UC Berkeley

Cardiovascular Disease Outcomes from Use of Antiretroviral Agents Among HIV-infected Individuals

By

Kunchok Dorjee

Doctor of Philosophy in Epidemiology

University of California, Berkeley

Professor Arthur L. Reingold, Chair

Combination anti-retroviral therapy (ART) has improved the quality of life of Human Immunodeficiency Virus (HIV)-infected individuals, and has helped them to live longer. A better understanding of the adverse drug events associated with use of various antiretroviral (ARV) drugs can help in further improving the health outcomes of HIV-infected patients. In the past years, use of various individual and combinations of ARV agents have been shown to be associated with an increased risk of cardiovascular disease (CVD) among HIV-infected patients. Of the various ARV agents, the propensity of abacavir, a nucleoside reverse transcriptase inhibitor, to increase the risk of CVD has received particular attention because of its central role as an anchor drug in combination ART. This dissertation aims to investigate the risk of acute myocardial infarction (AMI) associated with use of various antiretroviral agents among HIV-infected individuals in the United States. It further presents the results of an in-depth analysis of the risk of CVD associated with use of abacavir among HIV-infected individuals. Additionally, the results of a systematic review and meta-analysis of epidemiologic studies that were carried out to assess the risk of CVD associated with abacavir use are also presented in this dissertation.

Because a number of covariates that could potentially confound the relationship between use of ARV agents and the risk of CVD may also lie on the causal pathway, and because these factors could potentially be influenced by receipt of the exposure in the past, marginal structural Cox proportional hazard models using stabilized inverse probability of treatment weights were used to investigate this relationship. Results from unweighted Cox regressions were additionally presented for comparison. For the systematic review and meta-analysis, random-effects models were used when there was heterogeneity of results across studies, and fixed-effects models were used when there was no heterogeneity. The fixed-effects and random-effects models were weighted by inverse of variance.

Chapter One of this dissertation describes the risk of AMI associated with use of several individual and combinations of ARV agents among HIV-infected patients receiving ART. The risk of AMI was elevated among HIV-infected individuals currently exposed to abacavir, lamivudine, didanosine, lopinavir, and darunavir. Of the ARV drug combinations, current exposure to combinations of abacavir+lamivudine+atazanavir, abacavir+lamivudine+darunavir, and tenofovir+emtricitabine+raltegravir was associated with an increased risk of developing AMI. There was a protective effect against AMI from exposures to tenofovir, emtricitabine, and efavirenz, as individual agents, and as a combination regimen. Chapter Two of this dissertation presents the results of a further investigation into the risk of ischemic CVD associated with use of abacavir among HIV-infected patients. The investigation showed an increased risk of CVD and AMI associated with current, recent, and cumulative exposure to abacavir. The results of a systematic review and a meta-analysis of the epidemiologic studies, presented in chapter three of this dissertation, confirmed that recent and cumulative exposure to abacavir were associated with an increased risk of CVD among HIV-infected individuals.

In sum, exposure to various individual and combinations of ARV agents was associated with an increased risk of CVD among HIV-infected individuals. Risk and benefits should be carefully weighed while formulating antiretroviral treatment regimens for HIV-infected patients. A trans-disciplinary approach in future studies with a translational focus to achieve a better understanding of the biological mechanisms underlying the observed risk of CVD from use of ARV agents shall help to inform future development of ARV drugs with better safety profile.