HIV susceptibility to second-generation integrase strand transfer inhibitors among people with multidrug resistance: a systematic review and meta-analysis protocol

Background: With the rapid scale-up of dolutegravir-based regimens, there is a declining trend of HIV drug resistance in several resource-limited settings. However, treatment success using second-generation integrase strand-transfer inhibitors (2nd-Gen INSTI) among people living with HIV with long therapeutic experience could be jeopardized by pre-existing drug resistance mutations to first-generation INSTI or even to other drug class. Objectives: The aim of this systematic review and meta-analysis will be to provide a summary of existing evidence on the HIV susceptibility to 2nd-Gen INSTI among people with multidrug resistance. Design: This will be a systematic review and meta-analysis. Methods and analysis: This systematic review will include randomized and non-randomized trials, experimental studies, cohorts, cross-sectional studies, and governmental notices focusing on HIV susceptibility to 2nd-Gen INSTI. The search will consider studies conducted all over the world and published from 2013 to 2024, retrieved from PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Google scholar, African journals online, and Cumulative Index to Nursing and Allied Health Literature. Hand searching of the reference lists of relevant reviews and trials will be conducted, and we will also look for conference abstracts. We will include studies of adults and/or children exposed to dolutegravir, bictegravir, or cabotegravir following treatment failure to more than one drug class. The primary outcomes will be "the level of sensitivity to 2nd-Gen INSTI" and the "rate of viral suppression following exposure to 2nd-Gen INSTI." The secondary outcomes will essentially consist of the determinants of a good virological response (viral load < 1000 copies/mL at 48 weeks) under 2nd-Gen INSTI among participants with a history of multidrug resistance. Two reviewers will independently screen titles and abstracts, assess the full texts for eligibility, and extract data. If data permit, random-effects models will be used where appropriate. Subgroup and additional analyses will be conducted to explore the potential sources of heterogeneity (e.g., age, sex, baseline clinical data, treatment duration, and adherence level). Discussion: This review will help to strengthen evidence on the effectiveness of 2nd-Gen INSTI by contributing to current knowledge concerning people living with HIV with long therapeutic exposure. The results will, therefore, contribute to set up baseline data for optimal management of people living with HIV harboring multidrug-resistant viruses. Registration: PROSPERO: CRD42023470922.