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Cardiovascular Adverse Effects of Antiretroviral Therapy

Nina Friis-Møller

Summary

This ph.d. thesis includes 3 published articles and a summary, and is based on work conducted in the period 2000-2003 during my employment as study coordinator for the D:A:D study at the Copenhagen HIV Programme, Hvidovre Hospital.

The purpose of the thesis was, based on data from the D:A:D study (the Data-collection on Adverse events of anti-HIV Drugs), a multinational cohort study of 23,468 HIV infected patients, to describe the prevalence of risk factors for cardiovascular disease in HIV infected patients, the possible association of antiretroviral therapy with such risk factors, and to examine a possible association between antiretroviral combination therapy and the risk of coronary heart disease.

The use of combination antiretroviral therapy for the treatment of HIV-infection has become abundant in the industrialized countries since it was introduced in the mid-1990ies. Several of the drugs can induce metabolic adverse effects, including a raise in cholesterol and triglycerides and the development of diabetes, which confers potential risk for cardiovascular disease.

There is a high prevalence of cardiovascular disease risk factors in HIV-infected, both of such that can be associated to the antiretroviral therapy, and such that are unrelated (e.g. cigarette smoking). There is a clustering of risk factors among patients receiving regimens containing drugs from all three antiretroviral drug classes.

The HIV infected population is relatively young, 40 years on average, and the absolute risk of cardiovascular disease therefore relatively low (we observed an incidence of 3.5 per 1000 person-years of follow-up). We found that combination antiretroviral therapy was associated with a relative 26% increase in risk of myocardial infarction per year of exposure, and preliminary analyses suggest that this is largely mediated via metabolic changes. The observed risk was very similar to that predicted from the Framingham risk score, suggesting that such models can be applied in the setting of HIV infection and antiretroviral therapy, where the metabolic changes are partly or entirely medically induced.

These analyses are based on data from observational studies, why causality cannot be determined definitively. Nevertheless, the prospective study design, the extensive quality assurance measures, the carefully analysed data including multiple sensitivity analyses, the biological plausibility and confirmation from other studies comforts us on the reliability of the reported associations.

Additional follow-up is warranted before guidelines on possible medical intervention can be made, but based on the current evidence in this area clinicians are encouraged to carefully monitor the risk of cardiovascular disease in their patients receiving combination antiretroviral therapy, and to modify lifestyle risk factors where indicated.