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African American HIV Patients Experience More Aggressive Kidney Disease Progression

Several previous studies have shown that HIV positive African Americans have a higher risk of end-stage renal disease (ESRD), or kidney failure, compared with their white counterparts. This racial disparity is also apparent in the HIV negative general population.

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CROI 2008: Abacavir/3TC (Epzicom) Matches Tenofovir/Emtricitabine (Truvada) for Treatment-naive Patients: HEAT Study

While there is always much interest in new antiretroviral drug classes, research continues as well on the earliest type of anti-HIV therapy, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). At the 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008) this week in Boston, researchers presented data from the HEAT (Head-to-head Epzicom And Truvada) trial, a direct comparison of 2 double-NRTI backbones.

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NRTI Backbone Choice Affects Durability of Efavirenz- or Nevirapine-based HAART in Treatment-naive HIV patients

The calendar year in which HIV patients initiated HAART and durability of the nucleoside/nucleotide reverse transcriptase (NRTI) backbone are significant predictors of virological success and treatment failure, according to a study published in the April 6, 2009 early online edition of the Journal of Acquired Immune Deficiency Syndromes.

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Swiss Experts Claim HIV Patients with Undetectable Viral Load Who Adhere to Treatment Cannot Transmit the Virus to HIV Negative Partners

Several HIV/AIDS advocacy groups and scientists have expressed dismay and disbelief about the findings of a report from The Swiss AIDS Commission, based on several studies, that individuals using anti-HIV drugs cannot transmit HIV infection to their sex partners, if they have undetectable viral loads (< 40 copies/ml) for at least six months and if they remain adherent to their treatment regimens.

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Argos Therapeutics Reports Promising Phase 1 Data on AGS-004 Immunotherapy for HIV

Durham-based Argos Therapeutics this week announced promising results from an early (Phase 1) clinical trial of a novel type of individualized immune-based therapy for patients with HIV.

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Atazanavir (Reyataz) Label Changes Cover Drug Interactions, Kidney Impairment

The U.S. Food and Drug Administration this week announced revisions to the package insert for the protease inhibitor atazanavir (Reyataz), reflecting new information about administration with food, interaction with several drugs, and use by patients with impaired kidney function.

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AIDS Healthcare Foundation Calls for Halt to U.S. Government Funding of HIV Vaccine Research

Michael Weinstein, director of the AIDS Healthcare Foundation (AHF) of Los Angeles, the nation's largest provider of HIV/AIDS medical care, has called for the U.S. government to stop funding AIDS vaccine research and instead focus on funding that provides anti-HIV treatment to patients in need.

As previously reported by HIV and Hepatitis.com, the National Institutes of Allergy and Infectious Diseases (NIAID) held a meeting with HIV researchers in late March to re-evaluate the agency's nearly $500 million vaccine research program, in the wake of disappointing results that led to the cancellation of the STEP vaccine trials.

Following is the text of Weinstein's editorial published in the April 4, 2008 Los Angeles Times:

As the catalyst for the call to halt U.S. government funding of AIDS vaccine research, I was somewhat dismayed by The [Los Angeles] Times' recent editorial, "Revamping AIDS vaccine research," that took issue with the AIDS Healthcare Foundation's position without fully understanding it.

Our position is this: In light of over 20 years of failed AIDS vaccine research on which billions of dollars of U.S. taxpayer money have been spent, we believe it is simply unconscionable for the U.S. government to continue such wasteful funding while millions worldwide die for want of access to the AIDS research breakthrough that occurred more than 10 years ago -- life-saving antiretroviral treatment.

There are not just two or three AIDS vaccine candidates that have failed. Every AIDS vaccine candidate to date has failed. Leading scientists, including Nobel Prize winner Dr. David Baltimore, have even gone so far as noting that we are no closer to the discovery of an AIDS vaccine today than we were 20 years ago.

In fact, not only have all the AIDS vaccine candidates failed, the latest was hurriedly pulled from clinical trial after the vaccine was found to actually put people at a significantly increased risk of contracting HIV. Twenty-seven years into the AIDS pandemic, countless billions in taxpayer (and private) vaccine funding later, and our leading researchers can't even meet the most fundamental tenet to "do no harm."

Meanwhile, as AIDS vaccine candidates repeatedly fail, consensus continues to build that successful antiretroviral treatment offers a vaccine-like effect -- rendering most HIV-positive people noninfectious. This treatment offers a far more enduring benefit than anything that AIDS vaccine research has or will offer. At the same, more than 33 million people worldwide continue to live with -- and die from -- HIV/AIDS. Barely 2 million in the developing world have access to the treatment that we know works to save lives -- and reduces the likelihood of transmission.

The Times' editorial mentions the billions the U.S. gives to AIDS research and relief. While at first blush this seems like a generous amount, this funding provides treatment and support services for only a small fraction of the people worldwide living with HIV/AIDS who may be in need. With lifesaving antiretroviral treatment costing as little as $300 per patient per year in Africa and elsewhere in the developing world, the $700 million or so the U.S. currently spends annually on fruitless AIDS vaccine research could save an additional 2.3 million lives around the world each year. As successful antiretroviral treatment renders people less infectious, it would also help break the chain of new infections globally and bring the number of new infections down.

To be clear, what the AIDS Healthcare Foundation called for last week is a halt to U.S. government funding of AIDS vaccine research. Private donors and foundations may continue to fund whatever vaccine research they may deem appropriate. Regarding The Times' support for the NIH getting back to basic research (which the NIH appeared to commit to last week), Times' readers -- and writers -- should know that the NIH already funds basic AIDS research to the tune of several hundred million dollars per year, separate from its $700 million annually in AIDS vaccine research funding.

Early next week, the AIDS Healthcare Foundation will call on congressional leaders in Washington to demand a Government Accountability Office report on the history and current state of AIDS vaccine research. It is our hope that through the lens of dispassionate third-party investigators, a clearer light will be shone on the folly of government largesse continuing to blindly fund AIDS vaccine research.

Currently, the AIDS vaccine establishment continues its taxpayer-funded, repeatedly unsuccessful search for a preventive AIDS vaccine while an alternative many have seen work on multiple levels -- successful antiretroviral treatment as both treatment and prevention -- goes unchampioned.

This is why the AIDS Healthcare Foundation believes that it is time to pull the plug on U.S. taxpayer financing of the search for a vaccine, and leave it to private donors to back what has been and continues to appear to be a fruitless goal. To continue to invest hundreds of millions of dollars in a government-funded search for an AIDS vaccine in the vain hope of success someday while millions worldwide suffer and die is simply unacceptable when other currently available strategies offer practical -- and effective -- alternatives.

4/04/08

Sources

M Weinstein. Stop AIDS Vaccine Research: The U.S. should focus its funds on providing treatment to people in need (Editorial). Los Angeles Times. April 4, 2008.

Los Angeles Times. Revamping AIDS vaccine research (Editorial). April 1, 2008.

Monoclonal Antibody CCR5 Inhibitor PRO 140 Produces Long-lasting HIV Suppression in Single-dose Study

In order to enter human CD4 T-cells, HIV must bind to both the CD4 receptor on the cell surface and 1 of 2 co-receptors, CCR5 or CXCR4. If the virus cannot attach to a co-receptor, it cannot infect new cells. The first oral CCR5 antagonist, maraviroc (Selzentry) was recently approved, and another such agent, vicriviroc, has shown promising results in clinical trials.

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DHHS Treatment Guidelines Panel Says New Cardiovascular Data Do Not Warrant Changing Recommendations Regarding Use of Abacavir (Ziagen)

DHHS Treatment Guidelines Panel Says New Cardiovascular Data Do Not Warrant Changing Recommendations Regarding Use of Abacavir (Ziagen) As reported by HIV and Hepatitis.com on March 28, 2008, the U.S. Food and Drug Administration (FDA) published an Early Communication about recent findings from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study showing an elevated risk of heart attacks in HIV positive patients taking abacavir (Ziagen)or didanosine (ddI; Videx). Abacavir manufacturer GlaxoSmithKline (GSK) concurrently issued a statement in response to the FDA communication, noting that it had not observed a similar increase in risk in its own studies of the drug.

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Insulin Resistance and Liver Injury in Patients with Hepatitis C Are Not Associated with Virus-Specific Changes in Adipocytokines

There is a growing body of evidence linking hepatitis C virus (HCV) infection with metabolic abnormalities including type 2 diabetes mellitus. However, the role of adipocytokines in HCV-associated insulin resistance is not yet clear.

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100 mg Once- and Twice-daily Ritonavir (Norvir) Decreases HDL and CD36 Expression, but Only Twice-daily Dosing Increases Triglycerides

Most current HIV protease inhibitors (PIs) are used in combination with a low dose of ritonavir (Norvir) to raise their levels in the blood. This has led to interest in determining the impact of low-dose ritonavir on changes in blood lipids among patients using boosted PIs. In the current study, presented at the 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008) last month in Boston, researchers investigated the possible role of ritonavir in contributing to cardiovascular disease.

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Adult Circumcision Reduces Men's Risk of HIV Infection

Adult male circumcision is emerging as a potentially important public health measure for reducing the risk of HIV transmission to men during heterosexual sex. A previous study in South Africa showed that elective circumcision reduced men's HIV infection rate by 61% (Auvert et al 2005).

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AIDS-related Deaths in France Are More Frequent in Women than in Men since 2000

As reported at the 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008) last week in Boston, French researchers conducted a retrospective sub-study of the Mortalité 2000 and 2005 surveys to determine characteristics at the time of death in women compared to men with HIV/AIDS.

While numerous studies have looked at the changing causes of mortality in people with HIV/AIDS, few have focused on HIV positive women.

All deaths occurring in HIV-infected adults were reported through years 2000 and 2005 in national surveys. A standardized questionnaire collected social, demographic, clinical, biological, and therapeutic characteristics. 

Results

• 32% of HIV positive women who died were infected through injection drug use (vs 30% of men) and 53% were infected through heterosexual intercourse (vs 25% of men).

• In women, the age at death was lower than that of men (43 vs 46 years; P < 0.001).

• Socioeconomic "precariousness" was also more common among the HIV positive women compared with men (38% vs 28%; P = 0.006).

• Men also had a higher rate of dyslipidemia (4% vs 10%; P = 0.01).

• The 3 AIDS-related causes of death that were more frequent in 2005 were non-Hodgkin's lymphoma (19% vs 21% in 2000), progressive multifocal leukoencephalopathy (18% vs 3%), and cerebral toxoplasmosis (14% vs 17%).

• Breast cancer was a cause of death in 3% and cervical cancer in 2% of the women.

Conclusion

In conclusion, the investigators noted that, in the context of a global decrease since 2000, "AIDS-related deaths are nowadays more frequent in women than in men."

"Even in a setting of universal access to care, HIV positive women, especially migrants in poor socioeconomic conditions, may not benefit from optimal case management," they added.

Finally, they concluded, "Conversely, the lower proportion of non-AIDS causes of deaths observed in women may be explained by a lower prevalence of traditional risk factors of respiratory or cardiovascular diseases and of violent deaths."

INSERM U593, Bordeaux, France; Ctr Hosp Univ Bordeaux, France; Univ Bordeaux, France; HospPitie-Salpetriere, Paris, France; Univ Pierre and Marie Curie, Paris, France; Ctr Hosp Univ Cochin-Tarnier, Paris, France; Ctr Hosp Nancy, France; Ctr Hosp Univ Nice, France; INSERM U720, Paris, France. 


2/15/08

Reference

M Hessamfar-Bonarek, G Chene, D Salmon, and others. (for the Mortalité 2000 & 2005 Study Group). Causes of Death in HIV-infected Women and Their Evolution Since 2000: The Mortalité 2000 and 2005 Surveys, ANRSEN19. 15th Conference on Retroviruses and Opportunistic Infections. Boston, MA. February 3-6, 2008. Abstract 666.

SMART Data Confirm Risk of CD4-guided Treatment Interruptions

Interruption of antiretroviral therapy is a potentially hazardous strategy associated with an increased risk of disease progression or death, according to data from the large international SMART (Strategies for Management of Antiretroviral Therapy) study.

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CROI 2008: D:A:D NRTI Analysis Shows Abacavir (Ziagen) and ddI (Videx) Boost Cardiovascular Risk

As effective antiretroviral therapy has extended the lives of people with HIV/AIDS, there is growing concern about long-term drug-elated toxicities. With regard to increased cardiovascular disease risk, protease inhibitors (PIs) have taken most of the blame, but some studies have found an association with drugs in other classes.

The thymidine analogs, a subset of nucleoside reverse transcriptase inhibitors (NRTIs) that includes AZT (zidovudine, Retrovir) and d4T (stavudine, Zerit) have been linked to several long-term side effects including lipoatrophy (peripheral fat loss). Some data have shown an association with abnormal blood fat levels (dyslipidemia) and insulin resistance, both known risk factors for heart disease.

To explore this connection, researchers with the large D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) study assessed the association between various NRTIs used as part of combination therapy and risk of myocardial infarction (MI, or heart attack). Results were reported in a poster presented at the 15th Conference on Retroviruses and Opportunistic Infections this week in Boston.

D:A:D, begun in 1999, is a large ongoing collaboration of 11 prospective cohorts in North America, Europe, and Australia that has collected data on more than 33,000 patients. As previously reported, antiretroviral therapy overall, and PI use in particular, were associated with an increase risk of MIs.

In the present analysis, the investigators set out to assess the effect of cumulative, recent (current or within the past 6 months), and past (> 6 months ago) use of AZT, d4T, abacavir (Ziagen; also in the Trizivir and Epzicom combination pills), ddI (didanosine, Videx), and 3TC (lamivudine, Epivir). Emtricitabine (Emtriva) and the sole nucleotide reverse transcriptase inhibitor, tenofovir (Viread) (both combined in the Truvada and Atripla combination pills) were not included since they came on the market relatively late.

Results

• A large majority - 89% -- of the total 157,912 person-years of follow-up included in the present analysis was spent on NRTI(s).

• During this period, 517 individuals experienced heart attacks.

• 98% of the MIs occurred among patients exposed to 1 or more NRTIs.

• Neither cumulative nor recent use of the 2 thymidine analogs (AZT and d4T) nor 3TC were associated with increased risk of MI.

• However, cumulative use of abacavir and ddI were both significantly associated with an excess heart attack risk:

• abacavir: relative risk per year of use 1.14 (95% CI 1.08-1.21; P < 0.01);

• ddI: relative risk per year of use 1.06 (95% CI 1.01-1.12; P = 0.03).

• In a model focusing on recent use, use of abacavir and ddI within the past 6 months -- but not cumulative use - predicted an increased risk of MI (relative risk per year of use 1.90 and 1.49, respectively; both P < 0.01).

• In other models, recent use of these 2 drugs -- but not past use -- predicted elevated MI risk.

• Rates of MI per 1000 person-years for patients with recent use versus no recent use, stratified by level of Framingham cardiovascular risk, were as follows:

• Abacavir:

• Low risk: 3.3 vs 1.2;

• Medium risk: 9.8 vs 7.1;

• High risk: 31.3 vs 11.2.

• ddI:

• Low risk: 2.1 vs 1.5;

• Medium risk: 9.1 vs 7.5;

• High risk: 20.8 vs 14.9.

• The elevated risk of MI associated with recent abacavir or ddI use was seen regardless of duration of use.

• The increased risk remained after adjusting for HIV viral load, CD4 cell count, elevated blood lipids, and other metabolic factors.

• Preferential use of abacavir or ddI by patients with pre-existing elevated cardiovascular risk ("channeling") did not appear to explain the findings.

Conclusion

Based on these results, the D:A:D researchers concluded that, "Thymidine analogs were not associated with risk of MI." But, they continued, "Unexpectedly, recent use of abacavir and ddI were associated with increased risk of MI, by 90% and 49%, respectively."

"The excess risks of MI associated with abacavir and ddI use were most pronounced -- in absolute terms -- in patients with high underlying cardiovascular risk," they added. "Although it is impossible to rule out bias as an explanation, if these associations are causal, the unknown biological mechanism(s) appears reversible upon cessation of these drugs."

The latter finding - that elevated MI risk did not continue after patients stopped the drugs - is in contrast with use of PIs, which seems to confer a persistent increase in risk. While PI risk is thought to be related to elevated blood lipids that promote atherosclerosis, abacavir and ddI appear to be associated with a short-term effect, perhaps related to inflammation, though the biological mechanism is not clear at this time.

Based on these findings, abacavir manufacturer GlaxoSmithKline conducted a retrospective review of 54 past clinical trials of the drug. They reported at a community meeting prior to the conference that they did not find an increased MI risk, with rates of 1.7 and 2.4 per 1000 person-years, respectively, in abacavir-exposed versus non-exposed patients; the company said further analysis is ongoing.

Given the alarming nature of the study findings, the D:A:D Steering Committee issued a statement putting the results in context.

To give an estimate of the magnitude of the increase risk of heart attacks associated with the use of these drugs, the 1.9 fold (90%) increased risk associated with use of abacavir compares with a 2-3 fold increased risk of heart attack associated with current cigarette smoking,” they wrote.

However, they noted that the increased risk was concentrated in patients with other cardiovascular risk factors, including older age, smoking, diabetes, and high cholesterol, underling the need to tailor antiretroviral therapy on an individual basis – and to manage modifiable lifestyle factors that increase heart disease risk.

“The authors of this study recommend patients receiving abacavir or ddI should consult their doctor, and discuss whether a modification of their anti-HIV drug regimen is appropriate,” they wrote. “Patients should NOT stop any drug without prior discussion with their doctor.”

The full position statement and the poster are available from the D:A:D web site.

Univ Coll London and Royal Free Hosp, UK; Univ of Copenhagen, Denmark; Univ Hosp Zurich, Switzerland; Colombia Univ, New York, NY; Academic Med Ctr, Amsterdam, The Netherlands; Inst for Publ Hlth, Epi and Devt, Univ Victor Segalen Bordeaux 2, France; St Pierre Univ Hosp, Brussels, Belgium; Univ of New South Wales, Sydney, Australia; and Rigshospitalet, Copenhagen, Denmark.

02/08/08

Reference

C Sabin, S Worm R Weber, and others (D:A:D Study Group). Do Thymidine Analogues, Abacavir, Didanosine and Lamivudine Contribute to the Risk of Myocardial Infarction? The D:A:D Study.15th Conference on Retroviruses and Opportunistic Infections. Boston, MA. February 3-6, 2008. Abstract 957c.

Other Souce

D:A:D Steering Committee. Position Statement by the D:A:D Steering Committee.

AASLD 2006: Liver Transplantation in HIV Positive Patients

The Thomas E. Starzl Transplant Surgery State-of the-Art Lecture at this year’s American Association for the Study of Liver Diseases (AASLD) annual meeting was devoted to the outcomes following solid organ transplantation in HIV-infected recipients. The speaker, Peter G. Stock, MD, from the University of California at San Francisco, gave a very good update on the topic.

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CROI 2008: Boosted Atazanavir (Reyataz) and Lopinavir/ritonavir (Kaletra) Have Similar Efficacy, but Different Side Effects: CASTLE

As antiretroviral therapy had improved, there are now multiple drug regimens that can produce full HIV suppression. However other factors -- including immediate side effects, long-term toxicities, and convenience -- may vary considerably. At the 15th Conference on Retroviruses and Opportunistic Infections this week in Boston, researchers reported data from the CASTLE trial, which compared 2 of the most widely used protease inhibitors, ritonavir-boosted atazanavir (Reyataz) and lopinavir/ritonavir (Kaletra), in treatment-naive participants. 

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AIDS 2006: TNX-355 Produces Significant Reduction in HIV Viral Load at 48 Weeks

Data on several investigational anti-HIV drug candidates were presented at the XVI International AIDS Conference last week in Toronto, including the latest results from a study of Tanox’s investigational monoclonal antibody, TNX-355. TNX-355 is a recombinant human antibody that binds to domain 2 of the CD4 receptor, thereby blocking the entry of HIV into host cells. 

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