Cardiovascular disease and use of contemporary protease inhibitors: the D:A:D international prospective multicohort study. Lancet HIV
Ryom et al. on behalf of the D:A:D study aimed to assess whether cumulative use of ritonavir-boosted atazanavir and ritonavir-boosted darunavir was associated with increased incidence of cardiovascular disease in people living with HIV.
Participants were monitored from Jan 1, 2009, until the earliest of a cardiovascular event, 6 months after the last visit, or until Feb 1, 2016. Cardiovascular disease was defined as centrally validated myocardial infarction, stroke, sudden cardiac death, or use of invasive cardiovascular procedures, including coronary bypass, coronary angioplasty, and carotid endarterectomy.
49’709 participants were enrolled with a median 6.96 years of follow-up. Overall, 1’157 people developed cardiovascular disease (incidence rate 5.34 events per 1’000 person-years). The incidence rate of cardiovascular disease progressively increased from 4.91 events per 1’000 person-years in individuals unexposed to ritonavir-boosted darunavir to 13.67 events per 1000 person-years in those exposed to the drug for more than 6 years. The changes associated with ritonavir-boosted atazanavir were less pronounced, showing an incidence rate of 5.03 cardiovascular events per 1’000 person-years in unexposed individuals to 6.68 events per 1’000 person-years (5.02–8.35) in participants exposed for more than 6 years. After adjustment, keeping factors on the potential causal pathway from boosted protease inhibitor use to cardiovascular disease fixed at baseline, ritonavir-boosted darunavir use was associated with increased risk of cardiovascular disease (incidence rate ratio 1.59 per 5 years additional use), but use of ritonavir-boosted atazanavir was not. This association remained after adjustment factors on the potential causal pathway.
In conclusion, in this prospective multicohort study with rigorously defined cardiovascular disease endpoints and relatively long follow-up, a progressively increasing risk of cardiovascular disease with longer ritonavir-boosted darunavir use was identified. Although the strength of the association between ritonavir-boosted darunavir and cardiovascular disease was similar to that reported for the first-generation protease inhibitors, the ritonavir-boosted darunavir association did 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.