finding brain damage from HIV despite HAART and early aging of the brain, accelerated aging estimated to be 15-20 years! There were a number of studies on aging suggesting that HIV causes early aging, early senesence, aging of the T-cell repertoire similar to that seen in elderly HIV-negative individuals, and inflammation and immune activation due to HIV are also causative

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Tenofovir and PI Use Are Associated with an Increased Prevalence of Proximal Renal Tubular Dysfunction in the Swiss HIV Cohort Study: boosted PI+TDF associated with renal function
Proximal renal tubular dysfunction is frequent in cART-treated patients. The prevalence is increased in patients treated with TDF, especially in combination with a PI. This pathophysiologically plausible link between the documented renal dysfunction and osteopenia or osteoporosis should be assessed in further studies.

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yahoo

Microbicide gel 'highly encouraging' in lab tests
PARIS (AFP) – The dogged search for a vaginal gel to thwart the AIDS virus earned some good news on Wednesday as scientists announced that a cheap, commonly-used compound shielded monkeys from a lethal cousin of HIV.

They cautioned that a long road lies ahead before the microbicide can be verified as safe and effective for humans but hailed the outcome as a tremendous boost.

A cream that blocks or kills the human immunodeficiency virus (HIV) is a cornerstone of efforts in the fight against AIDS. It would be especially useful for women in sub-Saharan Africa, at risk from coercive sex from HIV-infected partners.

But the quest has suffered many blows. They include two trials that, dismayingly, found women who used a prototype gel ran a greater risk of HIV than those who used a dummy lookalike.

In a study published in Nature, researchers at the University of Minnesota tested a compound called glycerol monolaurate (GML).

GML exists naturally in the human body but is already licensed as an antimicrobial and anti-inflammatory agent in cosmetics and toiletries and as an emulsifier in foods.

Their hunch was that GML interferes with signalling processes in the immune system, thus blocking HIV's rampage at a key stage.

When the virus enters the body, defence systems unleash a cascade of orders, dispatching so-called T immune cells to the site of the infection.

It is these cells that are then hijacked by HIV and turned into virus-making mini-factories, enabling the agent to proliferate throughout the bloodstream.

"Even though it sounds counter-intuitive, halting the body's natural defence system might actually prevent transmission and and rapid spread of the infection," said chief investigator Ashley Haase.

The team gave a vaginal application of GML gel to five rhesus macaque monkeys and exposed them and a comparison group of five other animals to two large doses of simian immunodeficiency virus (SIV) -- the monkey equivalent of HIV.

Over the next two weeks, four of the control group contracted SIV. But none of the GML-treated group showed any acute infection, even though they were given up to two further shots of the virus.

GML, said the paper, breaks a "vicious cycle" of immune-system signalling and inflammatory response in the cervix and vagina.

"This result represents a highly encouraging new lead in the search for an effective microbicide to prevent HIV-1 transmission that meets the criteria of safety, affordability and efficacy," it declared.

Each dose of GML used in the experiment cost less than one US cent (0.75 of a euro cent).

GML's use as a microbicide and anti-inflammatory was discovered by one of the researchers, Pat Schlievert, when he probed so-called toxic shock syndrome in the use of menstrual tampons.

He found that GML inhibited the toxin-making mechanism of the germ Staphylococcus aureus. Tampons coated with GML protected women from the bacterium and eased vaginal inflammation.

"GML is exceptionally inexpensive, is widely used in foods and cosmetics and is easy to formulate in many ways for vaginal use," said Schlievert.

He added that the compound had been repeatedly tested as safe and had no effect on beneficial vaginal bacteria.

Last month, scientists reported the first positive trial of a microbicide, a formula called PRO 2000, but said it reduced the risk of infection only by around 30 percent.

This is only half of the minimum benchmark for success. Availability of a microbicide that is 60 percent effective would avert two and a half million infections over three years, according to a 2003 mathematical study.

Around 33 million people around the world have HIV, two-thirds of them south of the Sahara. Globally, women make up 50 percent of all HIV-infected people, but in Africa, this rises to nearly 60 percent.

Source


medicalnewstoday

Hospice For HIV-Positive People In Thailand
The Wat Phra Baht Nam Phu temple, a hospice for people living with HIV/AIDS in Thailand, has provided care to more than 10,000 HIV-positive people out of the estimated 610,000 people living with the virus in the country, the AFP/MSN.com reports. People often come to the temple anonymously and without notice, according to AFP/MSN.com. The hospice was founded 17 years ago as a place to care for HIV/AIDS patients, many of whom face discrimination because of the high amount of stigma surrounding the disease. People can access some medical services, and the temple's principles are "steeped in its Buddhist faith," AFP/MSN.com reports.

One Indian nurse and one Cambodian doctor -- who is not permitted to prescribe medicines -- care for 120 residents and 300 non-resident patients. In emergency cases, patients are sent to a nearby hospital to receive antiretroviral treatment. The temple's clinic workers attempted to hire more doctors by appealing to nearby hospitals and the health department, but they had no applicants. Ching Thangsing, the nurse who works at the clinic, said, "I think [doctors] are afraid of HIV, they don't want to work with HIV-positive patients." The temple aims to combat the stigma surrounding the disease by welcoming school groups to its museums and monuments, as well as to a shrine that contains the ashes of 10,000 former residents. Japanese volunteer Katsumi Suzuki said, "This is a very unique place. It crosses the area between Buddhism and medicine" (Truscott, AFP/MSN.com, 2/28).
Hospice For HIV-Positive People In Thailand

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aidsmap

Low HDL cholesterol linked to cardiovascular disease in people with HIV
Lower levels of beneficial high-density lipoprotein (HDL) cholesterol - but not of harmful low-density lipoprotein (LDL) - were associated with cardiovascular disease in the SMART treatment interruption study, researchers reported on February 11th at the Sixteenth Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal, Canada

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LDL cholesterol plays a role in the build-up of plaque on artery walls, a process that can result in loss of elasticity (atherosclerosis), inflammation, clotting and ultimately blockage of blood flow to the heart or brain. Very low-density lipoprotein (VLDL) particles contain more triglyceride and are also considered harmful. Conversely, HDL carries cholesterol away for disposal and therefore helps prevent atherosclerosis. HDL particles are roughly one-third the size of LDL particles, whilst VLDL particles are many times larger.

Studies in the general population have shown that high LDL (especially small, dense LDL particles) and low HDL levels are predictors of cardiovascular disease. Since HDL was found to decline significantly more in SMART participants who interrupted treatment than in those who remained on continuous therapy, this unfavourable lipid change could offer a possible explanation for the increased risk of cardiovascular events seen in the treatment interruption arm.

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Most study participants (about 80%) were men and the median age was 49 years. Not surprisingly, those in the cardiovascular disease group were more likely to have cardiovascular risk factors including smoking, diabetes and high blood pressure. Baseline total cholesterol, LDL and triglyceride levels were similar in both groups, but those with cardiovascular disease had a lower median HDL level.

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Continuous antiretroviral therapy improves survival in HIV/hepatitis C co-infected patients with liver cirrhosis
Antiretroviral therapy - but not treatment for chronic hepatitis C virus (HCV) infection - was associated with significantly improved survival in HIV/HCV co-infected individuals with liver cirrhosis, researchers reported on February 10th at the Sixteenth Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal, Canada.

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annals

Response to Newly Prescribed Lipid-Lowering Therapy in Patients With and Without HIV Infection
Background:  Antiretroviral agents, particularly protease inhibitors (PIs), may adversely affect lipid levels in patients with HIV infection. However, it is not known whether HIV-associated dyslipidemia is more difficult to treat.

Objective: To compare the effectiveness and safety of lipid-lowering therapy in patients with and without HIV infection.

Design: Retrospective cohort study.

Setting: Integrated health care delivery system from 1996 to 2005.

Patients: 829 patients with HIV infection and 6941 patients without HIV infection beginning lipid-lowering therapy for elevated low-density lipoprotein cholesterol or triglyceride levels.

Measurements: Percentage change in lipids within 12 months and adverse liver- and muscle-related clinical and laboratory events.

Results: Compared with patients without HIV infection, patients with HIV infection beginning statin therapy had smaller reductions in low-density lipoprotein cholesterol levels (25.6% vs. 28.3%; P = 0.001), which did not vary by antiretroviral therapy class. Patients with HIV infection beginning gemfibrozil therapy had substantially smaller reductions in triglyceride levels than patients without HIV infection (44.2% vs. 59.3%; P < 0.001), and reductions with gemfibrozil varied by antiretroviral therapy class (44.0% [P = 0.001] in patients receiving PIs only, 26.4% [P < 0.001] in patients receiving PIs and nonnucleoside reverse transcriptase inhibitors [NNRTIs], and 60.3% [P = 0.94] in patients receiving NNRTIs only). Rhabdomyolysis was diagnosed in 3 patients with HIV infection and 1 patient without HIV infection. No clinically recognized cases of myositis or myopathy were observed. The risk for laboratory adverse events was low (<5%), although it was increased in patients with HIV infection.

Limitations: Laboratory measurements were not uniformly performed according to HIV status, and adequate fasting before lipoprotein testing could not be verified. Results may not be completely generalizable to uninsured persons, women, or certain racial or ethnic minorities.

Conclusion: Dyslipidemia, particularly hypertriglyceridemia, is more difficult to treat in patients with HIV infection than in the general population. However, patients with HIV infection receiving NNRTI-based antiretroviral therapy and gemfibrozil had triglyceride responses similar to those in patients without HIV infection.

Funding: GlaxoSmithKline.

Source

[John2038]

biologynews

Gene therapy shows promise as weapon against HIV

A new UCLA AIDS Institute study has found that gene therapy can be developed as a safe and active technique to combat HIV.

Researchers involved in this first-of-its-kind study found that cell-delivered gene transfer has the potential to be a once-only treatment that reduces viral load, preserves the immune system and avoids lifelong antiretroviral therapy. The study appears in the current online edition of the journal Nature Medicine.

Though modest, the results do show some promise that gene therapy can be developed as a potentially effective treatment for HIV, said lead investigator Dr. Ronald Mitsuyasu, professor of medicine and director of the Center for Clinical AIDS Research and Education (CARE) at the David Geffen School of Medicine at UCLA.

"It is the first randomized controlled study done with gene therapy in HIV," said Mitsuyasu, who is also an associate director of the UCLA AIDS Institute. "What we were able to demonstrate was that the patients who received the gene-modified cells had a somewhat better suppression of their HIV viral replication after discontinuing their highly active antiretroviral therapy (HAART) treatment, compared with the controls."

This was the first randomized, double-blind, placebo-controlled gene-transfer clinical trial and involved 74 HIV-positive adults.

The patients received their own blood stem cells, either untreated or modified to carry a molecule called OZ1, which prevents viral replication by targeting a key HIV gene. OZ1 was safe, causing no adverse effects over the course of the 100-week trial.

At the primary end-point, the difference in viral load between the OZ1 and placebo group at weeks seven and eight, after they had stopped HAART treatment, was not statistically significant. But other viral parameters did demonstrate better HIV suppression and improvement in the counts of CD4+ lymphocytes — the cell population that is depleted by HIV.

The technique still needs to be developed further and perfected, Mitsuyasu said.

"Part of the reason that we didn't see a larger effect is that the persistence of the anti-HIV gene in the patient's blood was not as long as we would have liked," he said. "We need to find better ways to get the genes into the patients and maintain them, which could include using different vectors to get the gene into the cells or conditioning the patients prior to gene transfer."

Still, the results indicate that gene therapy could eventually be a useful tool in the fight against AIDS, said study co-author Dr. Thomas C. Merigan, the George and Lucy Becker Professor of Medicine emeritus at the Stanford University School of Medicine. He agrees that more needs to be done to perfect it.

"But in the way we set up the trial with randomized placebo controls, we could dissect out that there was a positive effect in patients who had the gene successfully installed," Merigan said. "This could be a first step in developing a new method of controlling a chronic infectious disease."

Source

[John2038]

news-medical


Positive emotions critical for upkeep of physical health

A researcher from the University of Kansas has spearheaded a new investigation into the link between emotions and health.

The research proves that positive emotions are critical for upkeep of physical health for people worldwide, above all for those who are deeply impoverished.

The study, a joint undertaking between KU and Gallup, will be presented today at the annual meeting of the American Psychosomatic Society in Chicago.

"We've known for a while now that emotions play a critical role in physical health," said Sarah Pressman, assistant professor of psychology at KU and a Gallup senior research associate. "But until recently, most of this research was conducted only in industrialized countries. So we couldn't know whether feelings like happiness or sadness matter to the health of people who have more pressing concerns - like getting enough to eat or finding shelter. But now we do."

Data from the Gallup World Poll drove the findings, with adults in more than 140 countries providing a representative sample of 95 percent of the world's population. The sample included more than 150,000 adults.

Participants reported emotions such as happiness, enjoyment, worry and sadness. They described their physical health problems - such as pain and fatigue - and answered questions about whether their most basic needs like food, shelter and personal safety were adequately met.

According to Pressman, positive emotions unmistakably are linked to better health, even when taking into account a lack of basic needs. The inverse holds true as well: Negative emotions were a reliable predictor of worse health.

Most strikingly, the association between emotion and physical health was more powerful than the connection between health and basic human physical requirements, like adequate nourishment. Even without shelter or food, positive emotions were shown to boost health. Indeed, this association was strongest in the poorest countries surveyed.

Thus, the link between emotional health and physical health looks to be a worldwide fact, and especially so for people living with the fewest creature comforts.

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