Virologic failure and emergent integrase strand transfer inhibitor drug resistance with long acting cabotegravir for HIV treatment: A meta-analysis

Background: The long-acting injectable regimen of cabotegravir plus rilpivirine (CAB/RPV) emerged as an alternative to oral standard of care integrase strand transfer inhibitor (INSTI)-based regimens for individuals with adherence challenges or preference for reduced dosing schedules. Although oral INSTI regimens have a high barrier to emergent resistance, less is known about the potency and durability of CAB/RPV.

Methods: We reviewed clinical trial registries, PubMed, EMBASE, and conference abstract databases to identify published reports of CAB/RPV for HIV therapy. We abstracted data on virologic failure (VF) and treatment-emergent INSTI resistance at 48 weeks (range 24-52 weeks). We used single-proportion meta-analysis to summarize outcomes in three populations: 1) antiretroviral (ART)-naïve individuals initiating CAB/RPV following suppression on oral ART, 2) ART-experienced individuals switched to CAB/RPV with virologic suppression, and 3) ART-experienced individuals switched to CAB/RPV with detectable viremia. Cochrane's RoB2.0 and ROBINS-1 tools assessed risk of bias. PROSPERO registration CRD42024543919.

Results: Thirty-three studies (N=9224) reported VF prevalence. Nineteen studies (N=5662) reported resistance data. VF prevalence was 1% (95% confidence intervals [CI] 1-3%) in induction-maintenance studies, 1% (CI 1-2%) in switch-suppressed studies, and 5% (CI 3-10%) in switch-viraemic studies. INSTI resistance prevalence among successfully genotyped participants at failure was 71% (CI 25-95%), 61% (CI 44-75%), and 41% (CI 20-65%) respectively. Dolutegravir cross-resistance was common (64% of those with emergent resistance).

Discussion: Although VF rates with CAB/RPV were low, INSTI resistance emerged in approximately 40-70% of individuals experiencing VF. These rates are significantly higher than those for oral INSTI-based regimens. Both individual-level and broader resistance surveillance may be warranted in individuals and populations with expanding CAB/RPV use.