Back HIV-Related Conditions Cardiovascular CROI 2017: Long-Term Darunavir/Ritonavir Modestly Increases Risk of Cardiovascular Disease

CROI 2017: Long-Term Darunavir/Ritonavir Modestly Increases Risk of Cardiovascular Disease


Long-term use of the boosted protease inhibitor darunavir (Prezista) 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. Investigators identified an independent association between cumulative use of the drug over 5 years and heart attack and stroke.

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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 (Crixivan), nelfinavir (Viracept), saquinavr (Invirase), and full-dose ritonavir (Norvir) -- 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 HIV treatment and care, many people with HIV are now living well into old age. Diseases normally associated with aging -- including cardiovascular disease -- are now an important cause of serious illness and death for people with HIV. Prevention of these diseases is now a priority of HIV care and it is important to establish which antiretroviral 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 ritonavir-boosted atazanavir (Reyataz), is associated with an increased risk of cardiovascular disease.

Lene Ryom and fellow investigators with the D:A:D study therefore designed an observational study to see if treatment 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 (5 year) treatment with darunavir/ritonavir or 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 men who have sex with men. A large proportion (38%) were assessed as having a 5% or greater risk of a cardiovascular event, with 5% having a 10% or greater risk.

Participants were followed for a median of 7 years. During this time 1157 people (3%) experienced a cardiovascular event, for an incidence rate of 5.3 per 1000 person-years of follow-up. The most common event was angioplasty (n=459), followed by stroke (n=379), heart attack (n=354), bypass surgery (n=93) and carotid endarterectomy (n=15).

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

After adjustment for potential confounders including CD4 cell count, body mass index, kidney disease, dyslipidemia, and diabetes, there was no association between long-term use of atazanavir/ritonavir and cardiovascular disease (IRR 1.01). However, an independent and significant relationship was seen for darunavir/ritonavir (IRR 1.53).

These findings were essentially unchanged after adjustment for bilirubin levels.

Focus on darunavir/ritonavir showed that cumulative 5-year use of the drug independently increased the risk of heart attack (IRR 1.51) and stroke (IRR 1.49). Associations were unchanged after taking into account baseline cardiovascular disease risk and whether darunavir/ritonavir was used as part of an individual's first-ever protease inhibitor-containing regimen.

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 concluded that cumulative therapy with darunavir/ritonavir was associated with a small but gradually increasing risk of cardiovascular disease per 5 years of therapy. They called for further research to identify the factors underlying this association.



L Ryom, JD Lundgren, WM El-Sadr, et al. Association between cardiovascular disease and contemporarily used protease inhibitors. Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017. Abstract 128LB.