Risk Factors and Therapeutic Consequences of Virologic Failure With Long-Acting Cabotegravir Plus Rilpivirine in the Dat'AIDS Cohort.

BACKGROUND: Long-acting cabotegravir plus rilpivirine (CAB + RPV LA) is highly effective as maintenance therapy in virologically suppressed people with HIV (PWH), but virologic failure (VF) may lead to resistance and compromise future antiretroviral options. METHODS: We conducted a multicenter observational study within the French Dat'AIDS cohort, including HIV-1 virologically suppressed adults who switched to CAB + RPV LA between December 2021 and December 2023. VF was defined as two consecutive HIV-1 RNA >50 copies/mL or one >200 copies/mL. Remaining options were interpreted using ANRS and Stanford algorithms. Cox models identified factors associated with VF. RESULTS: Among 2,196 participants followed for a median of 13 months, VF occurred in 42 individuals (1.9%) after a median of 103 days. Among 26 VF cases undergoing genotype, resistance emerged in 13 (50%), with susceptibility maintained more often for doravirine (ANRS 92%, Stanford 96%) than for dolutegravir/bictegravir (ANRS 58%, Stanford 65%). Resistance also emerged during low-level viremia or transient rebound with re-suppression (7/13 cases). In multivariable analysis, higher BMI (aHR 1.07; 95%CI 1.01-1.14), nadir CD4 < 200 cells/mm3 (aHR 2.44; 1.31-4.56), and prior suppression <12 months (aHR 2.39; 1.01-5.19) were independently associated with VF. Historical CAB and RPV RAMs also increased VF risk. CONCLUSIONS: CAB + RPV LA was associated with low incidence of VF and rare resistance emergence. When resistance occurred, it primarily compromised bictegravir/dolutegravir rather than doravirine. Low nadir CD4, shorter prior suppression, higher BMI, and historical CAB and/or RPV RAMs support individualized candidate selection and early resistance testing, even during low-level viremia.