Sex differences in long-acting cabotegravir trough concentrations in the SEARCH study in Kenya and Uganda.

OBJECTIVE: Long-acting cabotegravir (CAB-LA) pre-exposure prophylaxis (PrEP) is highly effective. In Phase 2a trials, males had higher CAB pharmacokinetic (PK) trough concentrations than females after the first injection but lower troughs than females after subsequent injections. We report the first analysis of sex differences in CAB PK in a high HIV-burden setting: Kenya and Uganda. METHODS: The SEARCH Dynamic Choice HIV Prevention study provided CAB-LA 600 mg intramuscularly (IM) as an HIV prevention option. Among randomly-sampled participants with injections ≤28 days after target date, plasma CAB trough concentrations were measured, compared by sex, and analyzed in relation to published targets of protein-adjusted concentrations for 90% inhibition of virus (PAIC90). RESULTS: Among 97 participants, at week 4, median CAB troughs were higher among men (2.1 μg/ml, IQR 1.4-2.5) than women (1.5, 1.0-1.8, P = 0.001). Median CAB levels were lower among men than women at weeks 24 (1.1, 0.4-1.7 vs. 1.8, 1.3-2.9, P < 0.001) and 48 (1.1, 0.6-2.1 vs. 1.8, 1.5-2.4, P = 0.02). At least 80% of participants had CAB levels ≥4× PAIC90 at weeks 4-16. At weeks 24 and 48, CAB levels were ≥4× PAIC90 among 92% of women and 68% of men. No participants receiving CAB-LA acquired HIV. CONCLUSIONS: In the first PK study of CAB-LA PrEP in East Africa, CAB concentrations were lower among men than women after the second and later injections. By weeks 24 and 48, fewer men than women had CAB troughs above published PK targets, though no participants acquired HIV. Findings highlight the importance of examining sex differences and real-world forgiveness in PK with long-acting PrEP scale-up.