Is There a Cardiovascular Risk When Taking Integrase Inhibitors?

Integrase strand transfer inhibitors (INSTI) are a form of antiretroviral therapy (ART), which are designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. INSTI are used in several FDA approved ART medications.

One of the ongoing questions has been if INSTI have any cardiovascular side effects for people living with HIV (PWLH). There have been mixed results with some studies showing a correlation and others not demonstrating a risk of cardiovascular events. However, a recent large European study, The RESPOND Outcomes trial, reported there was an increased risk of cardiovascular events when taking INSTI.

Bernard Surial, MD, Department of Infectious Diseases, University Hospital of Bern, Switzerland, and a team of investigators looked into this utilizing the Swiss HIV Cohort Study.

“We compared the risk for developing cardiovascular disease events between treatment-naïve PLWH who started INSTI based therapy and individuals who started other ART combinations using a target trial framework,” Surial said in an interview with Contagion. “This is a framework to analyze observational data that reduces the risk for selection bias and confounding by indication.”

From the Swiss HIV Cohort Study, they included patients who were ART treatment-naïve after May 2008, when the first INSTI became available in Switzerland. “Baseline was defined as the date of the first treatment start (INSTI vs. other ART), and individuals were followed until the first cardiovascular disease (CVD) event (myocardial infarction, stroke, or intervention on arteries), loss to follow-up, death, or last cohort visit,” The investigators wrote.

Patients were censored when they stopped INSTI or other forms of ART. The investigators then estimated CVD risk differences, “using pooled logistic regression with inverse probability of treatment and censoring weights, taking into account time-fixed and time-varying confounders (covariates listed in figure legend).” Surial discussed this study in his CROI presentation, “Impact of Integrase Inhibitors on Cardiovascular Events in Person Starting ART.”

In the two cohorts, 2032 individuals began INSTI-based ART, and 3255 individuals began other ART combinations. According to the investigators, individuals who started INSTI were less likely to be women (16% vs. 26%), less likely to be of African origin (12% vs. 19%), and had a higher median CD4 nadir (346 vs. 281 cells/µL) compared to individuals starting other ART.

Medical histories including smoking status, a history of cardiovascular disease, and use of antiplatelet agents, were similar in both groups but the investigators noted the individuals in the INSTI cohort were more likely to receive abacavir (26% vs. 11%).

“In adjusted analyses, risk differences between INSTI and other ART starters were -0.02% (-0.32% to 0.21%) after 1 year, -0.17% (-0.65% to 0.10%) after 2 years, and -0.38% (-1.29 to 0.52) after 5 years (Panel B),” the investigators wrote.

Their findings were positive in favor of utilizing INSTI. “After accounting for differences in patient characteristics and for differential censoring in both groups, we found no difference in cardiovascular disease risk between the two groups, Surial said. “This is reassuring as in 2021, 96% of PLWH who started ART in Switzerland received INSTI-based ART.”

This is significant not only for usage of the medications themselves, but also as PLWH age—because of ART—the normal expectations is that older individuals become more vulnerable to CVD events thus becoming significant patient management considerations for clinicians.

“With the effective antiretroviral treatments available, non-communicable diseases such as cardiovascular events have become one of the most important challenges in the care for PLWH,” Surial said. “And as the new ART drugs have been associated with metabolic side effects such as weight increase, development of arterial hypertension or diabetes, researchers became worried that our treatments contribute to the development of cardiovascular disease.”