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Long-acting capsid inhibitor effective as PrEP against vaginal SHIV transmission in macaques

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BACKGROUND: Daily oral preexposure prophylaxis (PrEP) is highly effective at reducing the risk of HIV acquisition, but its uptake, persistence, and efficacy are limited by the need for daily adherence. Long-acting PrEP could mitigate adherence challenges and improve population coverage. We recently reported the prophylactic efficacy of a long-acting capsid inhibitor GS-CA1, an analog of the investigational HIV treatment agent lenacapavir, in a rectal challenge macaque model. Here, we evaluated GS-CA1 PrEP efficacy in a macaque model of vaginal SHIV transmission.
METHODS: An optimal animal model and SHIV challenge titer were chosen by comparing the rates of vaginal SHIV transmission between naïve female pigtail macaques and Indian rhesus macaques, either untreated or pre-treated with 10 mg depot medroxyprogesterone acetate (DMPA) (n=6 per group). Twenty-four naïve female rhesus macaques then received a single subcutaneous administration of vehicle (placebo), 150 mg/kg or 300 mg/kg of GS-CA1 (n=8 per group) followed by 10 weekly vaginal SHIV challenges and a 6-week follow-up. Plasma GS-CA1 exposures and viremia were measured throughout the study and used to establish PrEP efficacy.
RESULTS: SHIV challenge with 10-100 TCID50 resulted in '¤ 1 out of 6 infections per challenge among untreated pigtail or rhesus macaques. DMPA pre-treatment increased vaginal transmission rate with 100 TCID50 titer among rhesus macaques to 50% per challenge and was selected for the efficacy evaluation. A single administration of GS-CA1 yielded exposures exceeding its protein adjusted EC95 value (30.2 nM) in the 150mg/kg and 300mg/kg groups for at least 10 and 16 weeks, respectively. All control animals became viremic by week 8 with a median time-to-viremia of 4 weeks. In contrast, only 4 animals became viremic in the 150mg/kg GS-CA1 group with a median time-to-viremia of 14 weeks, and no infections were observed in the 300mg/kg GS-CA1 group. Both GS-CA1 dose levels offered significant infection risk reduction relative to placebo (p<0.0001) based on a Cox regression analysis.
CONCLUSIONS: These preclinical data demonstrate that a long-acting GS-CA1 formulation can effectively protect against vaginal SHIV transmission in nonhuman primates and together with the rectal challenge study results support the clinical development of lenacapavir for HIV prevention in both males and females.