Preclinical evaluation of long-acting cabotegravir and rilpivirine for HIV post-exposure prophylaxis in a macaque model.

Abstract

Current guidelines for post-exposure prophylaxis (PEP) recommend 28 days of daily oral antiretroviral drugs. However, low adherence and inadequate regimen completion represent important challenges. We investigated in macaques whether a single injection of the combination of long-acting cabotegravir and rilpivirine (CAB LA/RPV LA) could serve as an effective PEP regimen. Six macaques received a clinically relevant dose of CAB LA/RPV LA 24 h after a single rectal exposure to a high dose of reverse transcriptase simian-human immunodeficiency virus (RT-SHIV). Infection outcome was compared with seven untreated controls. CAB LA/RPV LA conferred protection against infection, with two of the six treated macaques becoming infected with RT-SHIV compared with all untreated controls (p = 0.021, Fisher's, exact test). The two breakthrough infections were characterized by early detection of proviral DNA, delayed detection of plasma viral RNA and seroconversion within 3-10 months, and emergence of RPV resistance. The remaining four treated macaques tested negative by multiple serological and molecular assays through 16 months of follow-up. The calculated efficacy of CAB LA/RPV LA was 66.7% (95% CI = -3.4%, 89.3%; p = 0.0571) although the large confidence interval adds uncertainty to the point estimate. We document protection in macaques by one-time CAB LA/RPV LA PEP under highly stringent modeling conditions. Delayed breakthrough infections highlight potential diagnostic challenges associated with this PEP modality and underscore the need for prolonged follow-up. This work was funded by CDC intramural funds.