Sex differences in discontinuations due to side effects of second-generation integrase strand transfer inhibitors: a systematic review and meta-analysis.

Abstract

Dolutegravir and bictegravir are frequently prescribed second-generation integrase strand transfer inhibitors. Although sex and gender influence drug pharmacokinetics, little is known about the differences in side effects experienced by cisgender men and women on these agents. Therefore, we synthesize data on sex-disaggregated side effects leading to discontinuation in dolutegravir/bictegravir-based regimens. We conducted a systematic review and meta-analysis (PROSPERO: CRD42023427891) by searching Medline, Embase, Web of Science, and Scopus for studies published from January 2010 to August 2024. We included randomized controlled trials and observational studies reporting sex-disaggregated discontinuations of dolutegravir/bictegravir-based regimens due to general or neuropsychiatric side effects. Studies in pregnancy, post-partum, pediatrics, co-infections (e.g., TB), and monotherapy were excluded. Two reviewers screened and extracted data. Risk of bias was assessed using an adapted version of the Newcastle-Ottawa scale for cohort studies. Meta-analysis was conducted using random effects models on studies reporting raw dolutegravir discontinuations by sex. We screened 4179 abstracts, conducted 505 full-text reviews, and included 17 observational studies in the review (15 on dolutegravir, two on bictegravir). Notably, 287/505 articles were excluded for lack of sex-disaggregated data. Fifteen dolutegravir studies reported outcomes for 32,352 people with HIV (7506 women, 24,846 men). Meta-analysis showed higher odds of dolutegravir discontinuation due to side effects in women vs men (9.3% vs 7.5%; OR: 1.40 [1.23-1.60], p < 0.001). A second meta-analysis on neuropsychiatric-related discontinuations found no sex differences (3.5% in women vs 3.3% in men; OR: 1.14 [0.84-1.56], p = 0.40). Only two bictegravir studies met inclusion criteria and showed conflicting results. This review reports signals of higher discontinuation rates of dolutegravir due to general side effects in women compared to men which may not be accounted for by neuropsychiatric effects. Further research is needed to determine whether these trends extend to other second-generation integrase strand transfer inhibitors, such as bictegravir and cabotegravir, and to better understand the specific side effects contributing to dolutegravir discontinuation in women. Additionally, the lack of sex-disaggregated reporting during our literature search identifies a need to prioritize sex/gender-based analyses in future research on antiretrovirals. None.