Associations between integrase strand-transfer inhibitors and cardiovascular disease in people living with HIV: a multicentre prospective study from the RESPOND cohort consortium. Lancet HIV
Neesgard et al. investigated whether integrase strand-transfer inhibitors (INSTI) are associated with an increased risk for cardiovascular disease among people living with HIV in the International Cohort Consortium of Infectious Disease (RESPOND), a large collaboration of 17 European and Australian cohorts.
All patients without exposure to INSTI at cohort registration were included and followed over time. Cardiovascular events were defined as myocardial infarction (fatal or non-fatal), stroke, or invasive cardiovascular procedure. The authors calculated incidence rates of cardiovascular disease events over time stratified by exposure to INSTI (unexposed, 0-6 months, 6-12 months, 12-24 months, 24-36 months, and >36 months). Multivariable binomial regression models were used to evaluate associations between INSTI exposure and cardiovascular disease.
The study included 29’340 individuals (median age 44 years, 26% female, median CD4 nadir 200 cells/μL, 28% smokers). Of the 14’000 individuals (48%) who received INSTI during follow-up, most were exposed to dolutegravir (61.8%), followed by elvitegravir (23.9%), raltegravir (23.5%) and bictegravir (6%). 748 individuals (2.5%) had a cardiovascular event (4.67 per 1000 person-years, 95% CI 4.34 – 5.01). The highest incidence was observed in individuals with 0 to 6 months of INSTI exposure (8.46 events per 1000 PY, 95% CI 6.58-10.71), which then decreased gradually to 4.25 per 1000 PY (95% CI 2.89-6.04) after 24 months of INSTI use. Adjusted analyses similarly showed a higher risk for cardiovascular disease at 0-6 months compared to no INSTI exposure (adjusted incidence rate ratio 1.85, 95% CI 1.44-2.39). The results were similar for men and women and independent of the baseline cardiovascular disease risk.
In summary, the present study suggests that exposure to INSTI is associated with cardiovascular disease, irrespective of cardiovascular risk factors at INSTI start. The increased risk was observed mainly in the first 6 months but persisted until 24 months of exposure. As individuals with increased cardiovascular disease risk were more likely to receive INSTI in the present study, confounding by indication cannot be excluded despite statistical adjustment methods. With INSTI being the mainstay of antiretroviral therapy worldwide, replicating or refuting these findings and gaining insights for underlying mechanisms should be a high public health priority.