D:A:D study – long-term use of darunavir/ritonavir modestly increases the risk of cardiovascular disease

Long-term use of the protease inhibitor darunavir/ritonavir modestly increases the risk of cardiovascular disease, according to data from the ongoing D:A:D study presented to the recent Conference on Retroviruses and Opportunistic Infections (CROI 2017). Investigators identified an independent association between cumulative use of the drug over five years and heart attack and stroke.

The development of protease inhibitors represented a major breakthrough in antiretroviral therapy. However, a large body of research, including analyses from the D:A:D study, shows that cumulative treatment with first-generation protease inhibitors – indinavir, nelfinavir, saquinavir and full-dose ritonavir – increases the risk of cardiovascular disease. A possible explanation for the association is the increases in blood lipids caused by these drugs.

Thanks to improvements in treatment and care, many people with HIV are now living well into old age. Diseases normally associated with ageing – including cardiovascular disease – are now an important cause of serious illness and death in people with HIV. Prevention of these diseases is now a priority of HIV care and it is important to establish which anti-HIV drugs are independently associated with increased cardiovascular risk. It is unknown if cumulative therapy with the protease inhibitors in current use, especially darunavir/ritonavir and atazanavir/ritonavir, is associated with an increased risk of cardiovascular disease.

Investigators from the D:A:D study therefore designed an observational study to see if therapy with darunavir/ritonavir or atazanavir/ritonavir is independently associated with the risk of cardiovascular disease.

Cardiovascular disease was defined as myocardial infarction (heart attack), stroke, sudden cardiac death or invasive cardiovascular procedures such as coronary bypass, angioplasty or carotid endarterectomy (unblocking of the carotid artery).

People who received care between early 2009 and early 2016 were eligible for inclusion. Incidence of cardiovascular disease was stratified by cumulative (five year) treatment with darunavir/ritonavir and atazanavir/ritonavir. The investigators performed a series of statistical analyses to assess the independent associations between use of these drugs and cardiovascular disease risk, adjusting for potential confounders.

The study population consisted of 35,711 people. The median age was 44 years, 74% were male, 48% were white and 46% were in the men who have sex with men risk group. A large proportion (38%) was assessed as having a 5% or greater risk of a cardiovascular event, with 5% having a 10% or greater risk of cardiovascular disease.

People were followed for a median of seven years. During this time 1157 (3%) people experienced a cardiovascular event, an incidence rate of 5.3 per 1000 person-years of follow-up. The most common events was angioplasty (n = 459), followed by stroke (n = 379), heart attack (n = 354), bypass (n = 93) and unblocking of the carotid artery (n = 15).

Cumulative therapy with atazanavir/ritonavir was associated with a cardiovascular disease incidence of 6.68 per 1000 person-years of follow-up, with use of darunavir/ritonavir associated with an incidence of 13.67 per 1000 person-years.

After adjustment for potential confounders including CD4 cell count, BMI, kidney disease, dyslipidaemia and diabetes, there was no association between long-term use of atazanavir/ritonavir and cardiovascular disease (IRR = 1.01; 95% CI, 0.88-1.16). However, an independent and significant relationship was present for darunavir/ritonavir (IRR = 1.53; 95% CI, 1.28-1.84).

These findings were essentially unchanged after adjustment for bilirubin levels.

Focus on darunavir/ritonavir therapy showed that cumulative five-year use of the drug independently increased the risk of heart attack (IRR = 1.51; 95% CI, 1.13-2.02) and stroke (IRR = 1.49; 95% CI, 1.08-2.07). Associations were unchanged after taking into account whether darunavir/ritonavir was used in the first ever protease inhibitor-containing regimen and baseline cardiovascular disease risk.

The investigators do not believe their results are definitive. They acknowledge that there could be unmeasured confounding factors and that their findings are limited by the observational design of their study.

Nevertheless, they conclude that cumulative therapy with darunavir/ritonavir was associated with a small, but gradually increasing risk of cardiovascular disease per five years of therapy. They call for further research to identify the factors underlying this association.