Research in context
Evidence before this study
Several first-generation protease inhibitors used in HIV treatment have been associated with an increased risk of cardiovascular disease. We used PubMed to identify all clinical trials and observational studies that reported associations between protease inhibitors and cardiovascular disease endpoints. The search terms that we used were “myocardial infarction”, “MI”, “stroke”, “cerebrovascular”, “cardiovascular disease”, “CVD”, with “AND HIV” or “AND antiretroviral treatment”, “protease inhibitors”, “indinavir”, “lopinavir”, “saquinavir”, “atazanavir”, and “darunavir”. We also searched for “adverse effects” with “AND protease inhibitors”, “indinavir”, “lopinavir”, “saquinavir”, “atazanavir”, and “darunavir”. The search included studies from the beginning of time until Aug 6–8, 2016, with no language restrictions. Evidence from observational and mechanistic studies suggest that an underlying mechanism between longer cumulative use of indinavir and ritonavir-boosted lopinavir and cardiovascular disease risk could, at least partly, be mediated by dyslipidaemia, and drugs within the protease inhibitor drug class have different metabolic profiles. Whether use of more contemporary protease inhibitors such as ritonavir-boosted darunavir and atazanavir are also associated with an increased risk of cardiovascular disease is unknown.
Added value of this study
After a median follow-up of 7 years, 1157 of 35 711 study participants developed a centrally validated cardiovascular disease event. After adjustment for potential confounders, ritonavir-boosted darunavir was associated with a 59% increased risk of cardiovascular disease per 5 years of additional use, whereas use of ritonavir-boosted atazanavir was not associated with cardiovascular disease. Several sensitivity analyses confirmed the robustness of this association, including adjustment for several factors on the potentially causal pathway between protease inhibitor use and cardiovascular disease. These analyses also separated cardiovascular disease into myocardial infarction and stroke; adjusted for plasma bilirubin concentration, which may be cardioprotective and is associated with ritonavir-boosted atazanavir use; and stratified by participants for whom ritonavir-boosted darunavir use was their first ever protease inhibitor, by use of this drug in combination with a non-nucleoside reverse transcriptase inhibitor, by history of virological failure, and by participants at high risk of cardiovascular disease.
Implications of all the available evidence
With an ageing population of people living with HIV at increasing risk of cardiovascular disease, tailoring of antiretroviral treatment to fit the individuals' risk profiles is increasingly important. Ritonavir-boosted darunavir is currently recommended as part of first-line treatment regimens in several international guidelines. In this prospective multicohort study with rigorously defined cardiovascular disease endpoints and relatively long follow-up, we identified a progressively increasing risk of cardiovascular disease with longer ritonavir-boosted darunavir use. Although the strength of the association between ritonavir-boosted darunavir and cardiovascular disease is similar to that reported for the first-generation protease inhibitors, the ritonavir-boosted darunavir association does not seem to be moderated by dyslipidaemia. These findings should prompt evaluation of whether other antiretrovirals that do not impart a risk of cardiovascular disease are available as part of individual care, particularly for people with HIV who are at high risk of cardiovascular disease.