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Author Topic: http://natap.org/  (Read 126878 times)

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Offline red_Dragon888

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http://natap.org/
« on: January 13, 2010, 07:25:22 pm »
Chloroquine To Block Immune Activation

"Chronic immune activation is a hallmark of HIV-1 pathogenesis....Our results suggests that a safe well tolerated drug such as chloroquine can be proposed as an adjuvant therapeutic candidate along with HAART to control immune activation in HIV-1 infection.....Chloroquine is widely accessible, inexpensive and is well tolerated when administered over periods of several years making it a good candidate for adjuvant therapy along with HAART to control immune activation in HIV-1 infection. The relevance of the findings presented in this study are particularly important as it is now known that non AIDS defining illnesses such as atherosclerosis, liver disease, renal diseases that occur despite effective HAART contribute to mortality. Immune activation and inflammation are the key contributing factors linked to these co-morbidities (49). The use of chloroquine as an adjuvant with HAART could be an effective and inexpensive approach to control immune activation and reduce the risk of comorbidities in HAART treated HIV infected individuals. The use of chloroquine in HIV-1 infected individuals in resource rich and resource poor countries need to be further investigated.....HIV-1 infection hijacks the innate immune response which directly contributes to disease pathogenesis. Chronic stimulation of pDC with non-infectious and infectious virions leads to their enhanced activation, state, production of the cytokine IFNα and an up-regulation of IDO and PDL-1, all of which are known to directly contribute to decreased T cell survival, proliferation, and function. In this study, we have shown that chloroquine blocks TLR signaling in pDC, a critical step in its activation pathway. By blocking pDC activation we observed a decrease in the immunoregulatory cytokine IFNα which in turn could reduce IFNα mediated immune activation and improve T cell survival by blocking negative modulators like IDO and PDL-1."


Chloroquine Modulates HIV-1 Induced Plasmacytoid Dendritic Cell IFN{alpha}: Implication for T cell Activation



Antimicrob. Agents Chemother. doi:10.1128/AAC.01246-09

published online ahead of print on 30 November 2009



Jeffrey A. Martinson, Carlos J. Montoya, Xiomara Usuga, Rollie Ronquillo, Alan L. Landay, and Seema N. Desai*




Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL-USA; Group of Immunovirology-Biogenesis, University of Antioquia, Medellin-Colombia




* To whom correspondence should be addressed. Email: Seema_N_Desai@rush.edu.



ABSTRACT
Plasmacytoid dendritic cell (pDC) mainly contribute to antiviral immunity through recognition of microbial products and viruses via intracellular toll-like receptors (TLR) 7 or 9 that results in the production of type I interferons. Though interferons reduce viral burden in acute phase of infection their role in chronic phase is unclear. Presence of elevated plasma IFN{alpha} levels in advanced HIV disease and its association with microbial translocation in chronic HIV infection lead us to hypothesize that IFN{alpha} could contribute to immune activation. Blocking IFN{alpha} production using chloroquine an endosomal inhibitor was tested in a novel in vitro model system with the aim to characterize the effects of chloroquine on HIV-1 mediated TLR signaling, IFN{alpha} production and T cell activation. Our results indicate that chloroquine blocks TLR mediated activation of pDC and MyD88 signaling as shown by decrease in the downstream signaling molecules IRAK-4, IRF-7 and inhibition of IFN{alpha} synthesis. Chloroquine decreased CD8 T cell activation induced by AT-2 HIV-1 in PBMC cultures. In addition to blocking pDC activation, chloroquine also blocked negative modulators of T cell response like IDO (indoleamine 2, 3-dioxygenase) and PDL-1 (programmed death ligand-1). Our results indicate that TLR stimulation and production of IFN-{alpha} by pDC contribute to immune activation, and blocking these pathways using chloroquine may interfere with events contributing to HIV pathogenesis. Our results suggests that a safe well tolerated drug such as chloroquine can be proposed as an adjuvant therapeutic candidate along with HAART to control immune activation in HIV-1 infection.

NATAP http://natap.org/

« Last Edit: January 13, 2010, 07:31:09 pm by red_Dragon888 »
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Offline red_Dragon888

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Re: NATAP: Update
« Reply #1 on: January 13, 2010, 07:29:01 pm »
GS-9148 Nucleotide Active Against Resistance


 "GS-9148 retained its activity against viruses with four or more TAMs, including combinations containing the M41L and L210W mutations....Viruses carrying the K65R, K70E, L74V, or M184V mutation, as well as various combinations thereof, were fully susceptible or slightly hypersensitive to GS-9148.....GS-9148 showed a minimal loss of activity against a multidrug-resistant virus containing TAMs in combination with M184V and an insertion at T69......suggesting a less effective renal transport and possibly a lower potential for nephrotoxicity than that of acyclic nucleotide analogs. Finally, quantitative studies confirmed that despite increased cellular permeation, GS-9131 at concentrations of up to 50 µM did not cause any selective depletion of mtDNA in HepG2 cells (data not shown), an observation consistent with the low potential of GS-9148 to interfere with the replication of mtDNA."


The HIV-1 RT Mutant Q151L Shows Decreased Replication Capacity, Selective High-Level Resistance to GS-9148 and Hypersusceptibility to Tenofovir and Zidovudine - (06/15/09)
GS9148: A Novel Nucleotide Active Against HIV-1 Variants with Drug ...
Feb 6, 2006 ... Preliminary pre-clinical data shows GS9148 appears potent and safe, and did not show an effect on mitochondrial DNA; was effective against ...
www.natap.org/2006/CROI/CROI_02.htm
Inefficient Renal Transport of Nucleotide Reverse Transcriptase ...
GS-9148 is a novel nucleotide HIV RT inhibitor active against a variety of ... GS-9148 showed relatively inefficient transport by the renal uptake ...
www.natap.org/2008/CROI/croi_107.htm
Novel Nucleotide Inhibitor GS-9148 Selects for a K70E Mutation in ...
GS-9148 (Fig. 1) is a novel nucleotide HIV RT inhibitor with a favorable in vitro resistance profile against HIV-1 strains with clinically relevant ...
www.natap.org/2007/ICAAC/ICAAC_28.htm




Design and Profiling of GS-9148, a Novel Nucleotide Analog Active against Nucleoside-Resistant Variants of Human Immunodeficiency Virus Type 1, and Its Orally Bioavailable Phosphonoamidate Prodrug, GS-9131



Antimicrobial Agents and Chemotherapy, February 2008

Tomas Cihlar,1* Adrian S. Ray,1 Constantine G. Boojamra,1 Lijun Zhang,1 Hon Hui,1 Genevieve Laflamme,1 Jennifer E. Vela,1 Deborah Grant,1 James Chen,1 Florence Myrick,2 Kirsten L. White,1 Ying Gao,1 Kuei-Ying Lin,1 Janet L. Douglas,1 Neil T. Parkin,3 Anne Carey,1 Rowchanak Pakdaman,1 and Richard L. Mackman1

Gilead Sciences, Foster City, California,1 Gilead Sciences, Durham, North Carolina,2 Monogram Biosciences, South San Francisco, California3




GS-9131 is an attractive clinical development candidate for the treatment of patients infected with NRTI-resistant HIV.....The discovery of the favorable resistance profile of the previously described nucleoside phosphonate d4AP (20) was an important initial step toward the design of GS-9148.....Results from a PhenoSense analysis indicate that GS-9148 meets the target resistance profile set for the development candidate by maintaining its activity against multiple patient-derived HIV strains with the major known NRTI resistance mutations. Importantly, its profile appears to be distinct from that of the clinically approved NRTIs in that GS-9148 was the only inhibitor tested that showed no reduction in potency due to K65R, L74V, and M184V mutations, together with the minimal resistance associated with multiple TAMs

ABSTRACT


GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] is a novel ribose-modified human immunodeficiency virus type 1 (HIV-1) nucleotide reverse transcriptase (RT) inhibitor (NRTI) selected from a series of nucleoside phosphonate analogs for its favorable in vitro biological properties including (i) a low potential for mitochondrial toxicity, (ii) a minimal cytotoxicity in renal proximal tubule cells and other cell types, (iii) synergy in combination with other antiretrovirals, and (iv) a unique resistance profile against multiple NRTI-resistant HIV-1 strains. Notably, antiviral resistance analysis indicated that neither the K65R, L74V, or M184V RT mutation nor their combinations had any effect on the antiretroviral activity of GS-9148. Viruses carrying four or more thymidine analog mutations showed a substantially smaller change in GS-9148 activity relative to that observed with most marketed NRTIs. GS-9131, an ethylalaninyl phosphonoamidate prodrug designed to maximize the intracellular delivery of GS-9148, is a potent inhibitor of multiple subtypes of HIV-1 clinical isolates, with a mean 50% effective concentration of 37 nM. Inside cells, GS-9131 is readily hydrolyzed to GS-9148, which is further phosphorylated to its active diphosphate metabolite (A. S. Ray, J. E. Vela, C. G. Boojamra, L. Zhang, H. Hui, C. Callebaut, K. Stray, K.-Y. Lin, Y. Gao, R. L. Mackman, and T. Cihlar, Antimicrob. Agents Chemother. 52:648-654, 2008). GS-9148 diphosphate acts as a competitive inhibitor of RT with respect to dATP (Ki = 0.8 µM) and exhibits low inhibitory potency against host polymerases including DNA polymerase {gamma}. Oral administration of GS-9131 to beagle dogs at a dose of 3 mg/kg of body weight resulted in high and persistent levels of GS-9148 diphosphate in peripheral blood mononuclear cells (with a maximum intracellular concentration of >9 µM and a half-life of >24 h). This favorable preclinical profile makes GS-9131 an attractive clinical development candidate for the treatment of patients infected with NRTI-resistant HIV.




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Offline red_Dragon888

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Re: http://natap.org/
« Reply #2 on: January 14, 2010, 12:38:24 pm »
NATAP: Preventing Dementia -Hypertension Meds
Thu, January 14, 2010 9:42:56 AMFrom: "nataphcvhiv@natap.org" <nataphcvhiv@natap.org>Add to Contacts

--------------------------------------------------------------------------------

NATAP http://natap.org/
_______________________________________________

"This study suggests that angiotensin receptor blockers are associated with reduced incidence and progression of Alzheimer’s disease and dementia compared with other drugs for cardiovascular disease or hypertension.....As angiotensin receptor blockers and angiotensin converting enzyme inhibitors both decrease signalling through the AT1 receptor, we hypothesised that their combined use might result in added inhibition, leading to enhanced clinical efficacy......Combined use was generally associated with lower outcome rates than use of angiotensin receptor blockers alone, angiotensin converting enzyme inhibitor alone, or lisinopril alone....The additive benefits of both drug classes is consistent with recent prospective clinical trials.24 Combination therapy therefore could be particularly beneficial for patients."......"All of the patients had heart disease and were being treated either with ARBs, such as AstraZeneca's Atacand (candesartan), sanofi-aventis and Bristol-Myers Squibb's Avapro (irbesartan), Merck & Co.'s Cozaar (losartan), and Novartis' Diovan (valsartan), AstraZeneca's ACE inhibitor Zestril (lisinopril), or other cardiovascular drugs. Data from the study showed that those patients receiving ARBs were up to 24 percent less likely to develop dementia than patients taking other drugs."



Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis


Published 12 January 2010 BMJ 2010;340:b5465



Nien-Chen Li, statistician1,2, Austin Lee, senior statistician2,3, Rachel A Whitmer, research epidemiologist4, Miia Kivipelto, associate professor5, Elizabeth Lawler, epidemiologist6, Lewis E Kazis, professor1,2, Benjamin Wolozin, professor2,7




1 Center for the Assessment of Pharmaceutical Practices and Pharmaceutical Assessment, Management and Policy Program, Department of Health Policy and Management, Boston University School of Public Health, Boston, MA, USA, 2 Center for Health Quality Outcomes and Economic Research, Veteran Affairs Medical Center, Bedford, MA, 3 Department of Surgery, Massachusetts General Hospital, Boston, MA, 4 Division of Research, Epidemiology, Etiology and Prevention, Kaiser Permanente, Oakland, CA, USA, 5 Aging Research Center, Karolinska Institute, Stockholm, Sweden, 6 MAVERIC, VA Cooperative Studies Program, Boston, MA, 7 Department of Pharmacology and Department of Neurology, Boston University School of Medicine, Boston, MA 02118-2526, USA

Correspondence to: bwolozin@bu.edu
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Offline red_Dragon888

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Re: http://natap.org/
« Reply #3 on: January 14, 2010, 12:40:42 pm »
Chloroquine To Block Immune Activation - pdf attached - (01/13/09)

Antimicrob. Agents Chemother published online ahead of print on 30 November 2009

Chloroquine for Reducing Immune Activation in HIV- Infected Individuals
This study is currently recruiting participants.
Verified by National Institute of Allergy and Infectious Diseases (NIAID), August 2009
First Received: January 8, 2009   Last Updated: November 18, 2009   History of Changes
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00819390

  Purpose
HIV is characterized by frequent immune system activation. Early in the course of infection the body establishes an immune activation "set point" related to the amount of HIV in the blood stream. This set point affects the rate of CD4 cell loss. Without CD4 cells, or with very low levels of CD4 cells, the body cannot fight off illness. This is known as immunodeficiency. If left untreated HIV can lead to extreme immunodeficiency and AIDS.

Evidence suggests that by decreasing the rate of immune system activation, immune deficiency progression could be prevented. The purpose of this study is to learn how well chloroquine can reduce the level of immune activation and to test the safety and tolerance of chloroquine in people infected with HIV.
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Offline red_Dragon888

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Re: http://natap.org/
« Reply #4 on: January 15, 2010, 09:22:33 pm »
Atripla (Efavirenz/Emtricitabine/Tenofovir disoproxil fumarate) Product Label Updated - updated label pdf attached

On January 7, 2010, FDA approved an updated Atripla label including new efficacy, safety and resistance data in treatment experienced patients from a trial (Study 073: A Phase IV, Open-Label, Randomized, Multicenter Study Evaluating Efficacy and Tolerability of single Tablet Regimen of Efavirenz/Emtricitabine/Tenofovir DF Compared to Unmodified HAART in HIV-1 Infected Subjects Who Have Achieved Virological Suppression on their HAART Regimen) in which HIV-1 infected adults on a stable antiretroviral regimen were either switched to Atripla or remained on their background regimen to compare the effectiveness (efficacy, safety, and tolerability) of Atripla to that of subjects continuing unmodified HAART as measured by the proportion of subjects who maintain HIV-1 RNA <200 copies/mL on their original assigned regimen at Week 48 based on the time-to-loss of virologic response (TLOVR) analysis.



Atripla label update reflects new efficacy, safety and resistance data in treatment experienced patients
 

On January 7, 2010, FDA approved an updated Atripla label including new efficacy, safety and resistance data in treatment experienced patients from a trial (Study 073: A Phase IV, Open-Label, Randomized, Multicenter Study Evaluating Efficacy and Tolerability of single Tablet Regimen of Efavirenz/Emtricitabine/Tenofovir DF Compared to Unmodified HAART in HIV-1 Infected Subjects Who Have Achieved Virological Suppression on their HAART Regimen) in which HIV-1 infected adults on a stable antiretroviral regimen were either switched to Atripla or remained on their background regimen to compare the effectiveness (efficacy, safety, and tolerability)of Atripla to that of subjects continuing unmodified HAART as measured by the proportion of subjects who maintain HIV-1 RNA <200 copies/mL on their original assigned regimen at Week 48 based on the time-to-loss of virologic response (TLOVR) analysis.
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Offline red_Dragon888

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Re: http://natap.org/
« Reply #5 on: January 16, 2010, 10:35:13 pm »
http://www.natap.org/2008/HIV/102308_01.htm

Neurotoxic effect of HIV: HIV-1 RNA concentration and cognitive ...
"The failure to identify a relationship between viral load and severity of cognitive impairment is consistent with the notion that the neurotoxic effect of ...
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Offline red_Dragon888

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Re: http://natap.org/
« Reply #6 on: January 22, 2010, 02:50:03 pm »
HIV infection linked to aging of the brain

The study led by researchers from Washington University School of Medicine in St. Louis and the University of California-San Diego showed that blood flow in the brains of HIV patients is reduced to levels normally seen in uninfected patients 15 to 20 years older.

"The graying of the AIDS patient community makes this infection's effects on the brain a significant source of concern," said first author Dr Beau Ances, assistant professor of neurology at Washington University.

"Patients are surviving into their senior years, and a number of them are coming forward to express concerns about problems they're having with memory and other cognitive functions.

"We believe the virus crosses into the brain using infected immune cells.”Once in the brain, HIV doesn't directly infect neurons but instead affects supporting cells that can release immune factors that harm neurons," Ances added.

During the study, researchers used magnetic resonance imaging scanners and a new technique known as arterial spin labeling that allows precise, non-invasive blood flow measurement.

They recruited 26 subjects with HIV and 25 uninfected controls. When individuals were resting in the scanner, brain blood flow values were significantly reduced in subjects with HIV compared to uninfected controls.

These reductions decreased brain blood flow to levels roughly equivalent to readings seen for uninfected individuals 15 to 20 years older.

When scientists asked participants to perform a visual task, which normally triggers an increase in blood flow to particular regions of the brain involved in the task, participants with HIV had greater blood flow increases, suggesting the brain and its support systems had to work harder to get the task done.

"Brain blood flow levels decline naturally as we age, but HIV, the medications we use to control it or some combination of the two appear to be accelerating this process independent of aging," Ances added.

The study appears online in The Journal of Infectious Diseases

>>>I would like to interject that I have felt that my meds, Atripla, has lowered my mental activity.<<<
« Last Edit: January 22, 2010, 03:05:32 pm by red_Dragon888 »
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Re: http://natap.org/
« Reply #7 on: January 23, 2010, 11:07:38 am »
Vicriviroc in Combination Therapy with an Optimized Regimen for Treatment‐Experienced Subjects: 48‐Week Results of the VICTOR‐E1 Phase 2 Trial




The Journal of Infectious Diseases Feb 15 2010;201:590–599



Jamal Suleiman,1,a Barry S. Zingman,4,a Ricardo Sobhie Diaz,2 Jose Valdez Ramalho Madruga,3 Edwin DeJesus,5 Jihad Slim,6 Carmen Mak,7 Erin Lee,7 Michael C. McCarthy,7 Lisa M. Dunkle,7 and Sharon Walmsley8




1Brasilmed Assistęncia Médica e Pesquisas, 2Laboratorio de Retrovirologia, Federal University of Sao Paulo, and 3Centro de Referencia e Treinamento em DST/AIDS, Sao Paulo, Brazil; 4Montefiore Medical Center and the Einstein‐Montefiore Center for AIDS Research, Bronx, New York; 5Orlando Immunology Center, Orlando, Florida; 6St Michael’s Medical Center–Infectious Diseases, Newark, 7Schering‐Plough Research Institute, Kenilworth, New Jersey; and 8The University Health Network, Toronto, Ontario, Canada



ABSTRACT


Background. Agents that block the CCR5 coreceptor for human immunodeficiency virus (HIV) have demonstrated potent antiretroviral activity. In early clinical studies, the CCR5 antagonist vicriviroc proved to be a safe and effective component of combination antiretroviral therapy.




Methods. This double‐blind, dose‐ranging, phase 2 trial randomized subjects to receive 30 mg or 20 mg of vicriviroc or placebo once daily plus re‐optimized background therapy containing a protease inhibitor with ritonavir. Subjects were adults infected with CCR5‐tropic HIV who were experiencing failure of triple antiretroviral regimens. The primary end point was mean change in baseline log10 HIV RNA level at 48 weeks, based on an intent‐to‐treat analysis.




Results. One hundred fourteen persons received vicriviroc at 30 mg (n=39), vicriviroc at 20 mg (n=40), or placebo (n=35). The mean change in baseline HIV RNA level at week 48 was −1.77 log10 copies/mL for 30 mg of vicriviroc and −1.75 log10 copies/mL for 20 mg of vicriviroc, compared with −0.79 log10 copies/mL for placebo (=.002 and , p=,003 respectively, compared with placebo). Mean CD4 counts increased by 102, 136, and 63 cells/mm3 for 30 mg vicriviroc, 20 mg vicriviroc, and placebo, respectively ( and , respectively, compared with placebo). Rates of adverse events (mostly mild‐to‐moderate) were 111.4, 112.5, and 147.4 events per 100 subject‐years, respectively.




Conclusions. Vicriviroc administered with a protease inhibitor plus ritonavir–containing regimen shows potent antiretroviral and immunologic activity sustained over 48 weeks in treatment‐experienced patients.





The life expectancy of people with human immunodeficiency virus (HIV) infection has steadily increased since the introduction of antiretroviral therapy >2 decades ago [1]. Current guidelines recommend that patients receive >3 antiretroviral drugs of at least 2 classes [2]. Although antiretroviral therapy is effective in suppressing viral replication in many patients, treatment failure is relatively frequent. Virologic failure is commonly associated with drug resistance, which often involves cross‐resistance within classes of drugs [3, 4]. Many patients discontinue initial antiretroviral therapy because of adverse effects [5]. The need to replace drugs that are no longer effective or tolerable to maintain a fully active regimen creates an ongoing demand for agents from new classes with novel mechanisms of action and favorable adverse‐effect profiles. One new class of antiretrovirals is the CCR5 antagonists. These agents block the CCR5 chemokine receptor, which most strains of HIV use as a coreceptor for gaining entry to CD4+ cells. Blockade of CCR5 has been shown to provide potent antiretroviral activity [6].




Vicriviroc is a novel, small‐molecule CCR5 antagonist, which has demonstrated potent antiviral activity in early clinical studies. As a substrate of CYP3A4, vicriviroc may be administered in regimens containing a CYP3A4 inhibitor without dosage adjustment, and clinical development (including this protocol) has taken the strategy of vicriviroc use in regimens containing a ritonavir‐boosted protease inhibitor. This approach provides the convenience of a single dose of 30 mg once daily with no adjustment required for concomitant medications. In a phase 2 trial evaluating vicriviroc in daily doses of 5, 10, and 15 mg added to a failing ritonavir‐containing regimen, antiviral activity was observed in all 3 vicriviroc dosage groups [7]. However, because it was not clear that optimal antiviral benefit had been achieved and because no dose‐limiting toxicities had been observed, testing at higher doses was deemed advisable. This trial was designed to evaluate the efficacy and safety of 2 dose levels of vicriviroc, compared with placebo, each in combination with optimized background therapy (OBT) containing a protease inhibitor with ritonavir.




Results




The study was conducted in North and Latin America, Europe, and South Africa from June 2006 through October 2007. One hundred sixteen persons were randomized to receive vicriviroc at 30 mg (n=40), vicriviroc at 20 mg (=39), and placebo (n=37). The treatment groups were balanced with respect to demographic and baseline characteristics. Consistent with other similarly designed studies reported recently, over one‐half of subjects had <2 active drugs in their OBT (Table 1).



Subject disposition.
One hundred fourteen subjects received at least 1 dose of blinded study drug (modified intent‐to‐treat population) (Table 1). On the basis of a Kaplan‐Meier analysis, time to discontinuation for any reason was significantly longer in the vicriviroc groups than in the placebo group (p=.001 and p<.0001 for the vicriviroc 30 mg and vicriviroc 20 mg arms, respectively, compared with placebo). Treatment failure, the most common reason for discontinuation, occurred most frequently in the placebo arm. Twenty‐one (95%) of 22 treatment failures occurred by week 24 regardless of treatment assignment. No subject discontinued because of treatment‐related safety or tolerability issues.




Virologic response.
The mean change in baseline HIV RNA level at week 48 was −1.77 log10 copies/mL for the vicriviroc 30 mg recipients and −1.75 log10 copies/mL for the vicriviroc 20 mg recipients; the placebo arm exhibited a mean decrease in baseline HIV RNA of −0.79 log10 copies/mL (p=.002 and p=.003, respectively, compared with placebo) (Figure 1). The superior antiviral efficacy of vicriviroc at either 30 mg or 20 mg was apparent at week 12 (p<.001 and p=.002, respectively, compared with placebo) and was sustained thereafter (Figure 1).



Analysis of week 48 secondary end points was consistent with these results. The proportions of subjects with HIV RNA levels <50 copies/mL (modified intent‐to‐treat and noncompleter equals failure population) at week 48 were 56% (22 of 39), 53% (21 of 40), and 14% (5 of 35) in the vicriviroc 30 mg, vicriviroc 20 mg, and placebo groups, respectively (p<.001 for vicriviroc 30 mg and p<.001 for vicriviroc 20 mg, compared with placebo) (Figure 2). The modified intent‐to‐treat time to loss of virologic response virologic response rates were 59% (23 of 39), 50% (20 of 40), and 26% (9 of 35) for vicriviroc 30 mg, vicriviroc 20 mg, and placebo, respectively p=.003( and p=.027 , respectively, compared with placebo). Virologic suppression (HIV RNA level <50 copies/mL) was sustained significantly longer in the vicriviroc 30 mg or 20 mg groups, compared with placebo (p=.003 and  p=.018, respectively).



The benefit of vicriviroc in regimens regardless of the number of active drugs in the background regimen is suggested by the mean change in baseline log10 HIV RNA at week 48 (Figure 3). The magnitude of virologic suppression in subjects with fewer (<2) active drugs in the OBT appeared to favor the vicriviroc 30 mg group; the proportions of subjects with week 48 HIV RNA levels <50 copies/mL (modified intent‐to‐treat time to loss of virologic response analysis) were 57%, 29%, and 17%, respectively, for vicriviroc 30 mg, vicriviroc 20 mg, and placebo. A similar tendency to superior time to loss of virologic response with vicriviroc 30 mg appeared in subjects with baseline HIV RNA levels >100,000 copies/mL (33%, 17%, and 10%, respectively) or baseline CD4 count <200 cells/mm3 (50%, 36%, and 14%, respectively). Analyses of primary and secondary efficacy end point subgroups including age, sex, race, region, baseline HIV RNA, baseline CD4 count, overall sensitivity score, and use of enfuvirtide or darunavir yielded consistent results and supported the efficacy advantage of vicriviroc 30 mg over placebo (data not shown).



Immunologic response.
Mean CD4 counts increased by 102 cells/mm3 in the vicriviroc 30 mg group, 136 cells/mm3 in the vicriviroc 20 mg group, and by 63 cells/mm3 in the placebo group, but only the difference between the 20‐mg dose group and placebo was statistically significant (p=.039), possibly because the sample size did not provide adequate statistical power to distinguish changes in CD4 counts (Figure 4).



Coreceptor tropism.
Six subjects (5%) had CXCR4 virus (dual‐mixed or X4‐only) detected at baseline before any drug exposure (3 in the vicriviroc 30 mg group, 1 in the vicriviroc 20 mg group, and 2 in the placebo group). Subsequently, 19 additional subjects (9 in the vicriviroc 30 mg group, 7 in the vicriviroc 20 mg group, and 3 in the placebo group) had detection of DM/X4 virus after receiving treatment, with 11 detectable at or before week 8. Of the 25 subjects in whom DM/X4 virus was detected, 17 (68%) met protocol‐defined criteria for virologic failure, but only 9 discontinued the study. Four subjects who received vicriviroc and had detectable DM/X4 tropic virus experienced a >50% decrease in baseline CD4 count; 3 of these 4 subjects had detectable DM/X4 tropism at baseline (before receiving any study drug). One of these subjects discontinued the study.



Resistance.
One subject (3%) in the vicriviroc 30 mg group, 4 subjects (10%) in the 20 mg group, and no subjects in the placebo group developed vicriviroc‐resistant HIV infection at the time of study discontinuation. Among the 15 subjects receiving vicriviroc who experienced virologic failure, 2 developed resistance to the single active drug in their OBT. Among subjects with 0 or 1 fully active drugs in their OBT, the 30‐mg dose of vicriviroc appeared to confer an advantage, as resistance to vicriviroc developed less frequently (1 [4.3%] of 23 in the vicriviroc 30 mg group vs 4 [19%] of 21 in the vicriviroc 20 mg group).




Safety.
The mean duration of treatment for the 114 subjects who received study drug was 44, 45, and 33 weeks for the vicriviroc 30 mg, vicriviroc 20 mg, and placebo groups, respectively. Sixty‐eight (86%) of the 79 subjects randomized to receive vicriviroc completed 48 weeks of blinded treatment, compared with only 18 (49%) of 37 subjects in the control group.




Most subjects (>90%) experienced at least one treatment‐emergent adverse event; these occurred with similar frequencies across treatment groups (95% in vicriviroc 30 mg, 98% in vicriviroc 20 mg, and 94% in placebo group). Most adverse events were mild or moderate in severity and occurred at similar frequencies across treatment groups (74% in vicriviroc 30 mg, 78% in vicriviroc 20 mg, and 74% in placebo group). The rate of adverse events was higher among subjects in the placebo group (147.4 incidents per 100 subject‐years) than in the vicriviroc 30 mg (111.4 incidents per 100 subject‐years) and 20 mg (112.5 incidents per 100 subject‐years) groups. Table 2 lists treatment‐emergent adverse events occurring in >10% of patients, adjusted for subject‐years of exposure.



The most commonly reported adverse event was diarrhea; no trend in the rates was apparent across treatment arms. The numbers of adverse events overall were too small to draw conclusions.




The proportion of subjects with severe (grade 3/4) adverse events was similar across treatment groups (21% in vicriviroc 30 mg, 20% in vicriviroc 20 mg, and 20% in placebo group). Most grade 3/4 adverse events were isolated events in a single subject. It is notable that no seizures occurred in vicriviroc recipients.




Other events of interest included malignancies, hepatotoxicity, and ischemic cardiovascular events. No confirmed malignancies were reported in either vicriviroc group during the 48‐week treatment period of this study. The number of subjects who experienced liver‐related events was similar across treatment groups (2 in vicriviroc 30 mg, 3 in vicriviroc 20 mg, and 2 in placebo group), with the rates lower in both vicriviroc arms (6.02, 8.65, and 8.93 incidents per 100 subject‐years, respectively). Elevations in liver function test results (alanine aminotransferase or aspartate aminotransferase) were generally mild (grade 1 or 2) and were evenly distributed across treatment groups; none appeared to be dose‐related. No grade 3 or 4 elevations in alanine aminotransferase or aspartate aminotransferase were observed in the vicriviroc arms, and no subjects met the criteria for drug‐induced liver injury (Hy’s law). No ischemic cardiac events were reported.




Four deaths were reported, involving the 4 subjects who discontinued the study because of to adverse events. Two of the subjects were in the placebo group; both deaths occurred 60 days after the patient discontinued the study. One death was attributed to cardiorespiratory failure in a subject with either central nervous system toxoplasmosis or central nervous system metastases from lung cancer, and the other to hypokalemia secondary to diarrhea. Two deaths were in the vicriviroc 20 mg group; 1 occurred while participating in the study and was attributed to bilateral atypical pneumonia; the other was attributed to presumed disseminated tuberculosis complicated by multiple organ failure and occurred 15 days after the end of treatment. All deaths were deemed unlikely to be related to study drug.



http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Offline red_Dragon888

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Re: http://natap.org/
« Reply #8 on: January 27, 2010, 03:31:42 pm »
UPDATE: Diagnosis and Management of Acute HIV Infection

http://www.hivguidelines.org/GuideLine.aspx?GuideLineID=165

Note
Note: In the medical literature, as in this chapter, the terms acute HIV infection, acute retroviral syndrome, acute HIV seroconversion, and primary HIV infection are interchangeable. For consistency, the term acute HIV infection is used in these guidelines.


I. INTRODUCTION
Studies suggest that as many as 50% of HIV transmissions occur during the acute and early stage of the illness.1-5 A number of factors contribute to the increased risk for transmission during acute infection:

•Markedly increased viral load levels during acute infection (often much greater than 10 million viral copies/mm3)
•Likelihood that risky behaviors are ongoing during this period because the individual is unaware of his/her HIV status
•The nonspecific “flu-” or “mono-like” symptoms of acute HIV infection that are frequently unrecognized as an indication of HIV infection

Detection of acute HIV infection provides an opportunity to follow patients prospectively soon after infection and thereby reduce disease progression and incidence of OIs. Because patients with a recent diagnosis of HIV are more likely to reduce risk behaviors if they are linked to primary HIV care than if they are not receiving care,6 early detection may also be a critical component of preventing further transmission.
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Offline red_Dragon888

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Re: http://natap.org/
« Reply #9 on: February 01, 2010, 08:23:43 am »
Follow the Money: AIDS Funding and AIDS Deaths in the Bloomberg Years




A Study by Health People: Community Preventive Health Institute written by Chris Norwood



http://www.healthpeople.org/




"Summary: The massive redistribution of the city?s federal AIDS care and support funds, started by the Bloomberg Administration in early 2006, favored Manhattan to the extent that the city Department of Health allocated almost 60% of federal funds for AIDS medical care and support services to Manhattan-based agencies. As Manhattan AIDS deaths then began decreasing at twice the rate of deaths in the Bronx and Brooklyn, the other major AIDS-impacted boroughs; the significant progress that these two “outer” boroughs---which have the poorest, most minority and highest percentage of women?s AIDS cases---had shown in bringing down their AIDS deaths during the years before this funding redistribution collapsed. Overall, black and Hispanic women suffered the worst consequences of the funding and service redistribution and were clearly denied the full chance at life which is possible today with proper AIDS care.....



.....It is past time for the federal government, including investigative agencies, to completely probe the  contracting of New York City Ryan White funds......he city tried to block FOIL (Freedom of Information Law) requests for the most  basic information with responses that defied credulity.....



.....The available public record shows that the New York City Department Health and Mental Hygiene,  under Dr. Thomas Frieden, Commissioner during most of  the Bloomberg Administration, made little  effort to disguise its disdain for outer borough AIDS populations.  At one key stage after another, the  Administration would only involve Manhattan agencies and leaders in determining AIDS policy and  funding.....In 2005, when Mayor Bloomberg, on the advice of Commissioner Frieden, appointed a New York  City Commission on AIDS---to provide the Administration with “guidance” on improving NY AIDS  care and prevention---all 20 members came from Manhattan agencies or represented government.....in its clear intent to maximize AIDS funding in Manhattan, the city violated that  requirement of the City Charter.......



.......Brooklyn as a borough lost the most funding and overall now has the greatest disparity between the  number of residents who have HIV/AIDS (24.5% of the NYC total) and the number of their deaths (30.8% of the city total)......Bronx women lost the most funding and services; indeed, key Ryan White services were  so completely withdrawn from Bronx women with HIV/AIDS that by, the end of 2006, only 3% of all  Ryan White clients in the city receiving Supportive Counseling/Family Stabilization services---services specifically intended to help stabilize women with AIDS raising children---lived in the Bronx.  The result was to derail the significant progress the Bronx had been making in keeping women---and  mothers---alive......As a group, Manhattan men received the most funding and medical/support services from the funding  switch; they then had the largest decrease in deaths of any male or female group in the major AIDS  boroughs.....Treatment adherence support---namely teaching people to use their AIDS medications  correctly---was almost entirely confined to Manhattan, with 73.5% of clients  receiving this help being Manhattan residents......




.......Thousands of AIDS clients were just left without  services as de-funded programs shut down before new ones were in place. In an unprecedented act,  this disarray and disruption occurred as a direct result of an order from the New York City Health  Commissioner.  (The “carefully crafted” response, also given to the press, was that the delay occurred because the city  was developing better ways to evaluate the programs; not one piece of paper appeared in response to  FOILs to support this public claim.).....



..........Although the federal government largely allocates this money to AIDS-impacted cities  and states based on their caseload, the New York City Department of Health blatantly favored  Manhattan hospitals, clinics, social service and support agencies in contracting the AIDS services  provided with federal funds.  The city?s distribution of federal Ryan White AIDS funds directly  impacted death rates in the boroughs---and the prospects of life."........."
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Offline red_Dragon888

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Re: http://natap.org/
« Reply #10 on: February 06, 2010, 08:03:17 am »
TAT2, New HIV Treatment May Also Slow Aging Process\


"Across multiple assays on cells from nine individual HIV-1-infected donors, TAT2 significantly enhanced the CD8+ T lymphocyte suppression of HIV-1 replication"



"our studies indicate that telomerase activators, such as TAT2, may constitute a novel class of therapeutic agents which improve immune function at a fundamental, cellular aging level, thus complementing existing drugs for the treatment of HIV/AIDS and a variety of age-related diseases associated with immune deficiency....could be useful in treating HIV disease as well as immunodeficiency and increased susceptibility to other viral infections associated with chronic diseases or aging"



"We evaluated the effect of short-term exposure to TAT2 on PHA-activated PBMC from 21 individual adult donors, including healthy persons and HIV-infected individuals. In all cases, short-term exposure to TAT2 resulted in enhancement of telomerase activity.....Indeed, the most dramatic telomerase enhancement by TAT2 was observed in the PBMC that had the lowest levels of endogenous telomerase activity, i.e., from chronically HIV-1-infected and AIDS donors."



"Previous studies have found that people with HIV who go years without developing AIDS have killer T-cells with high telomerase activity and longer telomeres......Effros’ study found that TAT2 reduced telomere shortening, increased the ability of cells to divide, and supercharged their antiviral activity......Effros hopes that TAT2 might be used as a supplement to existing anti-retroviral drugs to boost the immune systems of those with HIV....."It is beginning to look like telomerase is doing more than just keeping telomeres from getting too short," Effros"




Antiaging Therapy with TAT2: Telomerase-Based Pharmacologic Enhancement of Antiviral Function of Human CD8+ T Lymphocytes - (06/02/09) Jnl of Immunology




http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Re: http://natap.org/
« Reply #11 on: February 09, 2010, 08:24:36 am »
NATAP: Neurologic Disease-Undetectable Viral Load
Mon, February 8, 2010 4:30:41 PMFrom: "nataphcvhiv@natap.org" <nataphcvhiv@natap.org>Add to

--------------------------------------------------------------------------------

NATAP http://natap.org/
_______________________________________________



Neurologic Disease Despite Undetectable Viral Load & The Use of Drugs That Penetrate Well the CSF - pdf of full article attached - (02/08/10)
Clinical Infectious Diseases March 1 2010



"We describe here 11 patients presenting with neurological symptoms in an unusual clinical and virological context, given that all had a good immune status with suppressed HIV viremia. We hypothesised that HIV RNA in the CSF was the cause of neurological symptoms for the following reasons"

"The highest drug levels in the CSF were found for indinavir, nevirapine, abacavir, maraviroc, and lamivudine"
"In conclusion, physicians should be aware of the possibility of acute HIV-associated CNS disorders even in the presence of minor neurological complaints that should prompt a CSF evaluation with the determination of viral replication and genotypic resistance testing. There is a specific need for a better understanding of the dynamics of viral replication in the CNS compartment and its consequences on potential neurological dysfunctions."
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Offline red_Dragon888

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Re: http://natap.org/
« Reply #12 on: February 11, 2010, 06:19:07 am »
Debio-025 Activity/Safety in 3 Studies Over 3 Years


In naives, genotype 1 and 2:


1000 mg once daily produced slightly greater than 2 log reduction in HCV RNA after 29 days in genotype 1/4 and 4 logs in genotype 2/3 but at this dose 8/18 patients receiving monotherapy had hyperbilirubinemia but not at lower dose of 600 mg:


EASL 2008: Efficacy and safety of increasing doses of the cyclophilin ...
Debio 025 at daily doses of 1000 or 60 mg demonstrates an additive anti-HCV ... Debio 025in daily doses of 200 or 600 mg in combination with PegIFNa-2 was ...
www.natap.org/2008/EASL/EASL_20.htm


In this study 400 mg monotherapy did not produce antivial activity in null-responders, using a loading dose however showed better results suggested better antiviral activity, at these doses there did not appear to be hyperbilirubinemia:


EASL 2009: EFFICACY AND SAFETY OF THE CYCLOPHILIN INHIBITOR DEBIO 025 IN ...
EFFICACY AND SAFETY OF THE CYCLOPHILIN INHIBITOR DEBIO 025 IN COMBINATION WITH PEGYLATED INTERFERON ALPHA-2A AND RIBAVIRIN IN PREVIOUSLY NULL-RESPONDER ...
www.natap.org/2009/EASL/EASL_40.htm


The cyclophilin inhibitor DEBIO-025 has a potent dual anti-HIV and anti-HCV activity in treatment-naive HIV/HCV co-infected subjects




AASLD 2006: The cyclophilin inhibitor DEBIO-025 has a potent dual anti-HIV and ...
DEBIO-025, a cyclophilin inhibitor, demonstrated strong antiviral activity in vitro against HCV1 and HIV-1. In a previous phase I study, DEBIO-025 showed ...
www.natap.org/2006/AASLD/AASLD_30.htm
In a previous phase I study, DEBIO-025 showed antiviral effect (< 1 Log10 reduction) in HIV-1-positive asymptomatic subjects treated with DEBIO-025 400 and 1200 mg daily for 10 days2. In this early study presented at AASLD 2006, Treatment-naive HIV-1 mono or HIV/HCV co-infected subjects received 1200 mg DEBIO-025 or placebo twice daily for 15 days. HCV genotypes in the 16 HIV-1/HCV co-infected subjects on active treatment were evenly distributed between genotype 1 (n=5), genotype 3 (n=6), and genotype 4 (n=5). HIV-1/HCV co-infected DEBIO-025-treated subjects experienced a significantly greater maximum HCV viral load reduction compared to placebo subjects, achieving a least squares mean of 3.6 vs. 0.7. The 3 HCV genotypes identified in the study responded well to the dose administered (Figure 2). one null-responder (genotype 4) achieved at least a 2 Log10 drop in HCV viral load during treatment. Three subjects (one of each genotype) decreased viral loads below detectable levels at treatment Day 15 (2 subjects) and Day 8 (1 subject). Total bilirubin increased by a median of 22 _mol/L (range -1 to +88) during treatment, leading to hyperbilirubinaemia in 10 subjects. A total of 4/19 (21%) subjects discontinued DEBIO-025 treatment prematurely for this reason. No increase in ALT/AST or _-GT was observed, and there were no signs of haemolysis. Bilirubin returned rapidly to baseline levels after treatment cessation. This phenomenon was not observed in previous DEBIO-025 studies at doses up to 1200 mg OD for 10 days
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Offline red_Dragon888

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Re: http://natap.org/
« Reply #13 on: February 11, 2010, 06:31:45 am »
NATAP HIV Highlights This Past Week


http://www.natap.org


National AIDS Treatment Advocacy Project - NATAP - HIV - AIDS ...HCV..HBV
Natap's web site is a leader in up-to-the minute HIV treatment information, covering the latest in drug development and research, comprehensive conference ...
www.natap.org/


Recent articles on HIV. Check out articles on HIV related Bone Issues and HIV and Aging.
 
 
 
 
 
 
 
  Neurologic Disease Despite Undetectable Viral Load & The Use of Drugs That Penetrate Well the CSF - pdf of full article attached - (02/08/10)
 

Effects of Tesamorelin, a Growth Hormone-Releasing Factor, in HIV-Infected Patients With Abdominal Fat Accumulation: A Randomized Placebo-Controlled Trial With a Safety Extension - pdf attached - (02/08/10)
 

HIV Brain Impairment - (02/08/10)
 

C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis - (02/08/10)
 

C-reactive protein and cardiovascular risk: more fuel to the fire - Comment - (02/08/10)
 

Addition of extended zidovudine to extended nevirapine prophylaxis reduces nevirapine resistance in infants who were HIV-infected in utero - (02/08/10)
 

Immunosupportive therapies in aging - pdf attached - (02/05/10)
 

The rate of mother-to-child HIV transmission among infants is 23 times higher for blacks than whites, the CDC reported. - (02/05/10)
 

Bone Loss in HIV+ Premenopausal Women & Fracture Risk - (02/04/10)
 

Protein in Urine Presages More Severe Problems - free full text link below - (02/04/10)
 

Hepatitis C and the Risk of Kidney Disease and Mortality in Veterans With HIV: "veterans coinfected with HCV have significantly higher rates of CKD and mortality" - (02/04/10)
 

Impairments in memory and hippocampal function in HIV-positive vs HIV-negative women (and men) - (01/29/10)
 
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Offline red_Dragon888

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Re: http://natap.org/
« Reply #14 on: February 17, 2010, 01:20:11 pm »
NATAP: Early Immune Senescence in HIV

Current HIV/AIDS Reports
Published online: 2 February 2010
Seema Desai1 and Alan Landay1


"Activation and inflammation due to persistent infection such as HIV also provide a milieu for accelerated replicative senescence of T cells that progressively accumulate during the normal course of aging.....aging in the post-HAART era with suppressed viral replication is an outcome of activation and inflammation, and is most accurately defined as "inflamm-aging"....Whether HIV alone drives immunosenescence or if there are alternative pathways that contribute to early aging in HIV-infected individuals also remains to be examined.....more than 99% of HIV-1 particles detected in the circulation are not productively infectious virions. These noninfectious particles contribute to HIV-induced immunopathogenesis, as they activate the innate and adaptive immune system to release mediators of inflammation that are known to be associated with age-associated co-morbidities. The proof of this concept comes from data from the Strategies for Management of Antiretroviral Therapy (SMART) study, which shows elevated levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 to be associated with non-AIDS-defining co-morbidities in HAART-suppressed patients. The persistence of HIV virions, infectious or noninfectious, in the circulation results in the constant stimulation of the immune system and likely drives early senescence in HIV infection.....alterations in immune homeostatic mechanisms may lead to progressive loss of the naďve and memory T-cell pool, resulting in an imbalance in T-cell phenotypes. Altered T-cell homeostasis impairs regulatory cell function. HIV may deplete regulatory CD4+ T cells, which are normally responsible for suppressing T-cell activation and limiting the amount of inflammatory damage to tissues. Excessive production and/or accumulation of proinflammatory mediators such as TNF-α, IL-1ß, and IL-6 in HIV infection and in the elderly suggests that immune activation coupled with lack of anti-inflammatory responses likely results in accelerated aging in HIV disease....direct activation of innate immune cells by HIV and by disruption of the gastrointestinal barrier due to HIV-mediated depletion of Th-17 cells, leading to microbial translocation, could be contributing factors to activation and inflammation in the accelerated aging process."

http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Offline red_Dragon888

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Re: http://natap.org/
« Reply #15 on: February 17, 2010, 01:22:37 pm »
Certain Syringes More Likely To Spread Hepatitis C Virus Among Drug Users

Published: February 15, 2010

http://opa.yale.edu

New Haven, Conn. — A Yale School of Medicine study reveals that the high prevalence of the hepatitis C virus (HCV) among injection drug users may be partly due to the resilience of the virus in certain types of syringes. The study, which could open new avenues in preventing the spread of HCV, will be the focus of a presentation and press conference at the 17th Conference of Retroviruses and Opportunistic Infections on Friday, February 19, 2010 at the Moscone Center West in San Francisco.

This is believed to be the first study establishing the survival of HCV in contaminated syringes and the duration of potential infectiousness. HCV is transmitted through blood-to-blood contact. There is currently no vaccine against HCV, and treatments are problematic because of limited efficacy, high cost and side effects. Untreated, HCV can cause severe liver disease and even death. HCV infection from people sharing contaminated syringes is one of the most common and predictable consequences of injection drug use.

The Yale team simulated the most common scenarios of injection drug use in order to measure the longevity of the residual virus-blood mixture left in syringes after injection. After loading blood spiked with HCV into various syringes and depressing their plungers, researchers tested the residual blood for the presence of infective HCV immediately and after storage for up nine weeks.


They observed a prolonged survival of HCV infection at all storage temperatures, with viable amounts measured even at nine weeks in tuberculin syringes that have detachable needles. They observed far less viable HCV in insulin syringes with attached needles.
“This tells us that syringes with detachable needles are the most dangerous in terms of potential HCV infection, because they are far more likely to transmit a surviving virus,” said lead author Elijah Paintsil, M.D., assistant professor of pediatrics and pharmacology at Yale School of Medicine.




The finding of prolonged HCV survival in detachable-needle syringes has greatest implication outside of the Untied States, where use of these syringes is more common. But it also has major health implications for cities and towns everywhere, including the U.S., that offer needle-exchange programs. “These programs often stress the importance of providing injection drug users with syringes that meet their needs,” Paintsil said. “Our findings suggest that if the goal is to reduce HCV transmission, these programs should discourage use of detachable-needle syringes.”




Other authors are Huijie He, Christopher Peters, Brett D. Lindenbach and Robert Heimer of Yale School of Medicine. This study was funded by grants from the National Institutes of Health, including a Clinical Translational Science Award (CTSA) Grant from the National Center for Research Resources
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Offline red_Dragon888

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Re: http://natap.org/
« Reply #16 on: February 17, 2010, 01:26:05 pm »
ICE CREAM COMPOUND MAY PREVENT HIV/AIDS

University of Minnesota researchers have identified a devalue that, practical vaginally, can forestall delivery of a monkey chronicle of HIV. While a not a heal as well as a devalue still contingency go by tellurian clinical trials prior to it used to forestall HIV a investigate is a outrageous step toward impediment of a harmful mildew which impacts 33 million people around a globe. For more, see: www.ahc.umn.edu/gml

http://heathpage.com/ice-cream-compound-may-prevent-hivaids/
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Re: http://natap.org/
« Reply #17 on: February 17, 2010, 01:34:21 pm »
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Offline red_Dragon888

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Re: http://natap.org/
« Reply #18 on: February 17, 2010, 02:58:18 pm »
Stem cells to stem HIV
February 16, 2010 , Posted by Vignesh at 6:14 PM


http://medicalmicro.blogspot.com/2010/02/stem-cells-to-stem-hiv.html

In a study published in PLoS One, scientists from the UCLA AIDS Institute and colleagues have demonstrated that human blood stem cells can be engineered into cells that can target and kill HIV-infected cells. The good news is that, this process could potentially be used to combat other chronic viral diseases as well.


In this proof-of-principle study, it has been demonstrated that this type of approach can be used to engineer the human immune system, particularly the T-cell response, to specifically target HIV-infected cells. The researchers have identified the T-cell receptor molecules from the CD8 cytotoxic T lymphocytes, which guide the T cell in recognizing and killing HIV-infected cells. Since not enough of these cells exist to clear the virus from the body, the researchers cloned the receptor and genetically engineered human blood stem cells, then placed the stem cells into human thymus tissue that had been implanted in mice. The engineered stem cells developed into a large population of mature, multifunctional HIV-specific CD8 cells that could specifically target cells containing HIV proteins.


Based on the encouraging results, the scientists are optimistic that this approach could be a breakthrough in combating HIV and other chronic viral infections and further studies based on this approach are in pipeline.
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Re: http://natap.org/
« Reply #19 on: February 17, 2010, 02:59:10 pm »
(in response to your youtube video) It's not a cure. It iis a drug replacement. It does not deal with archived viruses/reservoir. It might be less toxic than ARV (we'll have to see) and we might be able to ward off the possibility of having a mutant strain (we'll have to see too). But it is not a cure... :-)

Offline red_Dragon888

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Re: http://natap.org/
« Reply #20 on: February 17, 2010, 03:02:02 pm »
http://aids.4h5.net/scientists-employ-mango-mushroom-to-beat-cancer/

Scientists employ mango, mushroom to beat cancer

CAN meals rich in mangoes and edible mushroom help to prevent or/and stop the spread of cancers? Mangoes and mushrooms have been discovered to contain ingredients that could be used for the production of new drugs for the treatment of cancers.

Scientists have discovered how a promising cancer drug, first discovered in a wild mushroom, works. The University of Nottingham, United Kingdom, team believe their work could help make the drug more effective, and useful for treating a wider range of cancers.

Cordycepin, commonly used in Chinese medicine, was originally extracted from a rare kind of parasitic mushroom that grows on caterpillars. The study appeared in the Journal of Biological Chemistry.
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Offline red_Dragon888

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Re: http://natap.org/
« Reply #21 on: February 17, 2010, 03:07:03 pm »
(in response to your youtube video) It's not a cure. It iis a drug replacement. It does not deal with archived viruses/reservoir. It might be less toxic than ARV (we'll have to see) and we might be able to ward off the possibility of having a mutant strain (we'll have to see too). But it is not a cure... :-)

I am just putting it out there, also it is last years info.  thanks for the reply.  ;)
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Offline red_Dragon888

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Re: http://natap.org/
« Reply #22 on: February 18, 2010, 01:16:19 pm »
QUAD Four-in-One Pill as Strong as Atripla, But a Kidney Concern Arises

17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco

Mark Mascolini

A once-daily antiretroviral combining the integrase inhibitor elvitegravir with a non-ritonavir booster (GS-9350), tenofovir (TDF), and emtricitabine (FTC) proved as potent at Atripla (efavirenz plus TDF/FTC) after 24 weeks in previously untreated people [1].

This small double-blind, double-dummy phase 2 trial found substantially fewer overall side effects with the four-in-one pill (called Quad) than with Atripla. But presenter Calvin Cohen devoted a goodly number of slides to addressing potential concerns about nephrotoxicity with GS-9350. Kidney trouble with GS-9350 would be a blow to Quad development because of TDF's well-known effect on creatinine clearance. But Cohen maintained the impact of GS-9350 on creatinine approximates that of an over-the-counter ulcer drug....

http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Offline red_Dragon888

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« Reply #23 on: February 19, 2010, 10:24:05 am »
Raltegravir Metabolics Study 96 Weeks - see attached full poster report

Conclusions

• At Week 96, both the RAL and EFV regimens demonstrated modest effects on serum lipids and glucose.

– The mean changes from baseline in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglyceride concentrations were significantly smaller for RAL than for EFV recipients.

– The change in the total cholesterol/HDL-cholesterol ratio was not significantly different between the treatment groups.

• At week 96, DEXA showed small gains in body fat in both treatment groups.

• Longer-term experience with RAL suggests a favorable metabolic profile associated with minimal changes in body composition in treatment-naďve patients.
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« Reply #24 on: February 19, 2010, 10:26:32 am »
HIV Load Tied to Fibrosis Signal in Women Without Hepatitis or Alcohol Abuse
17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco

Mark Mascolini

Higher HIV load correlated with a higher FIB-4 fibrosis index in HIV-infected nonalcoholic women without hepatitis virus infection or antiretroviral experience, according to results of a 1227-woman analysis of the HIV Epidemiologic Research Study (HERS) [1].

HERS is a natural history study of HIV infection in US women that ran from 1993 through 2000. This fibrosis analysis involved four groups of women--196 infected only with hepatitis C virus (HCV), 320 infected only with HIV, 498 infected with both viruses, and 213 with neither infection. The investigators also assessed another 72 women infected only with HIV who were negative for hepatitis B surface antigen and HCV, never took antiretrovirals, and reported no alcohol use in the past 6 months.

The study relied on the FIB-4 scale, a composite fibrosis indicator including age, alanine aminotransferase, aspartate aminotransferase, and platelet count. Earlier research determined that a FIB-4 below 1.45 generally means a person does not have advanced fibrosis, while a FIB-4 above 3.5 suggests advanced fibrosis [2].

In HERS women, median FIB-4 was lowest in those not infected with HIV or HCV (0.60), higher and similar in HCV-monoinfected women (0.83) and HIV-monoinfected women (0.86), and highest in HIV/HCV-coinfected women (1.30). The 72 antiretroviral-naive women with HIV but without HCV or HBV had a median FIB-4 of 0.93, similar to the larger HIV-monoinfected group. A small minority of women had a FIB-4 above the suggested fibrosis cutoff of 3.5, with the highest prevalence in coinfected women (8.6%), followed by HCV-monoinfected women (4.6%), and HIV-monoinfected women (1.3%).

Multivariate analysis determined that albumin and CD4 count had a significant negative association with FIB-4 score in HIV-monoinfected women and HIV/HCV-coinfected women, but not in HCV-monoinfected women or uninfected women.

HIV-monoinfected women

·      Albumin: r = -0.188, P = 0.0007

·      CD4 count: r = -0.401, P < 0.0001

HIV/HCV-coinfected women

·      Albumin: r = -0.235, P < 0.0001

·      CD4 count: r = -0.332, P < 0.0001

In univariate analyses, higher viral load correlated positively with higher FIB-4 score in HIV/HCV-coinfected women (r = 0.177, P < 0.001), HIV-monoinfected women (r = 0.207, P = 0.0002), and alcohol-abstaining, antiretroviral-naive, HIV-monoinfected women without HBV or HCV (r = 0.202, P = 0.03).

Although the viral load associations with FIB-4 score did not hold up in multivariate analysis, the investigators propose that the correlations suggest "a potential relationship between HIV and hepatic fibrosis in vivo." That suggestion is especially compelling in the monoinfected women with no antiretroviral experience, no exposure to HBV or HCV, and no recent alcohol use. Although higher viral load may not independently correlate with higher FIB-4 in those women, the viral load risk is not confounded by alcohol, hepatitis, or antiretroviral hepatotoxicity.

References
1. Blackard J, Welge J, Taylor L, et al.  HIV mono-infection is associated with a non-invasive index of liver fibrosis in women. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 681.
2. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317-1325.
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Re: http://natap.org/
« Reply #25 on: February 20, 2010, 10:30:20 am »
Gene Therapy Shows Promise Against HIV

Early findings suggest it could work, but application remains years away

By Randy Dotinga

FRIDAY, Feb. 19 (HealthDay News) -- A new study is among the first to hint that gene therapy could become a weapon against the virus that causes AIDS.

However, any treatment remains far from being ready for use by patients, and would likely be expensive, experts said.

Still, the research is "a step in the direction of using gene therapy" to treat HIV patients, said Dr. Pablo Tebas, co-author of a new study and associate professor of medicine at the University of Pennsylvania.

Existing AIDS drugs allow many patients to live fairly normal lives despite being infected with HIV. But they can cause a variety of side effects, and some patients become immune to them over time.

"The next big challenge is going to be: Can you cure the infection or control it to a level that allows patients to not take these expensive and complex medications that can be toxic?" Tebas said.

One possible solution is to help the body fight off HIV without the use of drugs. That's where gene therapy comes in, Tebas said. "Can you make the patient resistant so they can control HIV on their own?"

In the new study, the Pennsylvania team tested a gene therapy approach in which scientists first remove immune cells from patients, tinker with their genes and then put them back into the bodies of the patients.

Eight HIV-infected people took part in the study. After the genetically modified cells were placed back into the patients, "we stopped HIV treatment and tried to see what happened," Tebas said.

The findings are scheduled to be reported this week at the Conference on Retroviruses and Opportunistic Infections in San Francisco.

The levels of HIV fell below the expected levels in seven of the eight patients, the team found. Signs of the virus disappeared altogether in one patient, although that happens sometimes -- it's not an indication that the disease is cured -- and the researchers aren't sure why it happened in this case.

"We need to understand why it happened and see if we can reproduce that in the general population," Tebas said.

It's still early in the development of the treatment: the current research is in phase 2 of the customary three phases of research that new medical treatments go through.

If gene therapy does become a treatment for HIV patients, it may be best for those who aren't doing well on existing antiretroviral drugs, said John Rossi, chairman of the molecular and cellular biology department at the Beckman Research Institute of City of Hope Medical Center near Los Angeles.

"There are thousands of people who are completely resistant to all the drugs that are out there, and this is one more option they could have," Rossi said.

But the cost of the treatment would probably be high, he added, perhaps reaching around $20,000. And it's not clear how long the treatment would last, he said, since the immune cells aren't permanent.

More information

There's more on gene therapy for another condition, cancer, at the U.S. National Cancer Institute.

SOURCES: Pablo Tebas, M.D., associate professor, medicine, University of Pennsylvania, Philadelphia; John Rossi, Ph.D., chairman, department of molecular and cellular biology, Beckman Research Institute of City of Hope National Medical Center, Duarte, Calif.; presentation, Feb. 18, 2010, Conference on Retroviruses and Opportunistic Infections, San Francisco
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« Reply #26 on: February 22, 2010, 10:30:20 am »
Discovery of Potent HIV-1 Capsid Assembly Inhibitors - see attached slide presentation

Reported by Jules Levin, 17th CROI, Feb 16-19 2010 SF

from Jules: there was very little in the way of new drug discovery presented at CROI regarding new targets. The GSK integrase & the Gilead integrase programs are moving ahead, Tobira updated on their CCR5. Tibotec has TMC278 development ongoing.
Steve Titolo1, Jean-François Mercier1, Elizabeth Wardrop1, Utavon Schwedler3, Nathalie Goudreau2, Chris Lemke2, Anne-Marie Faucher2, ChristianeYoakim2, Bruno Simoneau2, Wesley I. Sundquist3, Stephen Mason1

Boehringer Ingelheim (Canada) Ltd. Research & Development, Laval, Québec, Canada: 1Departments of Biological Sciences and 2Chemistry; 3Biochemistry Department, University of Utah, Salt Lake City, Utah, U.S.A.

Mason said “Assembly & stability of the capsid core is absolutely essential for HIV infectivity….in the presence of inhibitors the formation of the complexes is prevented….several hits were obtained….two chemotypes of advanced leads were identified that potently inhibit capsid assembly, with 2 different modes of action….mode of action is consistent with inhibition of capsid assembly….inhibitors are active in very late phase of viral replication which is also consistent with an effect on capsid assembly and viral replication….resistance mutations may indicate high genetic barrier to resistance….lead optimization was terminated, inihibition of capsid assembly is a potential viable approach for antiretroviral intervention”

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« Reply #27 on: February 22, 2010, 10:32:13 am »
Safety and Efficacy of TBR-652, a Chemokine Receptor 5 (CCR5) Antagonist, in HIV-1-Infected, Antiretroviral (ARV) Treatment-Experienced, CCR5 Antagonist-Naďve Patients - see attached full slide presentation

 Reported by Jules Levin

17thCROI, San Francisco, February 16-19, 2010

Calvin Cohen, MD*

Research DirectorCommunity Research Initiative of New EnglandHarvard Medical School

*On behalf of TBR-652-2-201 Study Team

from Jules: this CCR5 drug has a potentially unique characteristic in that it also binds CCR2 which appears to have potentially a clinically anti-inflammatory effect. The company will explore this in future studies. In the last attachedslide you can see the binding inhibition of  drug to MCP-1 which is a reflection of its anti-inflammatory affect.

CONCLUSIONS
TBR-652 is a potent inhibitor of CCR5-tropic, HIV-1 replication
- Median nadir response up to -1.8 log10
TBR-652 demonstrated potent CCR2 activity
Generally safe and well tolerated during short-term use
- No study drug–related discontinuations, SAEs or deaths
- No clinically significant trends in AEs, laboratory, vital signs, or ECGs
- Favorable and predictable pharmacokinetic profile*
TBR-652 warrants further investigation as an unboosted, once-daily, oral CCR5 antagonist with potentially important anti-inflammatory effects
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« Reply #28 on: February 22, 2010, 10:34:47 am »
T-cell Senescence and T-cel Activation Predict Carotid Atherosclerosis in HIV-infected Women
*******NATAP CROI POSTER OF THE YEAR 2010******


Reported by Jules Levin, CROI 2010 Feb 16-19 SF

Robert C Kaplan1, PhD, Elizabeth Sinclair2, PhD, Alan L Landay3, PhD, Nell Lurain3, PhD, Stephen J Gange4, PhD, Richey Sharrett4, MD, DrPH, Xiaonan Xue1, PhD, Peter Hunt2, MD, Howard N Hodis5, MD, Steven g Deeks,2, MD

Affiliations: 1Albert Einstein College of medicine, 2Univ of California-SF, 3Rush University Medical Center, 4Johns Hopkins Bloomberg School og Public Health, 5Univ of Southern California

Conclusions

Collectively, these observations are consistent with a model in which untreated HIV infection results in immune activation, accelerated immunologic aging and the emergence of a population of potentially dysfunctional immunosenescent T cells. Antiretroviral therapy-mediated suppression of HIV replication may only partially reverse or prevent this process. The presence of a large population of activated and/or senescent T cells may be causally associated with the premature onset of CVD.

SUMMARY OF RESULTS/DISCUSSION

- Consistent with prior data, HIV infection was associated with markedly elevated levels of activated (CD38+HLA-DR+) peripheral T-cells. Viremic suppression through effective antiretroviral therapy appeared to reduce but not completely reverse this process.

- Among HIV-infected women, T-cell activation was associated with markers of subclinical carotid artery disease after adjustment for multiple confounders.

- Among HIV-infected women, CD8+ T-cell senescence, and to a lesser extent CD4+ T-cell senescence (phenotypically defined by absence of CD28 and presence of CD57), were also associated with HIV disease and with the presence subclinical carotid artery disease.

- These associations of T-cell activation and senescence with carotid artery parameters were not observed in a population of HIV-uninfected controls who were studied using identical methods and who had comparable cardiovascular risk factor profiles. Relatively small sample size of the HIV-uninfected group is a limitation.
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« Reply #29 on: February 22, 2010, 10:41:53 am »
Maraviroc Levels in Cerebrospinal Fluid (CSF) and Seminal Plasma from HIV-Infected Patients
Reported by Jules Levin
CROI 2010 Feb 16-20 SF

Juan Manuel Tiraboschi, J Curto, J Niubo, and D Podzamczer
Hosp Univ de Bellvitge, Barcelona, Spain

Background:  Several studies have shown that penetration of ARV drugs into reservoirs may be associated with a decreased viral replication and clinical benefit. The aim of our study was determine Maraviroc levels in CSF and semen of a group of  HIV-infected patients

Methods:  Twelve CCR5+ HIV-1 adult antiretroviral-experienced patients receiving MVC-containing regimens for at least 1 month were  enrolled. Both CSF and semen plus a blood sample were taken around 12 hours after the last MVC dose. Liquid chromatography tandem mass spectrometry (Tandem Labs, NJ, US) was used to determine MVC levels. HIV-1 viral load  was determined by real time PCR, Abbott (detection limit 40 copies/mL).

Results:  A total of 12 plasma samples, 12 CSF samples, and 9 semen samples were collected. Median CD4 count was 281 cells/uL (120 to 759) and the median HIV-1 viral load at the screening was <40 copies/mL. The median time on Maraviroc was 13.5 (4 to 60) weeks. Raltegravir was part of the background regimen in 92%, darunavir in 62% and etravirine in 42% of the patients. Nucleoside analogues were given in only one case.

Conclusions:  MVC achieves levels in CSF within the range of IC50 or higher. Thus, MVC may be of benefit in patients with HIV neurological disorders. In semen, MVC exceeds several times the IC50. However, viral replication in semen may be observed despite virological suppression in plasma, suggesting semen may act as a dinstinct compartment. Most patients with undetectable plasma viral load while receiving nucleoside-sparing regimens, including new drugs, had viral suppression in reservoirs.
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« Reply #30 on: February 22, 2010, 10:43:33 am »
Vitamin D Deficiency and Bacterial Vaginosis among HIV-infected and -uninfected Women in the United States

Audrey French1,2, O Adeyemi1,2, D Agniel2, M Yin3, K Anastos4, and M Cohen1,2
1Rush Univ Med Ctr, Chicago, IL, US; 2CORE Ctr, Stroger Hosp of Cook County, Chicago, IL, US; 3Columbia Univ Med Ctr, New York, NY, US; and4Montefiore Med Ctr, Bronx, NY, US

Background:  Bacterial vaginosis (BV), the most frequent cause of vaginitis, is associated with morbidities such as premature labor and increased susceptibility to HIV. Recently an association between vitamin D deficiency (VDD) and BV was identified in pregnant women. We sought to replicate this finding in the Women’s Interagency HIV Study (WIHS).

Method:  A cross-sectional study of women participating in the WIHS, a longitudinal study of women with and at risk for HIV. Women in this substudy were from Chicago or New York. BV was defined by the Amsel criteria. VDD was defined as 25 (OH) D ≤20 ng/mL and insufficiency as >20 and ≤30 ng/mL.

Results:  Among 609 women studied (6 of whom were pregnant), BV was found in 19% (table). VDD was found in 60% and insufficiency in 23.5%. VDD was associated with black race, 268 of 397 vs 59 of 92 for whites, OR 3.16 (95%CI, 2.06 to 4.89), but not with HIV status, CD4, or age. Vitamin D level strongly correlated with BV (r= –0.14, P <0.001) and there was a dose response relationship; BV was most likely in women with VDD (OR 3.55), then women with insufficient levels (OR 2.12) compared with sufficient vitamin D. In multivariate analysis black race, AOR 6.03, VDD, AOR 2.46, and number of sex partners, AOR 1.54, were independently associated with BV.

Conclusions:  In this study of 609 HIV-infected and -uninfected women, BV and VDD were common and significantly correlated. VDD may partially explain the relationship between black race and BV and may be a modifiable risk factor for the disorder. Further study is needed to determine whether repletion of vitamin D will decrease the occurrence of BV.

Vitamin D and HIV-related Complications and HIV Disease Progression in Women in Tanzania



Saurabh Mehta1, D Spiegelman1, F Mugusi2, E Giovannucci1, G Msamanga2, and W Fawzi1

1Harvard Sch of Publ Hlth, Boston, MA, US and 2Muhimbili Univ of Hlth and Allied Sci, Dar es Salaam, Tanzania

Background:  Vitamin D has a potential role in preventing HIV-related complications, based on its extensive involvement in immune function. However, this relationship has not been examined in large studies or in resource-limited settings.
Methods:  Vitamin D levels were assessed in 884 HIV-infected pregnant women at enrollment in a trial of multivitamin supplementation (excluding vitamin D) in Tanzania. Information on HIV disease progression and related complications was recorded during follow-up (median, 70 months). Proportional hazards models and generalized estimating equations were used to assess the relationship of vitamin D status with these outcomes.


Results:  Women with low vitamin D status (serum 25-hydroxyvitamin D <32 ng/mL) had 45% higher risk of reaching a body mass index <18 kg/m2 during the first 2 years of follow-up, compared to women with adequate vitamin D levels (incidence rate ratio, RR:  1.45; 95%CI 1.04 to 2.01). The relationship between continuous vitamin D levels and risk of body mass index <18 kg/m2 during follow-up was inverse and linear (P=0.03; Figure 1). Low vitamin D status was associated with a 25% higher risk of progression to WHO HIV disease stage III or IV during follow-up (RR:  1.25; 1.05 to 1.50), compared to adequate vitamin D status. This risk decreased with increasing vitamin D levels linearly (P =0.05; Figure 2). Women with low vitamin D levels had significantly higher incidence of acute upper respiratory infections (RR: 1.28, 1.05 to 1.55) and thrush (RR:  2.92, 1.43 to 5.96) diagnosed during the first 2 years of follow-up. Women in the lowest vitamin D quintiles had higher incidence of mouth and throat ulcers, painful tongue or mouth, difficult or painful swallowing, diarrhea, and fatigue during the first 2 years of follow-up.


Connclusions:  Vitamin D status has a protective association with HIV disease progression and HIV-related complications during follow-up in HIV-infected women. If confirmed in randomized trials, vitamin D supplementation could represent a simple and inexpensive method to prolong the time to ART initiation in HIV-infected patients and improve health and quality of life, particularly in resource-limited settings.
« Last Edit: February 22, 2010, 10:47:09 am by red_Dragon888 »
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« Reply #31 on: February 22, 2010, 10:49:03 am »
T-Cell Activation and Senescence Linked to Carotid Lesions in HIV+ Women

from Jules: this appears to me to be THE POSTER of CROI because it's the first connection between a clinical comorbidity outcome & senescence. The findings were in a relatively more advanced patient population so a key question is if you look at patients with high CD4s of say 650 and treat them with HAART will you see similar correlation with senescence; my guess is yes, senescence occurs as a result of activation & inflammation which is ongoing at some level regardless of CD4 count & undetectable viral load due to the presence of virus, HIV, regardless of whether its low or high virus levels. Perhaps the degree of senescence is less if CD4 is high & viral load low but thisT is one of many studies that need to be conducted but I think yes you will still find senescence, maybe not as often or as much but it appears HIV causes senescence.
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« Reply #32 on: February 22, 2010, 04:09:29 pm »
Man Appears To Be Cured Of HIV After Stem Cell Transplant
http://www.queeried.com/potential-hiv-cure/

Following a stem transplant from a donor carring a gene mutuation that provides natural resistance to HIV  a 42 year old man who has leukaemia now appears to have no detectable HIV in his blood.

A report on the stem cell  transplant in the New England Journal of Medicine says that since  it has occurred the patient has not tested positive for HIV, with the Dr. Gero Hutter of Charite Universitatsmedizin Berlin in Germany confirming:

“Today, two years after his transplantation, he is still without any signs of HIV disease and without antiretroviral medication.”

Performed in Germany on an American, the transplant was performed not to treat the HIV, but the man’s leukemia, however they did deliberately chose the donor with the naturally occurring gene mutation that confers resistance to HIV. Causing the resistance via a mutation (CCR5 delta32) which cripples the CCR5 receptor on the surface of T cells, that is normally attacked by HIV, this is a mutuation found only in 1 percent to 3 percent of white populations of European descent. Some people only have one copy of CCR5 delta32 which results in them taking longer to get sick or develop AIDS if infected with HIV.  If they however have two ( a copy from each parent) then they may not become infected at all.

The patient in this case was given a transplatn with two copies of  CCR5 delta32 and whilst his findings are very promising, the reality according to  Dr. Jay Levy, a professor at the University of California San Francisco, is that it won’t help the majority as the treatment is too extreme to be used as a routine treatment. He also believes that the transplant won’t have completely cured the patient as it is likely the HIV may infect other cells and resurface at a later time. Whilst this may be true, it is important to note  that the patient was also found to be infected with low levels of a type of HIV known as X4 that does not require the CCR5 receptor before the surgery , but these have shown no sign of developing.

Admitting they had no real explanation for what has happened, Hutter said the “… finding is very surprising.”, however he has agreed with other researchers that it shouldn’t be used to treat HIV alone, with Levy suggesting  “A more logical — and potentially safer — approach would be to develop some type of CCR5-disabling gene therapy or treatment that could be directly injected into the body”.
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« Reply #33 on: February 26, 2010, 10:30:56 am »
Positive HBV Vaccine Response Halves HIV Progression and Death Risk in US Military

17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco

Mark Mascolini

A positive response to hepatitis B virus (HBV) vaccination approximately halved the risk of HIV disease progression or death in members of the US Military HIV Natural History Study, regardless of antiretroviral exposure or CD4 count [1]. The results underline the critical importance of HBV vaccination among people infected with HIV.

In addition, Michael Landrum and colleagues suggested, "HBV vaccine response may serve as a useful indicator for studying immunological correlates of HIV-related disease progression that are independent of the HIV RNA load or level of immune deficiency reflected by the CD4 count."
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« Reply #34 on: February 26, 2010, 10:33:04 am »
Cell Studies Point to Antiinflammatory Activity of Maraviroc

17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco

Mark Mascolini

Data from clinical trials presented at the Conference on Retroviruses suggested that the CCR5 antagonists maraviroc [1] and vicriviroc [2] hold no special advantage over other antiretrovirals in pumping up CD4 counts--results deflating expectation based on earlier research, although previous studies have reported higher CD4 increases associated with maraviroc. Poor results in two phase 3 vicriviroc trials [2] led Merck to suspend development of that drug for antiretroviral-experienced people, (from Jules: as they were unable to find in the overall study a benefit with vicriviroc in patients receiving 3 or more active ARTs in the background regimen but for patients with 2 active drugs or less vicriviroc does provide benefit and this is an issue in trying to design studies for new drugs in highly treatment-experienced patients).
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« Reply #35 on: February 26, 2010, 10:33:55 am »
Elvucitabine Versus 3TC in First-Line Regimens for 96 Weeks – see slides from poster in attached report



17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco

Mark Mascolini

Elvucitabine, a cytosine nucleoside analog, proved virologically equivalent to lamivudine (3TC) when combined with efavirenz and tenofovir as a first-line regimen taken for 96 weeks [1]. However, because of the small size of this phase 2 trial and the high dropout rate, elvucitabine lagged 3TC in a noncompleter-equals-failure virologic analysis, so further study will be needed to get a better fix on where elvucitabine may fit in treatment planning.

Elvucitabine has a half-life of about 100 hours and an in vitro 50% effective concentration of 1.1 ng/mL, suggesting 3 to 4 times greater antiviral activity than 3TC, according to Edwin DeJesus and collaborators. This double-blind trial at 16 US sites and three in India recruited 77 antiretroviral-naive people and randomized them take 10 mg of elvucitabine once daily or standard-dose 3TC plus efavirenz and tenofovir. All study participants had a CD4 count between 200 and 500, so the trial did not include people with relatively advanced HIV infection.
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« Reply #36 on: February 26, 2010, 10:36:10 am »
FDA: Invirase, Norvir combination may increase risk for heart abnormalities

by Lianne Dane

February 23, 2010

The FDA on Tuesday announced that a review of preliminary data suggests that the combination of Roche's Invirase (saquinavir) and Abbott's Norvir (ritonavir) for the treatment of patients with HIV could cause abnormal heart rhythms in some patients.


Data submitted by Roche suggest that when the two drugs are used in combination, they can produce dose-dependent changes in the QT and PR intervals on an electrocardiogram, the FDA stated. These changes may lead to heart abnormalities that can cause patients to experience lightheadedness, fainting or irregular heart rhythms, that could, in some cases, progress to ventricular fibrillation.


The agency also noted that the risk of heart abnormalities could be higher in patients who are using other medications known to cause QT interval prolongation, and in those patients who have a history of this disturbance.


The drugmaker provided the findings in response to a prior request from the agency for all manufacturers of protease inhibitors to study the effect of these drugs on heart rhythms. Tara Cooper, a spokeswoman for Roche's Genentech unit, said "we continue to monitor and report to FDA adverse event reports from patients and physicians." She added that the FDA is currently reviewing new labelling for the drug.
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« Reply #37 on: February 26, 2010, 10:37:12 am »
Low CD4 Nadir Predicts Neurocognitive Problems Despite Good CD4 Gains

17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco

Mark Mascolini

Neurocognitive problems persisted in many HIV-infected US residents despite good CD4 gains after starting antiretroviral therapy [1]. People whose lowest-ever (nadir) CD4 count never slipped below 350 had the best chance of averting neurocognitive problems. Those conclusions emerged from a 1525-person analysis of the prospective US CHARTER cohort, inspiring the investigators to "emphasize the importance of identifying HIV-seropositive subjects early in the course of their illness to prevent later complications."
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Offline red_Dragon888

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« Reply #38 on: February 28, 2010, 10:28:32 am »
House of Rep Resolution on HIV Aging




HRES 1100 IH

111th CONGRESS

2d Session

H. RES. 1100

Expressing the sense of the House of Representatives that the National Institutes of Health and the Centers for Disease Control and Prevention should expand and intensify programs of research and related activities regarding the population of older individuals living with or at risk for HIV.

IN THE HOUSE OF REPRESENTATIVES

February 23, 2010

Mr. CARSON of Indiana submitted the following resolution; which was referred to the Committee on Energy and Commerce

______________________________
__

RESOLUTION

Expressing the sense of the House of Representatives that the National Institutes of Health and the Centers for Disease Control and Prevention should expand and intensify programs of research and related activities regarding the population of older individuals living with or at risk for HIV.

Whereas from 2006 through 2007, newly diagnosed cases of HIV increased 25 percent among individuals over the age of 50;

Whereas since 2003, the number of women 50 years of age and older who have been newly diagnosed with HIV has increased 40 percent;

Whereas individuals over the age of 50 made up 15 percent of newly diagnosed cases of HIV in 2007 and almost 17 percent in the first half of 2008;

Whereas the number of older individuals with HIV is expected to increase substantially by 2015, with half of all individuals with HIV in the United States being over the age of 50;

Whereas few physicians are taught to start conversations with their elderly patients about sex or HIV education and are less likely to offer testing to older individuals;

Whereas the number of newly diagnosed HIV infections in older adults was 12 times higher among Blacks and 5 times higher among Latinos than Whites;

Whereas data collection should include an emphasis on breaking down age groups, tracking risk factors for infection for older adults, and behavioral data so the National Institutes of Health can better grasp what intervention is necessary or effective; and

Whereas more clinical research is needed for people over 50 living with or at risk for HIV, as it is imperative to gain a greater understanding about how treatments interact with aging bodies: Now, therefore, be it

Resolved, That it is the sense of the House of Representatives that the National Institutes of Health and the Centers for Disease Control and Prevention should expand and intensify programs of research and related activities regarding the population of older individuals living with or at risk for HIV.

Carl Schmid

Deputy Executive Director

The AIDS Institute

Washington DC

202/462-3042-office
202/669-8267-cell
202/328-0467-fax
cschmid@theaidsinstitute.org
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« Reply #39 on: February 28, 2010, 10:31:10 am »
Prevalence of hypovitaminosis D among HIV+ patients enrolled in a large italian cohort - see attached full poster report, interesting study

 

Reported by Jules Levin, 17th CROI Feb 16-19 2010 SF

Marco Borderi, Fabio Vescini, Alessandro Cozzi-Lepri, Antonio Di Caro, Maria Carla Re, Antonella d’Arminio Monfortefor the Icona Foundation Study Group

From Jules: although vitamin D insufficiency prevalence might be similar to that seen in the general population, the concerns in HIV are several: patients have so many risk factors for bone loss and fractures that vitamin D deficieny adds to the risk; if ARTs contribute to bone loss that increases a patients’ risk. S vitamin D loss among HIV+ individuals takes on a unique concern.

 

“Vitamin D insufficiency was defined as 25(OH)-vitD <75 nmol/l,while values <30 nmol/l were considered as vitamin Ddeficiency….VitD insufficiency and deficiency were found in 804 (54%) and 98 (7%) of the tests, respectively.”

 

AUTHOR CONCLUSIONS

This is the first large observational study confirming a very high prevalence of hypovitaminosis D in HIV positive patients living in western countries. Traditional risk factors for vit D deficiency are confirmed also in this setting: age, BMI, nationality, seasonality. Moreover, both immunodepression and high HIV viral load are associated with hypovitaminosis D.

Regarding the association with exposure to cART, we found that previous use of NNRTI-including regimens were associated with higher risk of vitD deficiency than previous exposure to PI. The analysis of the longitudinal changes in vitD according to the type of regimen started was largely unpowered and therefore the results are inconclusive.

Our data also seems to confirm that, in HIV positive individuals, vitamin D insufficiency is predictive of the risk of subsequent development of a number of severe events such as cardiovascular, renal disease and diabetes.

Overall, these data should be carefully considered in the management of HIV positive patients. Due to both the high prevalence of hypovitaminosis D and the safety of cholecalciferol administration, vitamin D supplements might be taken into account in our therapeutic choices.
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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« Reply #40 on: February 28, 2010, 10:32:04 am »
Engineering Adult Stem Cells Against HIV
by David Prentice
February 26, 2010

UCLA scientists have shown that they can engineer adult blood stem cells so that they lack a molecule necessary for HIV infection. The CCR5 receptor is a protein molecule on the surface of cells that is bound by HIV when the virus infects certain immune cells, acting as a receptor for the virus. The scientists used “short hairpin RNA” to knock down the expression of the CCR5 molecule in the human adult stem cells, effectively preventing the protein from being produced. These cells could reconstitute the immune system in a mouse model, indicating that the function of the immune cells was not inhibited. But the human cells, now without the CCR5 protein receptor, resisted HIV infection. The study, published in the journal Blood, provides a potential method for controlling HIV infection in patients.

The study follows a previous report of successful adult stem cell treatment for leukemia that also appears to have controlled HIV infection in the patient. The doctors specifically used an adult stem cell donor whose cells lacked the CCR5 molecule.
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« Reply #41 on: February 28, 2010, 10:35:05 am »
http://singularityhub.com/2010/02/26/stem-cell-transplant-defeats-hiv/

Stem Cell Transplant Defeats HIV? Patient Still HIV Free After 2 Years

Add one more name to the ever growing list of diseases that have been defeated by stem cell treatments: HIV. That’s right, according to a recent report in the New England Journal of Medicine, a stem cell transplant performed in Germany has unexpectedly removed all signs of HIV from a 42 year old American patient. The unnamed white male was treated two years ago for Leukemia with a dose of donor stem cells and his HIV RNA count has dropped to zero and remained there since. While the treatment was for Leukemia, Dr. Gero Hutter and colleagues at the Charite Universitatsmedizen in Berlin had selected the stem cell donor for his HIV resistant genes. While there are still many questions unanswered, this is the first such case of stem cells treating HIV that has been reported in a NEJM-caliber publication. Ladies and gentlemen, this is not a “cure” for HIV/AIDS, but it is certainly a remarkable and promising find. There’s more you need to know about the situation, so read on.
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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« Reply #42 on: February 28, 2010, 10:37:40 am »
Assessment of Vitamin D Levels Among HIV-infected Persons in the Study To Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (SUN Study) - see attached full poster report

 

Reported by Jules Levin 17th CROI Feb 16-19 2010 SF

Christian Dao (CDC) et al. Pragna Patel (CDC), Sherri Pals (CDC), Timothy Bush (CDC), Frank Rahme (Abbott-Northwestern Hospital, Minneapolis, MN), E Turner Overton (Wash U, St Louis School of Med), Erna Kojic (miriam Hosp, Rhode Island), Kathy Wood (Cerner Corp, Vienna, VA).



AUTHOR DISCUSSION


Efavirenz, like antiepileptic drugs, induces cytochrome p450 enzymes to accelerate turnover of 25(OH)D and 1,25(OH)2D to inactive compounds (calcitronic acid) leading to lower levels of 25(OH)D.


Ritonavir is a potent inhibitor of 1-alpha-hydroxylase activity to convert 25(OH)D to 1,25(OH)2D, leading to an accumulation of 25(O)D.


Renal insufficiency possibly caused by damage to the renal proximal tubule, where 25(OH)D is converted to 1,25(OH)2D, would lead to an accumulation of 25)OH)D


AUTHOR RECOMMENDATIONS


Given reported associations between low levels of 25(OH)D and an array of chronic conditions, which are prevalent among HIV-infected persons, screening for 25(OH)D insufficiency is warranted.


Although one study has shown increases in 25(OH)D with vitamin D supplementation, other larger studies are necessary to assess the impact of viramin D supplementation on risk reduction of chronic conditions, such as osteoporosis/osteopenia and cardiovascular disease, among HIV-infected adults.
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Offline red_Dragon888

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Re: http://natap.org/
« Reply #43 on: February 28, 2010, 10:39:26 am »
Chronic Inflammation in HIV:  CROI 2010

 

David H Shepp, MD

Associate Professor of Medicine, Hofstra University School of Medicine

Division of Infectious Diseases, North Shore University Hospital-Manhasset

 

Cardiovascular Disease (CVD). 



Pathogenesis research has firmly established a link between chronic inflammation and atherosclerotic CVD in the general population.  Untreated HIV infection causes a state of intense chronic inflammation, which accounts it least in part for the higher rates and younger age of onset of cardiovascular disease in HIV infected patients.  ART reduces immune activation caused by HIV and many of the markers of chronic inflammation linked to CVD also improve.  However, many studies have shown that levels of immune activation and inflammatory markers remain elevated in HIV-infected individuals when compared to the HIV-uninfected, even when ART has produced years of durable viral suppression.  This raises the specter of ongoing increased CVD risk even in successfully treated patients.   Strategies to further reduce immune activation to normal levels are not established and represent an important unmeet need in HIV treatment research. 
In a symposium on Wednesday afternoon, Dr Priscilla Hsue, a cardiologist and associate professor of medicine at the UCSF gave an excellent review of HIV, inflammation and cardiovascular disease.  She cited new research presented at this conference exploring the relationship between immune activation/inflammatory markers and markers of CVD risk, the pathogenesis of residual chronic inflammation in patients treated with ART and of potential interventions that might be used in conjunction with traditional ART to further reduce inflammation.
http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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Offline red_Dragon888

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« Reply #44 on: February 28, 2010, 10:40:25 am »
Vitamin D Deficiency and Bacterial Vaginosis among HIV-infected and -uninfected Women in the United States

Reported by Jules Levin
17th CROI, Feb 16-19 2010 SF

Audrey French1,2, O Adeyemi1,2, D Agniel2, M Yin3, K Anastos4, and M Cohen1,2
1Rush Univ Med Ctr, Chicago, IL, US; 2CORE Ctr, Stroger Hosp of Cook County, Chicago, IL, US; 3Columbia Univ Med Ctr, New York, NY, US; and 4Montefiore Med Ctr, Bronx, NY, US

Background:  Bacterial vaginosis (BV), the most frequent cause of vaginitis, is associated with morbidities such as premature labor and increased susceptibility to HIV. Recently an association between vitamin D deficiency (VDD) and BV was identified in pregnant women. We sought to replicate this finding in the Women’s Interagency HIV Study (WIHS).

Method:  A cross-sectional study of women participating in the WIHS, a longitudinal study of women with and at risk for HIV. Women in this substudy were from Chicago or New York. BV was defined by the Amsel criteria. VDD was defined as 25 (OH) D ≤20 ng/mL and insufficiency as >20 and ≤30 ng/mL.

Results:  Among 609 women studied (6 of whom were pregnant), BV was found in 19% (table). VDD was found in 60% and insufficiency in 23.5%. VDD was associated with black race, 268 of 397 vs 59 of 92 for whites, OR 3.16 (95%CI, 2.06 to 4.89), but not with HIV status, CD4, or age. Vitamin D level strongly correlated with BV (r= –0.14, P <0.001) and there was a dose response relationship; BV was most likely in women with VDD (OR 3.55), then women with insufficient levels (OR 2.12) compared with sufficient vitamin D. In multivariate analysis black race, AOR 6.03, VDD, AOR 2.46, and number of sex partners, AOR 1.54, were independently associated with BV.

Conclusions:  In this study of 609 HIV-infected and -uninfected women, BV and VDD were common and significantly correlated. VDD may partially explain the relationship between black race and BV and may be a modifiable risk factor for the disorder. Further study is needed to determine whether repletion of vitamin D will decrease the occurrence of BV.
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Offline red_Dragon888

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« Reply #45 on: February 28, 2010, 10:41:31 am »
High Prevalence of Severe Vitamin D Deficiency in cART Naďve and Successfully Treated Swiss HIV Patients - see attached full poster report

 

Reported by Jules Levin, 17th CROI Feb 16-19 2010 SF

N Muller1*, CA Fux2*, B Ledergerber1, L Elzi3, P Schmid4, T Dang5, L Magenta6, A Calmy7, A Vergopoulos8, H Bischoff-Ferrari9 and the Swiss HIV Cohort Study. 1 University Hospital Zürich; 2 University Clinic for Infectious Diseases and University of Berne; 3 University Hospital Basel; 4 Kantonsspital St Gallen; 5 Centre Universitaire Hospitalier Vaudois, Lausanne; 6 Ospedale Civico Lugano; 7 Geneva University Hospital; 8 Institute of Clinical Chemistry, University Hospital Zurich; 9 Centre on Aging and Mobility, University of Zurich; 10 Department of Rheumatology and Institute of Physical Medicine, University Hospital Zurich Switzerland. * contributed equally

 

CONCLUSIONs

- With 42-52% in spring and 14-18% in fall vitamin D deficiency was highly prevalent

- Black ethnicity was a significant risk factor for vitamin D deficiency

- NNRTI-use was associated with significantly lower 25(OH)D levels

- TDF-use correlated with higher serum 1,25(OH)2D and serum alkaline phosphatase levels

- we suggest systematic screening for vitamin D deficiency in all HIV-positive patients

 

BACKGROUND

Recent studies have increased the awareness of beneficial effects of vitamin D. Besides being essential for bone growth and preservation, antineoplastic and immunmodulatory effects have been described.

Considering the high prevalence of osteopenia (up to 60%) and osteoporosis (up to 15%) as well as the increasing number of neoplasias, adequate vitamin D levels seem particularly important in the HIV-population.

AIMS

To determine vitamin D levels in HIV-positive patients comparing measurements by season as well as before and after the initiation of cART. To look for predictors for vitamin D deficiency
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« Reply #46 on: March 01, 2010, 10:13:23 am »
Valganciclovir Reduces CD8+ T Cell Activation among HIV-infected Patients with Suboptimal CD4+ T cell Recovery During Antiretroviral Therapy - see attached full poster report

 

Reported by Jules Levin, CROI 2010 SF

Peter Hunt1, Jeffrey Martin1, Elizabeth Sinclair1, Lorrie Epling1, Juli Teague1, Mark Jacobson1, Russell Tracy2, Lawrence Corey3, and Steven Deeks1. 1University of California, San Francisco; 2University of Vermont; 3University of Washington



from Jules: there is a paper at CROI finding in HCV coinfected inflammation and non-AIDS death rates in the SMART Study (I send out report on this earlier today) is higher so I think that any major coinfection increases activation can cause what was found in this study regarding CMV. I'm not convinced its unique to CMV. But for CMV-positive individuals valgancyclovir appears to be helpful in reducing activation, just like my guess is curing HCV with peg/rbv.




AUTHOR CONCLUSIONS/IMPLICATIONS


Valganciclovir durably suppresses CMV replication (in CMV-positive, HIV+ individuals) and CD8+ T cell activation in HIV-infected patients with poor CD4 recovery during ART.



This reduction in CD8 activation does not appear to be mediated by a direct effect on HIV replication, but appears to be the result of reductions in CMV (or other herpesvirus) replication.



Thus, CMV (and possibly other herpesviruses) appears to be a major determinant of CD8+ T cell activation during antiretroviral therapy.



Given the potential impact of inflammation and immune activation on clinical outcomes (see poster 306), and the potential role of CMV in cardiovascular disease, T cell senescence, and aging, strategies to reduce CMV replication in HIV-infected individuals are worth pursuing in larger trials.
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« Reply #47 on: March 01, 2010, 10:15:01 am »
Impact of CD8+ T Cell Activation on CD4+ T Cell Recovery and Mortality in HIV-infected Ugandans Initiating Antiretroviral Therapy - see attached full poster report



 ****NATAP Major CROI Poster*****

Reported by Jules Levin, CROI 2010 Feb SF

 

Peter W. Hunt1, Jeffrey N. Martin1, Isaac Ssewanyana2, John Bennett,1 Nneka Emenyonu3,4, Annet Kembabazi3, Torsten Neilands1, David R. Bangsberg4, Huyen Cao5, and Steven G. Deeks1. 1University of California, San Francisco; 2Joint Clinical Research Center, Kampala, Uganda; 3Mbarara University of Science and Technology, Uganda; 4Harvard School of Medicine; 5CA Department of Health Services



AUTHOR CONCLUSIONS/Implications
HIV+ Ugandans have higher CD8 activation than HIV+ San Franciscans both before and during suppressive ART.

- Unclear if these differences are explained by host genetics, viral factors, or prevalent co-infections.

High pre-therapy CD8 activation predicts poor CD4 recovery during suppressive ART in HIV+ Ugandans.

- Immune activation is an important determinant of CD4 recovery even in resource- limited settings with prevalent co-infections.

Persistently high CD8 activation during ART-mediated viral suppression predicts earlier mortality, independent of CD4 count.

- To our knowledge, this is the first demonstration that CD8 activation predicts mortality in the setting of suppressive ART.

- Interventions to decrease immune activation in this setting should be explored.
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« Reply #48 on: March 01, 2010, 10:15:48 am »
T cell Senescence and Proliferation Defects Persist in Treated HIV-infected Individuals Maintaining Viral Suppression and Are Associated with Poor CD4+ T Cell Recovery - see attached full poster report

****NATAP Major CROI Poster****



Reported by Jules Levin, 17th CROI Feb 16-18 2010 SF

Peter Hunt, Elizabeth Sinclair, Lorrie Epling, Juli Teague, Qi Xuan Tan, Jeffrey Martin, Paula Lum, and Steven Deeks, University of California, San Francisco





Author Conclusions / Implications



• Despite having abnormally high T cell “activation” and entry of T cells into cell cycle, HIV-infected individuals also have significant T cell proliferative defects, which fail to normalize during ART.



• These proliferative defects may be the result of decreased T cell responsiveness, failure of cells to complete cell cycle, or apoptosis of proliferating cells.



• CD4+ T cell proliferative defects may contribute to poor CD4+ T cell recovery during antiretroviral therapy, independent of the extent of T cell activation and the extent of naďve CD4+ T cell depletion.



• Persistent proliferative defects may also explain why many CD28-CD8+ T cells fail to terminally differentiate and express CD57 in the setting of HIV infection.



• Elucidating the mechanisms responsible for T cell proliferative defects (i.e., IDO induction, lymphoid fibrosis, IL-7 responsiveness, etc.) may help identify targets for interventions to improve CD4 recovery and immune function during ART.

http://www.youtube.com/watch?feature=player_embedded&v=I3ba3lnFHik

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« Reply #49 on: March 08, 2010, 10:32:31 am »
HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs - pdf of full article attached



Nature Medicine

Published online: 7 March 2010 | doi:10.1038/nm.2109




Christoph C Carter1,2,7, Adewunmi Onafuwa-Nuga3,7, Lucy A McNamara4,5, James Riddell IV3, Dale Bixby3, Michael R Savona3,6 & Kathleen L Collins1,2,3,4





Abstract




HIV causes a chronic infection characterized by depletion of CD4+ T lymphocytes and the development of opportunistic infections. Despite drugs that inhibit viral spread, HIV infection has been difficult to cure because of uncharacterized reservoirs of infected cells that are resistant to highly active antiretroviral therapy (HAART) and the immune response. Here we used CD34+ cells from infected people as well as in vitro studies of wild-type HIV to show infection and killing of CD34+ multipotent hematopoietic progenitor cells (HPCs). In some HPCs, we detected latent infection that stably persisted in cell culture until viral gene expression was activated by differentiation factors. A unique reporter HIV that directly detects latently infected cells in vitro confirmed the presence of distinct populations of active and latently infected HPCs. These findings have major implications for understanding HIV bone marrow pathology and the mechanisms by which HIV causes persistent infection.






Despite the host immune response and treatment with HAART, HIV causes a persistent infection. Viral persistence is due in part to latent HIV reservoirs in resting CD4+ T cells1 that do not express viral proteins but can be induced to active infection by a variety of stimuli. However, recent studies of viral genetics have revealed that additional reservoirs probably exist2.





HPCs have been considered as a possible reservoir, but it has been difficult to establish that these cells are infected by HIV3, 4, 5, 6 because they are difficult to maintain in culture, and indirect measurements of infection may be confounded by contamination with other cell types. Here we used flow cytometry and recently developed culture conditions7 that have allowed us to conclude that a proportion of HPCs become infected after exposure to HIV both in vivo and in vitro.



Results



HIV infects and is cytotoxic to HPCs




To assess the susceptibility of HPCs to HIV, we examined intracellular expression of the HIV capsid protein Gag in purified bone marrow CD34+ cells treated with an HIV molecular clone derived from peripheral blood (89.6)8. 89.6 is a dual tropic virus that can use either CCR5 or CXCR4 as a co-receptor to enter cells. In this case, we used an envelope-deleted molecular clone (89.6ΔE) complemented with 89.6 envelope (89.6ΔEenv89.6) (Fig. 1). Three days after infection, 6% of CD34+ HPCs expressed intracellular HIV Gag (Fig. 2a). Antiretroviral treatment blocked Gag expression (Fig. 2a), and experiments with five other HIVs yielded similar results (Supplementary Fig. 1a). As previously reported for HIV-infected T cells9, 10, infected CD34+ cells downmodulated major histocompatibility complex class I (Fig. 2b).



HPCs are a heterogeneous collection of cells that include multipotent HPCs and stem cells (HSCs). Multipotent HPCs have a Lin−CD34+CD133+CD38− surface phenotype, where 'Lin' represents markers of specific hematopoietic lineages. After treatment with wild-type HIV 89.6 (Fig. 1b), both Lin+ and Lin− cells expressed intracellular Gag (Fig. 2c).




A time-course analysis revealed that Gag+ cells were lost rapidly in culture (Fig. 2d and Supplementary Fig. 1b). Moreover, infected cells showed high annexin V reactivity (Fig. 2e), and a high fraction of Gag+ cells had light scatter properties of dead cells (Supplementary Fig. 1c). Cell death required active viral gene expression, as transduction of the cells with a reporter virus (Fig. 1c) pseudotyped with an HIV envelope did not result in cell loss unless the HIV long terminal repeat (LTR) actively expressed HIV genes (Supplementary Fig. 1d).



Multipotent HPCs are susceptible to HIV infection




To assess the developmental capacity of infected HPCs, we used a minimal HIV genome (HIV-7SF-GFP, Fig. 1d) pseudotyped with 89.6 Env, which 'tagged' infected cells without causing cell death. We found that a proportion of CD34+ cells were infected (GFP+) (1–6% in replicate experiments (for example, Fig. 3a; initial sort purity shown in Supplementary Fig. 2a)), and a more primitive subset of these cells (CD34+CD38−CD133+) had a similar infection rate (Fig. 3b). Infection of CD133+ HPCs purified from bone marrow yielded similar results (Supplementary Fig. 2f,g). These infection rates were comparable to those of the fraction of CD34+ cells expressing both HIV co-receptors (Supplementary Fig. 3a,b).



CD133+ HPCs from umbilical cord blood (UCB) infected with HIV-7SF-GFPenv89.6 generated GFP+ colonies of erythroid (CFU-E), myeloid (CFU-M and CFU-GM) and multilineage (CFU-GEMM) origin, indicating that HIV can infect multipotent HPCs (Fig. 3c). Quantification revealed similar numbers of total colonies from uninfected and infected cells (Fig. 3d). We obtained similar results with a full-length HIV reporter (89.6-SIΔE-SF-GFP, Fig. 1e) that did not express HIV genes because of an LTR mutation (Fig. 3e,f).



Induction of latent HIV from infected HPCs




To assess latent infection, we asked whether induction of differentiation with phorbol 2-myristate 13-acetate (PMA) induced viral gene expression. In these experiments, we used bone marrow–derived HPCs (99.5% CD34+, Supplementary Fig. 2b) infected with a replication-defective HIV (HXB-ePLAP (Fig. 1f)) pseudotyped with the VSV-G envelope (HIV HXB-ePLAPenvVSV−G). This virus expresses a marker protein, placental alkaline phosphatase (PLAP). We found that PMA treatment increased the number of cells expressing PLAP 12-fold (Fig. 4a) and resulted in more viral particle production (Supplementary Fig. 4a) than treatment of cells with DMSO alone. Bone marrow immunodepleted for CD34+ cells was not viable under these conditions (Supplementary Fig. 4b).



We found similar numbers of integrated genomes in the presence or absence of PMA (Fig. 4b), indicating that PMA-induced gene expression was not due to effects on integration. Consistent with these results, the integrase inhibitor raltegravir blocked initial infection but not PMA-induced gene expression (Supplementary Fig. 5). We obtained similar results when the replication-defective PLAP-expressing HIV was pseudotyped with a bona fide HIV envelope (HXB-ePLAPenv89.6), albeit with lower infection rates (Fig. 4c).




We infected purified bone marrow–derived HPCs (98% CD34+, Supplementary Fig. 2d) with wild-type HIV 89.6 (Fig. 1b) and cultured them with or without granulocyte-macrophage colony–stimulating factor (GM-CSF) and tumor necrosis factor-α (TNF-α) to induce myeloid differentiation11. Treatment of infected HPCs with GM-CSF and TNF-α resulted in rapid release of HIV into the culture supernatant (Fig. 4d). In contrast, bone marrow mononuclear cells (BMMCs) immunodepleted for CD34+ cells did not release HIV (Fig. 4d) and rapidly died (Supplementary Fig. 4b–d,f). Flow cytometric analysis of the cells confirmed that treatment with GM-CSF and TNF-α stimulated intracellular HIV Gag expression (Fig. 4e) and that cells cultured with GM-CSF and TNF-α acquired myeloid markers (CD83) (Fig. 4f).




To assess the stability of latent HIV in HPCs, we infected CD34+ bone marrow–derived HPCs (99% pure, Supplementary Fig. 2e) with wild-type HIV 89.6. After 7 d, when the culture was uniformly Gag negative, we added GM-CSF and TNF-α to half of the cells. Addition of GM-CSF and TNF-α resulted in a resurgence of HIV gene expression compared with the untreated culture (Fig. 4g,h). We obtained similar results with a wild-type virus that uses only CXCR4, although, as expected, there was less viral spread in the differentiated myeloid cells (Supplementary Fig. 6b). The spread of infection in the culture was inhibited by treatment with the antiretroviral drug raltegravir, and supernatant from infected cells could be used to infect T cell lines (Supplementary Fig. 6).



Direct detection of latency




To detect latent infection in situ without inducing changes in the infected cells, we developed a new latency reporter virus (HIV 89.6-ΔE-SF-GFP (Fig. 1c)) that expresses GFP independently of the HIV LTR. Infection of T cells with HIV 89.6-ΔE-SF-GFPenv89.6 yields some cells expressing Gag and others expressing only GFP (Fig. 5a). Confirming that GFP+Gag− cells were latently infected, we found that CD4 downmodulation, which occurs only when HIV Nef, Vpu or Env is expressed12, occurred in Gag+ but not GFP+Gag− cells (Fig. 5a). In contrast, when we infected cells with a virus that expresses GFP from the HIV LTR (89.6-ΔE–IRES-GFP, Fig. 1g), the GFP-expressing cells downmodulated CD4 (Fig. 5a). We obtained similar results with peripheral blood mononuclear cells infected with 89.6ΔE-SF-GFPenv89.6 (Fig. 5b). Moreover, PMA and ionomycin treatment of Jurkat cells infected with the reporter virus increased Gag+ cell frequency and lowered GFP+Gag− cell frequency (Fig. 5c).



We observed separate populations of Gag+ and GFP+ cells in UCB-derived CD34+ HPCs infected with the latency reporter virus, indicating that active and latent infection occurred in this cell type (Fig. 5d). In culture, the Gag+ cells were rapidly lost, whereas the GFP+Gag− \cells persisted for at least 20 d (Fig. 5e and Supplementary Fig. 1d). Analysis of these cells revealed that many had a cell surface phenotype consistent with primitive HPCs (CD34+Lin− or CD34+CD38−) (Fig. 5f).



Evidence that CD34+ bone marrow cells are infected in vivo




We obtained samples from HIV-infected people with high viral loads (donors 1–6, Supplementary Table 1) and found that we could detect Gag+CD34+ cells in three of six freshly isolated samples (Fig. 6a and Supplementary Table 1). When we cultured the cells in GM-CSF and TNF-α, we could detect Gag expression in samples from all six donors (Fig. 6b,c). In contrast, donor BMMCs specifically depleted of CD34+ cells did not express Gag after culturing (Fig. 6c,d). The addition of the anti-HIV drug raltegravir, which inhibits new in vitro infection in T cells (Supplementary Fig. 7), partially suppressed the induction of Gag expression (Fig. 6c,d), confirming that a component of the infection we observed was the result of viral spread. We obtained similar results from a donor (number seven) who had undetectable viral loads for 2 years (Fig. 6e and Supplementary Table1).



Using a real-time PCR assay for integrated HIV DNA, we detected viral genomes in freshly isolated CD34+ cells from four of nine donors on HAART with undetectable viral loads for longer than 6 months (44%) (Fig. 6f,g). In these donors, we detected 40 (donor 7), 3.1 (donor 12), 39 (donor 14) and 2.5 (donor 15) HIV genomes per 10,000 CD34+ cells. We detected HIV genomes in BMMCs immunodepleted of CD34+ cells only for donor 12, for whom we detected1.2 HIV genomes per 10,000 CD34− cells. The limit of detection for this assay varied by donor but was approximately 1 genome per 10,000 cells, owing to the limited number of CD34+ cells obtained from each donor. Thus, it is likely that the proportion of donors in which we detected HIV genomes underestimates the percentage of HIV+, HAART-treated individuals harboring integrated HIV genomes in CD34+ cells.



Discussion




Long-lived cellular reservoirs of latent HIV genomes are a major obstacle to viral eradication. Here we demonstrate that HIV can infect hematopoietic progenitor cells in vivo and in vitro to cause an active, cytotoxic infection as well as a latent infection that can be induced to active infection by cytokine treatment.




Our finding that HIV infects HPCs with an immature phenotype has clear ramifications for HIV disease, because some of these cells may be long lived and could carry latent HIV for extended periods of time. Although further studies are needed to show that CD34+ stem cells are infected, our detection of HIV genomes in HPCs isolated from people effectively treated with HAART for more than 6 months confirms that HIV targets some long-lived HPCs. One might expect these results to predict the presence of identifiable proviral records in differentiated lineages that are known not to be susceptible. However, we show that actively infected HPCs are rapidly killed. Therefore, we expect latently infected HPCs will be killed by viral activation shortly after differentiation is induced.




Further studies are now needed to show that residual circulating virus in individuals on HAART is derived in part from HPCs, as previously demonstrated for resting memory T cells2. Additionally, studies examining the factors influencing HIV infection and latency in CD34+ cells, as well as limiting-dilution experiments to determine the fraction of proviral genomes in these cells that can be reactivated, would further understanding of this viral reservoir.



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