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 PIsIn 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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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. 


 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.


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. 



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.

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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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.


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:


Low risk: 3.3 vs 1.2;

Medium risk: 9.8 vs 7.1;

High risk: 31.3 vs 11.2.


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.


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.



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.


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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