Antiretrovirals Differ in Cardiovascular Disease Risk

Lene Ryom, PhD

Two first-line protease inhibitors for treating HIV infection in treatment-naive adults were found to pose distinctly different risks for cardiovascular disease (CVD) in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) international study.

The study sought to determine whether contemporary protease inhibitors are less likely than older agents to contribute to CVD risk. The 7-year surveillance determined that cumulative use of darunavir (Prezista, Janssen), but not atazanavir (Reyataz, Bristol-Myers Squibb), is also associated with progressively increasing risk of CVD.

A rising prevalence of CVD in persons with HIV reflects, in part, the effectiveness of treatments in enabling the population to attain older age. Although, these treatments are coming under scrutiny to determine relative safety and potential adverse effects on cardiovascular health, explained Lene Ryom, PhD, from the Department of Infectious Diseases, part of the Centre of Excellence for Health, Immunity and Infections, at the University of Copenhagen, in Denmark, lead author of the report, and colleagues from the D:A:D study group.

"With an aging population of people living with HIV, at growing risk of cardiovascular disease, antiretroviral treatment tailored to fit individuals' risk profiles are increasingly needed," Ryom and colleagues indicated.

The D:A:D is a prospective, collaboration study of 49,709 participants in 11 cohorts in Australia, Europe, and the US established in 1999. The current report is from monitoring for CVD in 35,711 participants on the contemporary protease inhibitors from January 2009 until the earliest of either a cardiovascular event, 6 months after the last visit, or the study end date of February 2016. The study defined CVD as myocardial infarction, stroke, sudden cardiac death or use of invasive cardiovascular procedures.

During a median 6.96 years of follow-up, 1157 persons developed CVD, a rate of 5.34 events per 1000 person-years (95% CI, 5.03 to 5.65). The CVD incidence rate progressively increased from 4.91 events per 1000 person-years (95% CI, 4.59 to 5.23) in those without exposure to ritonavir-boosted darunavir to 13.67 events per 1000 person-years (95% CI, 8.51 to 18.82) in those receiving that regimen for more than 6 years. The rate of those not exposed to ritonavir-boosted atazanavir of 5.03 events per 1000 person-years (95% CI, 4.69 to 5.37) was closer to the 6.68 events per 1000 person-years (95% CI, 5.02 to 8.35) associated with 6 years of that regimen.

After adjusting for possible factors contributing to CVD, the ritonavir-boosted darunavir use was associated with increased risk of cardiovascular disease, with an incidence rate ratio 1.59 (95% CI, 1.33 to 1.91) per 5 years additional use, but ritonavir-boosted atazanavir was not.

After Ryom and colleagues presented these findings at a conference in 2017, the darunavir manufacturer conducted a separate assessment of safety data without finding evidence to support an association with CVD. Ryom and colleagues point out in their report, however, that the manufacturer's study had "substantially less power compared with our data."

In commentary that also followed the conference presentation of these findings, an alternative approach to choosing between protease inhibitors to reduce CVD risk was suggested by Bluma Brenner, PhD, from the Lady Davis Institute at Jewish General Hospital, and Jean-Guy Baril, MD, from the Clinique de Médecine Urbaine du Quartier Latin, in Montreal, Quebec, Canada.

"Dolutegravir may be a treatment option of choice for an aging population with risk factors for CVD," Brenner and Baril opined.

Dolutegravir (Tivicay, ViiV) is an unboosted integrase strand transfer inhibitor that has recently been shown in a switch trial to have comparable efficacy to a ritonavir-boosted protease inhibitor and greater tolerance in patients with high CVD risk.

"This is the first switch trial targeting a population with moderate to high cardiovascular risk," Brenner and Baril pointed out, before adding an important caveat. "It remains to be demonstrated if a strategy of switching from a boosted protease inhibitor regimen to dolutegravir could be done safely in those with proven or suspected resistance mutations."

The study, “Cardiovascular disease and use of contemporary protease inhibitors: the D:A:D international prospective multicohort study,” was published in The Lancet HIV.