Virological Failure on Long-Acting Injectable Cabotegravir and Rilpivirine: An Analysis of Subtypes, Drug Levels, Resistance, and Therapeutic Implications

BACKGROUND: Virological failure (VF) with long-acting injectable cabotegravir and rilpivirine (CAB/RPV-LA) is uncommon but often associated with selection of resistance, potentially limiting future treatment options. Registration trials associated VF risk with baseline RPV resistance, A1/A6 subtypes, and body mass index (BMI) >30 kg/m2, but these factors have rarely been analyzed in other clinical settings. We summarize the first ∼100 reported VF cases, focusing on subtypes, drug levels, and resistance patterns. METHODS: Published data on CAB/RPV-LA through July 2025 were analyzed for risk factors. Resistance mutations were interpreted using the Stanford HIVdb database. RESULTS: After excluding duplicates, 94 VF cases were analyzed. Only 4.4% met the high-risk threshold of ≥2 risk factors. Subtype A lineages were reported in 26.4%, preexisting RPV mutations in 14.7%, and BMI >30 kg/m2 in 36.9%. At failure, low CAB or RPV levels were observed in 29% but did not differ from treatment successes. Predicted reduced susceptibility to CAB or RPV was observed in 87.2% (56% for both), with CAB resistance mutation N155H more frequently observed among subtype A lineages. Predicted susceptibility to dolutegravir/bictegravir (44.3%), doravirine (39.7%), or etravirine (35.9%) was common, but high-level resistance was rare. CONCLUSIONS: Emergent resistance in VF cases often resulted in cross-resistance to other nonnucleoside reverse transcriptase inhibitors and integrase strand transfer inhibitors. Although most cases did not meet the high-risk profile as defined by registration trials, subtype A lineages were overrepresented. Low drug levels were not elevated versus treatment successes. These data suggest that subtype-specific factors beyond A6 may influence VF risk and merit further study.