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Author Topic: Fifty small breakthroughs in HIV science part3 picture of how hiv drugs work  (Read 2245 times)

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Offline bimazek

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great pretty picture on how and where all the hiv classes of drugs work

http://www.mja.com.au/public/issues/186_03_050207/che10490_fm.html

   and a great chart of drug contra indications as well as hepatic cytochrome P450 (CYP450 3A4) and specific drug–drug interactions*(http://www.hiv-druginteractions.org/). 

 *  Over the past 10 years, the management of HIV infection has been transformed by an increased number of effective antiretrovirals (ARVs), with more convenient dosing and improved tolerability.
 *  Optimal management of HIV infection includes at least three effective ARVs; from at least two different drug classes.
 *  Current strategies and drugs can effectively control HIV and significantly reduce morbidity and mortality. However, no cure is yet possible.
 *  Appropriate use of ARVs leads to suppression of virological replication (to below the limit of detection using commercial assays to measure HIV in plasma) and an increase in CD4+ T cells with few adverse effects.
 *  Greater than 95% adherence to drug therapy is required for effective viral suppression and immunological improvement.
 *  Monotherapy, two-drug combinations, sequential ARVs, drug “cycling”, and treatment interruptions are ineffective management strategies and lead to earlier disease progression and emergence of drug resistance.
 *  Drug–drug interactions are common and caution is required when prescribing ARVs that inhibit or induce the cytochrome P450 pathway.
   great pretty picture on how and where all the hiv classes of drugs work
   http://www.mja.com.au/public/issues/186_03_050207/che10490_fm.html
   and a great chart of drug contra indications as well as hepatic cytochrome P450 (CYP450 3A4) and specific drug–drug interactions*(http://www.hiv-druginteractions.org/).
   
     
   
 RNAi Therapy for HIV Infection:...     RNAi Therapy for HIV Infection: Principles and Practicalities.  Leading Article  Biodrugs. 21(1):17-22, 2007.  Bennasser, Yamina; Yeung, Man Lung; Jeang, Kuan-Teh  Abstract:  Inside eukaryotic cells, small RNA duplexes, called small interfering RNAs (siRNAs), activate a conserved RNA interference (RNAi) pathway which leads to specific degradation of complementary target mRNAs through base-pairing recognition. As with other viruses, studies have shown that replication of the HIV-1 in cultured cells can be targeted and inhibited by synthetic siRNAs. The relative ease of siRNA design and the versatility of RNAi to target a broad spectrum of mRNAs have led to the promise that drug discovery in the RNAi pathway could be effective against pathogens.  This review discusses the current experimental principles that guide the application of RNAi against HIV and describes challenges and limitations that need to be surmounted in order for siRNAs to become practical antiviral drugs. The practical use of RNAi therapy for HIV infection will depend on overcoming several challenges, including the ability to establish long-term expression of siRNA without off-target effects and the capacity to counteract mutant escape viruses. 
   
     
 
  Treatment interruption in chronic HIV-1 infection: does it deliver?.
   Treatment interruption  Current Opinion in HIV & AIDS. 2(1):26-30, January 2007.
  Willberg, Christian B; Nixon, Douglas F   Abstract:
  Purpose of review: This review sets out to overview treatment interruption in chronic HIV-1 infection: what treatment interruption promised, results from recent trials, and what the future holds.
   Recent findings: Recent studies have produced mixed results; several trials have been prematurely halted, whereas others have reported more positive outcomes. One consistent finding has been the identification of the CD4 T-cell count nadir as a critical parameter in determining the outcome of treatment interruption.
  Summary: The use of treatment interruption is still controversial, but it is becoming clear that certain individuals could benefit, and partial treatment interruption strategies warrant further investigation.
 
 
 
 
 
 
 Why G3139 works poorly in cancer trials but might work well against HIV.
  2007 Mar 13;  * Parris GE.  9601 Warfield Road, Gaithersburg, MD 20882, USA.
  The antisense drug G3139 (oblimersen sodium, Genta, Inc.) is a phosphorothioate oligodeoxynucleotide (ODN) containing unmethylated CpG units, which is targeted to suppress Bcl-2. To date, its effectiveness in cancer clinical trials has been minimal. Some suggestions are provided for that disappointment and recent citations are provided that support the idea that G3139 may be effective at clearing viral infections, specifically HIV. At the time G3139 was conceived as an anti-cancer drug candidate, it was viewed optimistically because Bcl-2 was widely believed to be the most important protein blocking p53-dependent apoptosis caused by internal stress. Since that time, we have learnt that Bcl-2 is not the only protein that inhibits apoptosis and that p53 itself is frequently malfunctioning in tumors. Thus, the anti-cancer utility of suppressing Bcl-2 in cancer cells is limited. Moreover, Bcl-2 has a role in halting the cell cycle (though p27), which may slow down tumor growth; and Bcl-2 even has pro-apoptotic roles in the execution of apoptosis initiated by external death signals (via Fas/CD95 and caspase 3). Overall, in the clinical setting, G3139 usually has statistically significant but medically unimportant benefit. These results have greatly diminished the enthusiasm for the drug especially when the side effects are considered. Specifically, the unmethylated CpG ODN (and/or the phosphorothioate group) activates the immune system, but this potentially important anti-cancer effect is lost when the immune cells undergo premature apoptosis apparently because their Bcl-2 levels have been lowered by the antisense effect of G3139. While this effect on immune cells is usually undesirable, it is exactly what would be useful for activating immune cells, initiating provirus transcription in retrovirus-infected cells, and facilitating selective apoptosis of these infected cells. In general, G3139 might have benefit in clearing chronic infections by intracellular parasites including viruses (HIV, SIV, HTLV, HBV, coronavirus, etc.). Indeed, G3139 has been shown to cause apoptosis in EBV-infected cells leading to clearance of the virus.
 
 
 
 
 
 natural defensive genes that some cells in human body have that resist and stop hiv... may be drug target
 2007 by the American Society for Clinical Investigation
 An intrinsic host defense against HIV-1 integration?
 Paul D. Bieniasz   Aaron Diamond AIDS Research Center and Laboratory of Retrovirology, The Rockefeller University, New York, New York, USA. HSCs are one of only a few cell types that resist HIV-1 infection despite the presence of HIV-1 receptors. An increasing number of genes have been identified that can reduce the sensitivity of cultured cells to retrovirus infection, and in this issue of the JCI, Zhang et al. identify p21Waf1/Cip1/Sdi1 (p21) as a gene product that can influence the sensitivity of HSCs to HIV-1 infection (see the related article beginning on page 473). Strikingly, p21 appears to alter the fate of nuclear HIV-1 DNA, promoting the formation of circular viral DNA forms rather than functional proviruses.
 
 
 
 
 
  2007 Jan 1;12:2330-43. Links
   T cell immune responses to HIV-1.
     * Vasan S,
    * Schlesinger SJ,
    * Arrode G.
    The Aaron Diamond AIDS Research Center, 455 First Avenue, 7th Floor, New York, New York 10016, USA.
 The recent use of multiparametric flow cytometry to monitor T cell immune responses complements traditional assays, such as IFN-gamma ELISPOT, to provide more information on the functional complexity of CD4+ and CD8+ T cell immune responses induced either by natural infection, or by immunization. In this review, we provide a general background on T cell subsets, and describe the cellular immune response during natural HIV-1 infection. We then review T cell responses to current candidate HIV-1 vaccines. Taken together, this helps to formulate our understanding of the immune correlates of protection required for an effective prophylactic HIV-1 vaccine. Finally, we emphasize current dendritic cell based vaccine strategies designed to modulate immunity to establish immune protection against HIV-1.
 
 
 
 
 

Follow-up data for patients newly diagnosed with HIV infection in Taiwan (HIV/AIDS Cohort) from 1 May 1997 to 30 April 2003 (n = 3351, only 1% are injecting drug users) were analysed using the Kaplan-Meier method. The survival function for an age- and gender-matched reference population was generated by the Monte Carlo method from the life-table of the general population. A constant excess hazard model was used to project long-term survival of HIV-infected patients, with linear extrapolation of a logit-transformed curve of survival ratio between HIV-infected patients and the reference population. Results: The 5-year survival rate was 58% in patients who had already developed AIDS at diagnosis (AIDS group), and 89% in those who had not (non-AIDS group). Extrapolation yielded an expected mean survival time of 10.6 years after diagnosis for the AIDS group, and 21.5 years after diagnosis for the non-AIDS group.
Discussion: Our results support the expansion of HIV screening programs to minimize delay in diagnosis. With continuing advances in HAART, this estimate of survival in initially asymptomatic patients may be conservative. Their long life expectancy raises questions about what kind of preventive heath services should be offered. These should be addressed through further analysis of overall benefit and cost-effectiveness.

Trends in mortality and causes of death among persons with HIV infection, 1985-2004] published march 2007
Instituto de Salud Publica de Navarra, Departamento de Medicina Preventiva y Salud Publica, Universidad de Navarra, Spain.
OBJECTIVE: To describe the changes in causes of death among persons with HIV infection. METHODS: An analysis of mortality according to cause was performed in persons diagnosed with HIV infection and residing in the province of Navarre (Spain) from 1985 to 2004. RESULTS: Among 1,649 persons diagnosed with HIV infection up to 2004, 709 (43.0%) had died. Mortality reached the maximum in 1993-1996 with 83.1 deaths per 1,000 person-years (PY). Since that time and up to 2001-2004, mortality due to AIDS decreased from 68.3 to 14.1 per 1,000 PY (p = 0.0001). From 1989-1992 period to the 2001-2004 period, mortality due to drug overdose dropped from 9.2 to 3.6 per 1,000 PY (p = 0.0035) and mortality due to hepatic disease rose from 1.6 to 6.6 per 1000 PY (p = 0.0061), with no significant changes in all other causes. In 2001-2004, AIDS continued to be the first cause of death (44.4%) in this population, followed by hepatic disease (20.9%) and drug overdose (11.3%). In the era of potent antiretroviral therapy (1997-2004), death caused by AIDS (rate ratio = 0.63; p = 0.0344) and by all other causes (RR = 0.59; p = 0.0232) was lower among women. In addition, mortality due to causes other than AIDS was higher in persons 40 years of age and older (RR = 1.77; P = 0.0050) and mortality was lower in homosexual men (RR = 0.22; p = 0.0360). A simultaneous diagnosis of HIV infection and AIDS was associated with higher mortality by AIDS (RR, 3.39; p < 0.0001). CONCLUSIONS: AIDS continues to be the primary cause of death in HIV-infected people, and mortality due to hepatic diseases and drug overdose is high. Early diagnosis of HIV-infection would reduce the incidence of deaths due to AIDS

 

Fruit pulp extract of Momordica balsamina for anti HIV property Dept. of Chemical Pathology, Plateau Specialist Hospital, Jos, Nigeria. Department of Biochemistry, F.C.A.H & P.T., Vom, Nigeria. Vaccine Production Unit, N.V.R.I; Vom , Nigeria. 4Institute of Human Virology, Maryland, USA. Plateau State Human Virology Research Center, Jos, Nigeria. Accepted 15 September, 2006 Anti-HIV properties of the fruit pulp extract of Momordica balsamina, a plant of the cucurbitacea family commonly used in the Northern part of Nigeria for its anti-viral efficacy in poultry, was studied in vitro. Peripheral blood mononuclear cells (PBMCs) were prepared from both HIV sero positive and sero negative patients and categorized into group A (sero negative), group B (PBMC co-culture), group C (PBMC co-culture containing 3.12 mg/ml of the plant extract) and group D (only the enriched culture medium). The PBMCs were cultivated for 28 days using standard methods. CD4+ counts and virus detection assay ( ) were determined on the PBMC. Results showed that the plant extract treatment significantly (P<0.05) increased the CD4+ count when compared to the untreated PBMC, a contrary effect was observed on the P 24antigen level (P<0.05). The implication of these findings is discussed. Key words: Momordica balsamina, PBMC, HIV. INTRODUCTION Momordica Balsamina also refers to as balsam fruit or apple belongs to the family of cucurbitacea. It is a plant commonly used by local poultry farmers in Plateau State, Nigeria for general well being of birds (Mgbojikwe et al., 2002). The Balsam apple is a climber or trailer with annuals stems attaining 4-5 m length, a plant of dry savannah and clearings in secondary bush of Northern Nigeria. The fruit is orange yellow, beaked, 21/2 inches in length bursting and exposing red brown seeds (Hutchinson, 1954). This species is closely related to Momordila charantia (Bitter mellon) which occurs in areas of greater rainfall and whose properties and actions includes antibacterial, anti-inflammatory, anti-oxidant, antiviral, immunostilmulant, hypoglycemic among others *Corresponding Author’s E-mail: botson2003@yahoo.com. (Bk. of Royal Bot. Gard., 1985). This study is aimed at verifying the claims of some traditional practitioners and AIDS patients in Plateau State of Nigeria, that the agueous fruit pulp of M. balsamina has healing quality. We decided to investigate this claim by measuring its direct effect on HIV-1- an RNA virus belonging to the family retroviridae and is also called lymphodenopathy associated virus (LAV), and is the causative agent for AIDS. (Gallo et al., 1982) The disease caused by this virus in human still remains a serious and major challenge to mankind in the history of human viral infection in view of its high mortality records (WHO, 1994). The only reliable option for its prevention and control is to avoid risky behaviours such as those that tend to promote exchange of blood, or body fluids containing HIV virus and/or HIV infected cells (Dimmork and Primrose, 1993). In patients infected with HIV-1, there exists a significant and steady decline in CD4+ lymphocytes (helper/inducer) Page 2 048 Afr. J. Biotechnol. that correlates with progression to disease. The steady decline in CD4+ cells is related to the trophism of HIV-1 for the CD4 receptors. The percentage as well as the total numbers of CD4+ lymphocytes in the peripheral blood of patients infected with HIV is one of the parameters to monitor prognostically. During the course of HIV infection, the first proliferative dysfunction which appears is the inability of CD4+ T-cells to recognize and proliferate in response to soluble antigens such as tetanus toxoid (TT), diphtheria, or purified protein derivative and during the end stage disease, a decline in proliferative responses to polyclonal mitogens such as phytohemaglutinin (PHA), pokeweed mitogen (PWM), and concanavalin A (Con A) can be see RESULTS CD4+ counts There was a steady and significant rise in mean CD4+ counts of positive control (group A) and cocultures of groups that were treated with the plant extract (group C) within the first two weeks P(<0.05). While those that the plant extract was not added to (group B), showed a decline in the mean CD4+ counts. However, a persistent decline in the mean CD4+ counts was observed in all the groups in the third and fourth weeks probably due to prolonged culturing of primary cells in vitro (Figure 1) Phytochemicals and mineral elements The phytochemicals present in the dried powdered extract of the fruit pulp include resins, tannins, alkaloids, flavonoids, saponin, glycosides, steroidal ring and terpenes while the mineral elements include: Mg2+, Fe 2+,Na+and K+ Se and Pb were not detected (Tables Hence, the remarkable ability of the plant extract to protect the cells from been destroyed by the virus in vitro is interesting (Tables 3) Tannins have been reported to complex with proteins and inactivate microbial adhesion enzymes, cell enve- lope, transport protein, etc (Haslam, 1996). They also complex with polysaccharides (Ya et al., 2988). At least two studies have shown tannins to be inhibitory to viral reverse transcriptase (Kaul et al., 1985; Nonaka et al., 1990). Alkaloidal glycosides isolated from Solanum khas- ianum have been reported to have antiviral activity (Moore and Pizza, 1992). Generally, phytochemicals extracted with water such as fabatin and various lectins are more commonly effective as inhibitors of viral adsorption. The role of minerals in HIV/AIDS has long been established (Figures 3). Zinc, calcium and magnesium are known to serve as coenzy- mes in many enzymes activities. In addition, zinc has been shown to be essential in maintaining the immune system function and HIV infected individuals are particu- larly susceptible to zinc deficiency (Wellinghansen et al., 2000) in view of our study and research on the above findings on M. balsamina as a potent inhibitor of HIV-1 replication in vitro, the research on fruit pulp extract should be further pursued for its potential in the prophylaxis and therapy of retrovirus infections in humans.

its cold in norway so people die all the time both with and without HIV ..................
in the HAART era the mortality in HIV patients was reduced by 80%. However, the mortality in the HAART era was still 4 times higher than in the general population.... seems sad to me, and discouraging but this woudl be all people even those souls who have been poz for 20 and 25 years...Vidar Ormaasen, Leiv Sandvik, Susanne G. Dudman, Johan N. Bruun Abstract The objective of the study was to compare the mortality in HIV infected individuals to the general population, and to explore the relative contribution of HIV to mortality before and after the introduction of highly active antiretroviral therapy (HAART). All HIV patients attending Ullevål University Hospital, Oslo, Norway before (cohort 1) and after (cohort 2) the introduction of HAART were included. Causes of deaths were classified as HIV related or not. Mortality in the Norwegian general population was standardized according to the distribution of age and gender in our cohorts. Ratios between mortality in our cohorts and the standardized mortality were calculated. The risk ratio (RR) for 5-y mortality compared to the general population was 22.6 (95% confidence interval (CI), 19.5–26.4) in cohort 1 (n=782), and 3.96 (95% CI 2.25–6.97) in cohort 2 (n=398). The non-HIV related mortality RR was 4.42 (95% CI 3.18–6.13) in cohort1 and 0.89 (95% CI 0.29–2.76) in cohort 2. Higher age and low CD4 cell count were associated with increased mortality. Thus, in the HAART era the mortality in HIV patients was reduced by 80%. However, the mortality in the HAART era was still 4 times higher than in the general population.

http://scholar.google.com/scholar?q=hiv&num=100&hl=en&lr=&as_ylo=2007&as_yhi=2007&as_subj=bio+med&start=400&sa=N

 


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