Adverse Drug Reactions to Integrase Strand Transfer Inhibitors

Katherine J. Lepik; Benita Yip; Ana C. Ulloa; Lu Wang; Junine Toy; Linda Akagi; Viviane Dias Lima; Silvia Guillemi; Julio S.G. Montaner; Rolando Barrios


AIDS. 2018;32(7):903-912. 

In This Article

Abstract and Introduction


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

Design: Population-based, retrospective cohort.

Methods: 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.

Results: 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.

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


The integrase strand transfer inhibitors (INSTIs) raltegravir, elvitegravir, and dolutegravir are widely used in first-line and alternative antiretroviral therapy (ART).[1,2] Postmarketing observational studies have documented a 3–14% incidence of adverse drug reactions (ADRs) leading to INSTI discontinuation,[3–11] compared to 1–4% ADR-related discontinuations in clinical trials.[12–17] INSTI ADR rates have varied between real-world cohorts, and few studies have compared all three INSTIs.[8–11]

The increasing selection of ART alternatives permits treatment individualization, and antiretroviral tolerability remains an important consideration for both initial ART selection and subsequent regimen changes.[1,18,19] Understanding the possible differences in ADR profiles between INSTIs can better inform personalized ART selection.

The purpose of this retrospective cohort study was to characterize the incidence and type of INSTI ADRs resulting in INSTI discontinuation within the first 2 years of treatment. The main objective was to compare ADR rates in raltegravir, elvitegravir, and dolutegravir-treated persons, adjusted for confounders. For persons with an ADR, additional objectives were to describe and compare ADR symptoms between INSTIs, characterize ADRs associated with early (first year) and late (second year) discontinuations, and describe subsequent ART decisions following the INSTI ADR, with particular interest in the tolerability of switches between INSTIs.