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Risk for CVD Increases Following INSTI Use for HIV


A possible connection between integrase strand-transfer inhibitor (INSTI) use for HIV and cardiovascular disease (CVD) was investigated in this new study from an international team wanting more knowledge on the drug class’s treatment effects.

Persons living with HIV (PLWH) have a greater risk of early-onset cardiovascular disease (CVD), as well as a greater incidence of the disease, within 2 years of starting treatment with integrase strand-transfer inhibitors (INSTIs), according to new study findings published in Lancet HIV.

“Although associations between older antiretroviral drug classes and CVD in people living with HIV are well described,” the authors wrote, “there are a paucity of data regarding a possible association with INSTIs.” This first drug in this class, raltegravir, was approved by the FDA in 2007.

Their analysis was a substudy of data from the RESPOND study. Seventeen patient cohorts form Europe, Australia, and Austria provided data on more than 32,000 adults living with HIV and actively involved in their clinical care since January 1, 2012. Prior INSTI use before 2012 visit was prohibited, and participants were followed to either their first CVD event—for this study, myocardial infarction, stroke, invasive cardiovascular procedure), last follow-up, or December 31, 2019. The 5 exposures for a relationship between CVD and INSTI use in this study were 0 to more than 6 months, more than 6 to 12 months, more than 12 to 24 months, more than 24 to 36 months, and more than 36 months.

Among the 29,340 trial participants, who were mostly male (74.4%), just under half (47.7%) reported INSTI use by December 31, 2019. During the median (IQR) follow up of 6.16 (3.87-7.52) years, which the study authors note is equivalent to 160,252 person-years (PYs), 2.5% of the PLWH had a CVD event. The overall incidence rate was 4.67 events (95% CI, 4.34-5.01) per 1000 PYs of follow-up.

Most participants (69%) were White and lived in Western Europe (43%) or Northern Europe and Australia (24%). Forty-five percent was gay or bisexual men, and 13% reported injection drug use.

There was an overall INSTI use rate of 47% of the study cohort, with the most common medication being dolutegravir (61%), followed by elvitegravir and raltegravir (23% earch), and bictegravir (6%).

When comparing outcomes for PLWH with no INSTI use and PLWH who had up to 6 months of INSTI use, the crude CVD incidence rate was more than twice as high in the latter group: 4.19 (3.83-4.57) vs 8.46 (6.58-10.71) per 1000 PYs. By the 24-month mark, the CVD incidence rate among PLWH who had INSTI exposure was nearly identical to that among the group with no exposure: 4.25 (2.89-6.04) events per 1000 PYs.

Similar to CVD incidence rate, after 2 years, risk of CVD dropped following INSTI use:

  • > 0 to 6 months’ exposure: 1.85 (1.44-2.39) events
  • > 6 to 12 months’ exposure: 1.19 (0.84-1.68) events
  • > 12 to 24 months’ exposure: 1.46 (1.13-1.88) events
  • > 24 to 36 months’ exposure: 0.89 (0.62-1.29) events
  • > 36 months’ exposure: 0.96 (0.69-1.33) events

These numbers correspond with an 85% higher risk of a CVD event in the first 6 months, a 16% higher risk for months 6 to 12, and a 46% higher risk for months 12 to 24.

Risk was not affected by changes in CD4 count, weight, lipids, blood pressure, platelet count, or kidney disease; cardiovascular risk score or age at baseline; antiretroviral treatment history; or CD4 count or viral load when INSTI treatment was initiated.

Despite these positive outcomes among patients, the study investigators were unable to determine just why INSTIs seem more harmful in the first 2 years of use

“These early findings call for analyses in other large studies, and the potential underlying mechanisms explored further,” the authors concluded.

This is especially important because most PLWH in lower- and middle-income countries are being treater with dolutegravir, noted an accompanying editorial.


Neesgaard B, Greenberg L, Miró JM, et al. Associations between integrase strand-transfer inhibitors and cardiovascular disease in people living with HIV: a multicentre prospective study from the RESPOND consortium. Lancet HIV. Published online June 7, 2022. doi:10.1016/S23512-3018(22)00094-7

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