Predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis across three phase 3 studies.

OBJECTIVE Efficacy and safety of long-acting (LA) cabotegravir (CAB) and rilpivirine (RPV) dosed intramuscularly every 4 or 8 weeks has been demonstrated in three Phase 3 trials. Here, factors associated with virologic failure at Week 48 were evaluated post hoc. DESIGN AND METHODS Data from 1039 adults naive to CAB+RPV LA were pooled in a multivariable analysis to examine the influence of baseline viral and participant factors, dosing regimen, and drug concentrations on confirmed virologic failure (CVF) occurrence using a logistic regression model. In a separate model, baseline factors statistically associated with CVF were further evaluated to understand CVF risk when present alone or in combination. RESULTS Overall, 1.25% (n = 13/1039) of participants experienced CVF. Proviral RPV resistance-associated mutations (RAMs), HIV-1 subtype A6/A1, higher body mass index (BMI, associated with Week 8 CAB trough concentration), and lower Week 8 RPV trough concentrations were significantly associated (p < 0.05) with increased odds of CVF (all except RPV trough are knowable at baseline). Few participants (0.4%) with zero or 1 baseline factor had CVF. Only a combination of ≥2 baseline factors (observed in 3.4%; n = 35/1039) was associated with increased CVF risk (25.7%, n = 9/35). CONCLUSIONS CVF is an infrequent multifactorial event, with a rate of ∼1% in the LA arms across Phase 3 studies (FLAIR, ATLAS, and ATLAS-2 M) through Week 48. Presence of ≥2 of proviral RPV RAMs, HIV-1 subtype A6/A1, and/or BMI ≥30 kg/m2 was associated with increased CVF risk. These findings support the use of CAB+RPV LA in routine clinical practice.