Impact of sex, age and body composition on rilpivirine and cabotegravir trough concentrations in people with HIV receiving long-acting injectable antiretroviral therapy

Background: Considerable inter-individual variability in the pharmacokinetics of long-acting injectable (LAI) rilpivirine and cabotegravir has been reported. Here, we sought to evaluate intra- and inter-individual variability of rilpivirine and cabotegravir plasma trough concentrations and to assess the influence of demographic factors and body composition on drug exposure in people with HIV (PWH) receiving LAI therapy. Methods: This retrospective observational study included PWH treated with LAI rilpivirine and cabotegravir for ≥16 months, with at least three consecutive plasma trough concentration assessments. Body composition was estimated by bioelectrical impedance analysis. Associations between drug levels and clinical variables were analysed using univariate and multivariate regression analysis. Results: Forty-eight PWH were included (mean age 47 ± 15 years, 17% females). Rilpivirine and cabotegravir showed moderate intra-individual variability in trough concentrations (28-30%), with <1% of samples below the therapeutic threshold. Cabotegravir trough concentrations were significantly higher in women than in men (3285 ± 921 versus 2096 ± 775 ng/mL; P < 0001) and in participants aged >65 years compared with younger individuals (2826 ± 455 ng/mL versus 2119 ± 1006 ng/mL; P = 0044); in addition, cabotegravir levels inversely correlated with skeletal muscle mass (r = -0.45; P = 0.008) and bone mass (r = -0.47; P = 0006). On the contrary, rilpivirine concentrations showed no significant associations with demographic or body composition variables. Multivariate analysis confirmed age, sex and muscle mass as independent predictors of cabotegravir exposure. Conclusions: Sex, age and muscle mass significantly influence cabotegravir-but not rilpivirine-trough concentrations in PWH receiving LAI therapy. Therapeutic drug monitoring combined with body composition assessment may help to optimize dosing interval adjustment.