Estimation of Prevention-Effective CAB-LA Concentrations Among Men Who Have Sex With Men (MSM) and Transgender Women (TGW) in HPTN 083

Background The HIV Prevention Trials Network (HPTN) 083 Trial demonstrated the superiority of long-acting, injectable cabotegravir (CAB) over daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis among cisgender men (MSM) and transgender women (TGW) who have sex with men. Plasma CAB concentrations associated with HIV protection in humans are unknown. Methods We conducted a nested case-control study to investigate the association between plasma CAB concentrations and HIV risk. Plasma CAB concentrations were estimated for participants with confirmed HIV and for HIV-negative controls, who were matched on region, gender, and race. The window of HIV acquisition for cases was defined as the time between the last HIV-negative visit and the first HIV-positive visit; this window was used to evaluate CAB exposure for cases and their matched controls. Participants were categorized by the minimum estimated CAB concentration (CAB_min) during this window relative to the protein-adjusted 90% CAB inhibitory concentration (1× PA-IC₉₀) and 4× PA-IC₉₀. HIV risk was modeled using conditional logistic regression. Results Plasma CAB_min was ≥4× PA-IC₉₀ in 26% of HIV-positive cases, compared with 76% of matched controls. Plasma CAB_min ≥4× PA-IC₉₀ was associated with a 93% reduction in risk of HIV acquisition compared with CAB_min <1× PA-IC₉₀ (95% CI: 76%, 98%, P <. 001). CAB_min between 1× and 4× PA-IC₉₀ had an estimated risk reduction of 79% compared with CAB_min <1× PA-IC₉₀ (95% CI: -19%, 96%, P =. 07). Conclusions Consistent plasma CAB concentrations ≥4× PA-IC₉₀ were estimated to provide 93% protection against HIV in MSM and TGW.