Cumulative use of ritonavir-boosted darunavir, a contemporary protease inhibitor used to treat HIV, is associated with an increasing risk of cardiovascular disease, according to results from the D:A:D study.

"The size of the association is similar to that of older protease inhibitors (59% per 5 years' use), but intriguingly the association with boosted darunavir did not, in contrast to the association with older protease inhibitors, seem to be modified by dyslipidemia," Dr. Lene Ryom reported. "Our data, therefore, also suggests (that) the cardiovascular disease association with use of certain protease inhibitors does not represent a protease inhibitor drug class effect."

Ritonavir-boosted darunavir and atazanavir have supplanted indinavir and lopinavir as protease inhibitor components of the recommended first-line treatment combinations for treatment-naïve adults with HIV and most guidelines. Whether they pose a similar risk of cardiovascular disease as previous protease inhibitors has been unclear.

The new findings are drawn from more than 49,000 adults living with HIV in the D:A:D study. During a median follow-up of 6.96 years, 3.2% of participants overall had a cardiovascular disease event, for an incidence rate of 5.34 events per 1000 person-years of follow-up.

At baseline, 18.4% of participants had been exposed to ritonavir-boosted atazanavir, and 4.0% had been exposed to ritonavir-boosted darunavir, according to the Lancet HIV online report. By the last reported visit, 26.6% and 22.3%, respectively, had been exposed to these protease inhibitors.

After adjustment for potential confounders, ritonavir-boosted darunavir was associated with a significantly increased risk of cardiovascular disease (59% increased risk per 5 years), whereas ritonavir-boosted atazanavir was not tied to a significant increase in cardiovascular risk.

The number needed to treat to harm for ritonavir-boosted darunavir was 533 for those at low risk of cardiovascular disease and 15 for those at very high risk. The association between darunavir and cardiovascular disease was not mediated by any other cardiovascular risk factors, including dyslipidemia or plasma bilirubin level.

Darunavir was also significantly associated with increased risk of the individual components of the composite cardiovascular disease endpoint: the 5-year risk of myocardial infarction was increased by 51%, and that of stroke was increased by 49%.

"It is important to recognize that our data is of an observational nature, and causal inference (is) therefore not possible," Dr. Ryom said. "We therefore encourage for mechanistic studies to be undertaken to investigate possible mechanisms that could drive an association between boosted darunavir and cardiovascular disease."

Efficacy of antiretroviral therapy

"With the significant improvements in survival due to efficient antiretroviral therapy (ART) we are now facing increasing rates of comorbidities, including cardiovascular disease, amongst people living with HIV, which poses new challenges for successful treatment. As such, efforts to personalize treatment to fit the individual risk profile need to become a high priority for everyone engaged with HIV care."

"Large, prospective cohort studies, such as the D:A:D study, remain an incredibly valuable research tool to increase our understanding of the long-term consequences of HIV infection and to identify the unmeasured risks," write Dr. Padraig M. C. McGettrick and Dr. Patrick W. G. Mallon.

"As many new antiretrovirals are introduced into clinical practice, the D:A:D study now faces an uncertain future, leaving us less well equipped to face the challenges associated with managing healthy ageing in people with HIV."

"Because cardiovascular disease is already an important contributor to overall mortality in people with HIV, any drug safety signal that has the potential to modify life-threatening outcomes requires robust exploration in appropriately designed studies, driven by those responsible for ensuring drug safety," they conclude.