Influence of patient characteristics and oral lead-in on long-acting cabotegravir and rilpivirine pharmacokinetics and outcomes in people with HIV: a real-world study.

Factors influencing suboptimal pharmacokinetics (PK) of long-acting (LA) cabotegravir (CAB) and rilpivirine (RPV) in people with HIV (PWH) remain poorly understood. Lower plasma concentrations in underrepresented populations in clinical trials and direct initiation without an oral lead-in (OLI) require further investigation. This study examined CAB and RPV plasma levels in a real-world cohort, focusing on OLI's role. This prospective cohort study followed PWH transitioning from oral antiretroviral therapy to CAB + RPV injections. Participants were sequentially assigned to start with injections (SWI) or with OLI. Plasma CAB and RPV levels were measured before each injection over 7 months, with virological monitoring up to 11 months. Mixed-effects models were used to identify the predictors of lower CAB and RPV levels, adjusting for OLI use, age, sex, body mass index (BMI), and smoking. Among 172 participants (median age: 48 years, 12.8% female, 14.7% BMI ≥30 kg/m², 45.5% smokers), 81 (47.1%) initiated therapy via SWI, and 91 (52.9%) via OLI. CAB concentrations were lower in participants with higher BMI ( = 0.019), male sex ( = 0.021), and smoking ( = 0.057). RPV levels were reduced in smokers ( = 0.011) and younger participants ( = 0.064). PK profiles and virological outcomes were similar between SWI and OLI groups, with trough concentrations above inhibitory thresholds. Rates of virological failure (1 SWI vs. 2 OLI; = 0.999) and low-level viremia (18.5% vs. 17.6%, = 0.999) were comparable. Sex, BMI, and smoking influenced CAB and RPV levels, whereas OLI use had no significant impact on PK or virological outcomes, supporting flexible CAB +RPV LA initiation strategies.