Adverse drug reactions to integrase strand transfer inhibitors

To describe and compare integrase strand transfer inhibitor (INSTI) adverse drug reactions (ADRs) for raltegravir, elvitegravir-cobicistat, and dolutegravir.

Population-based, retrospective cohort.

Antiretroviral-experienced and naive persons at least 19 years old were included if they received their first prescription for raltegravir, elvitegravir-cobicistat, or dolutegravir in British Columbia, Canada, in 2012-2014, and were followed for 2 years until 31 December 2016. The primary outcome was an ADR resulting in INSTI discontinuation. ADR rates and 95% confidence intervals (95% CIs) were calculated by Poisson method. Cox proportional-hazards regression estimated the hazard ratio for ADR-related INSTI discontinuation, adjusted for confounders. ADR symptoms were compared across INSTIs.

There were 1344 persons contributing 1464 person-INSTI exposures. The cohort was predominantly male (79%) and antiretroviral therapy-experienced (85%). ADR events and unadjusted ADR rates (95% CI) per 100 person-years were raltegravir 24 of 551 (4.4%), 2.91 (1.95, 4.35); elvitegravir-cobicistat 38 of 394 (9.6%), 5.94 (4.32, 8.16); and dolutegravir 27 of 519 (5.2%), 2.96 (2.03, 4.31). The ADR rate for elvitegravir-cobicistat was double that of dolutegravir (adjusted hazard ratio 2.24, 95% CI 1.13, 4.44), but not significantly different for either dolutegravir or elvitegravir versus raltegravir. Elvitegravir-cobicistat-treated persons had a significantly higher proportion of gastrointestinal and general (fatigue, malaise) ADRs. Neuropsychiatric ADRs were more frequent with dolutegravir, but not significantly different between INSTIs. Among those switching between INSTIs, there was no apparent relationship between experiencing an ADR to one INSTI and subsequent intolerance to another.

This study affirms INSTIs are well tolerated during routine clinical use. Consideration of differences in side effect profiles can inform antiretroviral therapy individualization.