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French Hospital Study and Further D:A:D
Analyses Suggest MI Risk With Abacavir
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16th Conference on Retroviruses and Opportunistic Infections,
February 8-11, 2009, Montreal
Mark Mascolini
Work from the French Hospital Database on HIV supported a finding from last year's Conference on Retroviruses--an apparent link between recent abacavir use and myocardial infarction (MI) [1]. Armed with further follow-up, the D:A:D cohort group also confirmed their earlier finding on recent abacavir use and a higher MI risk [2].
The D:A:D study also buttressed its correlation of recent didanosine use with MI and found that cumulative exposure to indinavir and lopinavir/ritonavir made MI more likely. The French team repeated the MI association with cumulative lopinavir/ritonavir, while also implicating amprenavir or fosamprenavir, but not indinavir or saquinavir. Neither analysis tied any other nucleoside or nucleotide analog, or any nonnucleoside, to a higher MI risk.
French investigators tallied new MIs in HIV-infected people seen from January 2000 through December 2006. They matched these 286 MI cases with 884 controls of similar age, the same gender, and the same center who did not have an MI. Most people who suffered an MI (89%) were men, and their median age was 47 years.
Statistical analysis adjusted for cardiovascular risk factors, viral load, CD4/CD8 ratio, and other antiretrovirals determined that abacavir exposure of less than 1 year and recent (but not cumulative) abacavir exposure independently doubled the MI risk (odds ratio [OR] 1.97, 95% confidence interval [CI] 1.09 to 3.96). The researchers found no association between abacavir use and number of classic cardiovascular risk factors.
Analysis of the other nucleosides discerned trends toward a higher MI risk with cumulative exposure to zidovudine or stavudine. Principal investigators Dominique Costagliola noted that these findings support the original D:A:D study hypothesis that thymidine nucleoside analogs would heighten MI risk. But she stressed that both correlations were modest and lacked statistical significance.
Every year of treatment with lopinavir/ritonavir boosted the MI risk 1.37 times (95% CI 1.09 to 1.72), while every year of treatment with amprenavir or fosamprenavir hoisted the risk 1.52 times (95% CI 1.10 to 1.72). The French also saw trends toward higher MI risk with each year of ritonavir-boosted or unboosted indinavir (odds ratio [OR] 1.10, 95% CI 0.98 to 1.22) and nelfinavir (OR 1.12, 95% CI 0.98 to 1.28), but not with boosted or unboosted saquinavir.
D:A:D investigators and SMART trial researchers published their initial findings on abacavir and MI risk in 2008 [3]. The updated D:A:D analysis considered 580 MIs during 178,835 person-years of follow-up in analyses that factored in demographics, cardiovascular risk factors, and other antiretrovirals, this time including tenofovir (which they excluded from the first analysis because they lacked sufficient follow-up) plus zidovudine, didanosine, zalcitabine, stavudine, and lamivudine, the nonnucleosides efavirenz and nevirapine, and the protease inhibitors (PIs) lopinavir/ritonavir, nelfinavir, indinavir (boosted and unboosted), and saquinavir (boosted and unboosted). D:A:D statisticians had more than 30,000 person-years of follow-up on any individual antiretroviral they considered.
Recent exposure to abacavir (meaning current treatment or treatment within the past 6 months) independently raised the MI risk 68% (relative risk [RR] 1.68, 95% CI 1.33 to 2.13), and recent didanosine upped the risk 41% (RR 1.41, 95% CI 1.09 to 1.82). Cumulative abacavir use and cumulative zidovudine also had borderline significant associations with MI in the D:A:D population.
Among the PIs and nonnucleosides, only cumulative use of indinavir (RR 1.12 per year, 95% CI 1.0 to 1.18) and lopinavir/ritonavir (RR 1.13 per year, 95% CI 1.05 to 1.21) made an MI more likely. Adjusting these analyses for lipids moderately diminished the impact of indinavir and lopinavir/ritonavir on MI risk, but further adjustment for other metabolic measures had no impact. Ritonavir had no measurable effect on MI risk with indinavir or saquinavir.
Even before the French findings supported D:A:D results on abacavir, US guideline writers had moved abacavir/lamivudine off the list of preferred first-line nucleoside combinations, citing potential cardiovascular risk as one reason [4].
Other research presented at this conference, which NATAP will summarize separately, found no link between abacavir and heart disease.
References
1. Lang S, Mary-Krause M, Cotte L, et al. Impact of specific NRTI and PI exposure on the risk of myocardial infarction: a case-control study nested within FHDH ANRS CO4. 16th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2009, Montreal. Abstract 43LB.
2. Lundgren J, Reiss P, Worm S, et al. Risk of myocardial infarction with exposure to specific ARV from the PI, NNRTI, and NRTI drug classes: the D:A:D study. 16th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2009, Montreal. Abstract 44LB.
3. Strategies for Management of Anti-Retroviral Therapy/INSIGHT; DAD Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS. 2008;22:F17-F24.
4. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. November 3, 2008.
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