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 similar to 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.