# Effectiveness of islatravir post‐exposure prophylaxis after intravenous challenge with simian immunodeficiency virus in rhesus macaques

## TL;DR

A new drug called islatravir effectively prevents SIV infection in monkeys when given shortly after exposure, suggesting potential for human HIV prevention.

## Contribution

Islatravir as a long-acting oral nucleoside reverse transcriptase translocation inhibitor for post-exposure prophylaxis is demonstrated for the first time in non-human primates.

## Key findings

- Two weekly doses of islatravir prevented SIV infection in rhesus macaques after intravenous exposure.
- Viral infection occurred when islatravir triphosphate levels were undetectable in infected animals.
- Islatravir showed robust protection in three stages of experimental challenge but partial protection in a fourth stage.

## Abstract

Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) with robust antiretroviral activity. The efficacy of ISL administered for post‐exposure prophylaxis (PEP) was evaluated in a simian immunodeficiency virus (SIV) rhesus macaque intravenous (IV) challenge model.

Twelve rhesus macaques were challenged with SIVmac251 via IV administration. After 24 hours, six animals received ISL 3.9 mg/kg (the minimum effective dose that gives maximal protection) and six animals were untreated controls. In stage 1, treated animals received 4 weekly oral doses of ISL and were monitored for SIV infection for 7 weeks after the last dose. In stage 2, uninfected, treated animals from stage 1 were challenged similarly; 24 hours after challenge, 3 weekly oral doses of ISL 3.9 mg/kg were initiated. The treated animals were monitored for 7 weeks, as in stage 1. Uninfected, treated animals (from stage 2) entered stage 3. In stage 3, the animals were challenged as in stage 2; 24 hours after challenge, 2 weekly oral doses of ISL 3.9 mg/kg were initiated. The treated animals were monitored for 7 weeks, as before. Finally, in stage 4, uninfected, treated animals were challenged using IV administration and 24 hours later were treated with a single oral dose of ISL 3.9 mg/kg and monitored for 7 weeks. Infection was monitored through plasma viral RNA and proviral DNA amplification. Virus‐specific antibody responses were measured using a commercial assay. ISL concentrations in plasma and ISL triphosphate (ISL‐TP) levels in peripheral blood mononuclear cells were measured longitudinally.

All untreated controls were viraemic 7 days after SIVmac251 IV challenge. All six ISL‐treated animals were completely protected in stages 1–3 (Fisher exact test p = 0.0022). In stage 4, two of six ISL‐treated animals became infected with wild‐type SIVmac251: viraemia was observed at days 14 and 49 in the two animals (Fisher exact test p = 0.06). Both animals had unquantifiable ISL‐TP on the day viraemia was observed.

Two weekly oral doses of ISL 3.9 mg/kg, administered 24 hours post IV SIV exposure, prevents infection of rhesus macaques. These results support further investigation of a long‐acting oral NRTTI for PEP.