Islatravir (ISL, MK-8591, EFdA) is a novel nucleoside reverse transcriptase translocation inhibitor with robust antiviral activity and has demonstrated efficacy as weekly oral PrEP in the SHIV/Rhesus macaque (RM) rectal challenge model for doses ranging from 0.1 mg/kg to 3.9 mg/kg. We tested ISL’s efficacy as post-exposure prophylaxis (PEP) in the SIV/RM IV challenge model.
12 RM were challenged IV with 10 AID50 of SIVmac251. After 24 hr, 6 animals received 3.9 mg/kg ISL and 6 animals served as untreated controls. Treated animals in Stage I received a total of 4 weekly oral doses of ISL and were monitored for SIV infection for 7 wk after the 4th dose of ISL. In Stage II uninfected animals from Stage I were challenged as in Stage I and beginning 24h later 3 weekly oral doses of ISL at 3.9 mg/kg was initiated. Animals were monitored for 7 wk after the 3rd dose of ISL. Uninfected animals entered Stage III and were similarly challenged and treatment initiated at 24 h with 2 weekly oral doses of ISL at 3.9 mg/kg and animals monitored for 7 wk after the 2nd dose of ISL. Finally in Stage IV, uninfected animals were challenged IV and 24 hours later treated with a single oral dose of ISL at 3.9 mg/kg and followed for 7 wk. Animals were monitored for infection using RT-PCR and proviral DNA amplification. Virus-specific antibody responses were measured using a commercial assay. Plasma ISL levels as well as ISL-triphosphate (ISL-TP) levels in PBMC were measured longitudinally.
All untreated control animals were viremic 7 days after IV challenge with SIVmac251. 6/6 treated animals were completely protected in Stages I-III (Fisher’s exact test P=0.0022). ISL-TP levels became undetectable in PBMC 3 weeks on average after the last ISL oral dose. In Stage IV, two of 6 animals became infected with wild type SIVmac251, one with viremia at day 14 ([ISL-TP] < 0.02 pmol/106 PBMCs ) and another at day 49 (Fisher’s exact test P=0.06).
As few as 2 weekly oral doses of ISL at 3.9 mg/kg given 24h after IV challenge with SIVmac251 completely prevented infection. However, a single ISL dose 24h after IV challenge failed to provide statistically significant protection. As the ISL-TP T1/2 in human PBMCs (79-214 hr) is substantially longer than RM (50 hr), it is conceivable that a single low oral dose given within 24 hours of HIV exposure may provide effective PEP. These results support the potential utility of ISL as a simplified PEP agent.