SUMMARY: People with HIV who use abacavir (Ziagen, also in the Epzicom and Trizivir combination pills) were not significantly more likely to experience cardiovascular events such as myocardial infarction, or to die from any cause, compared with those taking other NRTIs, according to a recent meta-analysis of randomized clinical trials and an analysis of a large observational cohort. The latter analysis found that an apparent link between abacavir and heart attacks disappeared after excluding cocaine and injection drug users.
By Liz Highleyman
At the 2008 Conference on Retroviruses and Opportunistic Infections, investigators with the large D:A:D cohort first reported that people with HIV who recently used abacavir or didanosine (ddI; Videx) had a significantly higher rate of myocardial infarction, or heart attack.
Since that time, however, analyses of a large number of observational cohorts and randomized clinical trials have produced conflicting evidence, and the issue remains unresolved.
Meta-analysis
The first of the recent studies, presented by Mario Cruciani from the HIV Center in Verona, Italy, and colleagues at the XVIII International AIDS Conference (AIDS 2010) last month in Vienna, was a meta-analysis of clinical trials looking at the possible link between abacavir and cardiovascular events.
The investigators aimed to combine all the available evidence from randomized clinical trials (RCTs) in order to estimate the effect of combination antiretroviral therapy (ART) containing abacavir on major cardiovascular events such as myocardial infarction. They carried out a comprehensive medical literature search and sought information about unpublished trials from drug manufacturers, collecting data about cardiovascular events and overall mortality.
The researchers identified 29 RCTs conducted between 1996 and 2010 that compared ART regimens containing abacavir versus other nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). Of these, 19 were from published literature and 10 from the data repository of abacavir manufacturer GlaxoSmithKline (GSK); 3 other trials in the data repository were also published and were only counted once. Together, these studies represented a total of 9611 patients.
Data on myocardial infarction were available from 16 RCTs, representing 6617 patients (3629 from published trials, 2988 from the GSK data repository). A total of 26 myocardial infarctions were reported, 11 among abacavir recipients and 15 among patients taking control drugs -- not a significant difference (relative risk [RR] 0.74; P = 0.36).
Data on mortality were available from 22 studies, representing 6801 patients; again, there was no significant difference between patients taking abacavir versus comparator NRTIs (RR 1.57; P = 0.17).
Results were similar when comparing abacavir only against its common competitor tenofovir (Viread, also in the Truvada and Atripla coformulations), with relative risks of 0.79 for myocardial infarction and 1.08 for overall mortality.
"Observational studies are prone to biases and should be interpreted with caution given the potential for confounding," the investigators concluded. For example, clinicians may prescribe abacavir more often for people with cardiovascular risk factors such as metabolic syndrome or kidney disease.
"Randomized trials provide stronger evidence than do observational studies," they continued. "Our meta-analysis was based on RCTs, and did not show an increase in the occurrence of myocardial infarction, overall mortality, and occurrence of adverse events in abacavir recipients."
French HIV Cohort
As described in the second report, published in the July 26, 2010 issue of the Archives of Internal Medicine, investigators with the Clinical Epidemiology Group of the French Hospital Database on HIV also looked at the association between abacavir exposure and risk of myocardial infarction.
The researchers conducted a case-control study nested within the French Hospital Database on HIV. They identified 289 case patients who had a first definite or probable myocardial infarction between January 2000 and December 2006. A total of 884 control subjects without heart attacks matched for age, sex, and clinical center were selected at random (up to 5 per case) from among clinic patients.
In an initial analysis, short-term or recent abacavir exposure was associated with an increased risk of myocardial infarction in the overall sample population (odds ratio [OR] 2.01, or about twice the risk). This association was no longer seen, however, after excluding the approximately 20% of matched case and control patients who used cocaine or intravenous drugs (OR 1.27).
Cumulative exposure to all protease inhibitors except saquinavir (Invirase) was associated with an increased risk of myocardial infarction. The association was significant for amprenavir (Agenerase, now discontinued)/fosamprenavir (Lexiva) with or without ritonavir boosting (OR 1.53 per year), and for lopinavir/ritonavir (Kaletra)(OR 1.33 per year). No non-nucleoside reverse transcriptase inhibitors (NNRTIs) were associated with increased myocardial infarction risk.
Based on these findings, the study authors concluded that while the risk of myocardial infarction was increased by cumulative exposure to all the studied protease inhibitors with the exception of saquinavir, "the association with abacavir cannot be considered causal."
Investigator affiliations:
Cruciani study: HIV Center, Verona, Italy; University of Padua, Padua, Italy.
French cohort study: Unité 943, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Unité Mixte de Recherche Santé 943, Université Pierre et Marie Curie, Univ Paris 6, Paris, France; Service d'hépatologie, Hôtel Dieu, Hospice Civil de Lyon, Lyon, France; Service des maladies infectieuses et tropicales, Hôpital Necker, Assistance Publique Hôpitaux de Paris, Paris, France; Hôpital de jour du Comité de Coordination de la lutte contre l'infection par le vih, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Service de médecine interne 1 (Dr Simon) and Service des maladies infectieuses et tropicales, Hôpital Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, Paris, France; Service de cardiologie, Hôpital Saint-Antoine, Assistance Publique Hôpitaux de Paris, Paris, France.
8/13/10
References
M Cruciani, V Zanichelli, G Serpelloni, and others. Abacavir use and cardiovascular disease events: a meta-analysis of published and unpublished data. XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract WEPE0121.
S Lang, M Mary-Krause, L Cotte, D Costagliola, and others (Clinical Epidemiology Group of the French Hospital Database on HIV). Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus-infected patients: a case-control study nested within the French Hospital Database on HIV ANRS cohort CO4. Archives of Internal Medicine 170(14): 1228-1238 (Abstract). July 26, 2010.
For further information or to review the entire article, go to: http://www.hivandhepatitis.com/2010_conference/AIDS2010/docs/0813a_2010.html
