Virologic Failure and Emergent Integrase Strand Transfer Inhibitor Drug Resistance With Long-Acting Cabotegravir for...

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.

We reviewed clinical trial registries, PubMed, EMBASE, and conference abstract databases to identify 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). We used single-proportion meta-analysis to summarize outcomes in 3 populations: antiretroviral therapy (ART)-naive individuals initiating CAB/RPV following suppression on oral ART, ART-experienced individuals switched to CAB/RPV with virologic suppression, and ART-experienced individuals switched to CAB/RPV with detectable viremia. Cochrane's RoB 2.0 and ROBINS-1 tools assessed risk of bias.

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

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 populations with expanding CAB/RPV use. Clinical Trials Registration. PROSPERO registration CRD42024543919.