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

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: SIV; islatravir; islatravir‐TP; pharmacokinetic; post‐exposure prophylaxis; rhesus macaque.

Figure 1

Rhesus macaque SIVmac251 challenge model with PEP dosing at different stages. The black arrow shows the schedule of SIVmac251 inoculations at day −1. The blue arrows show the schedule of blood collection, and the green arrows show the schedule of weekly doses by oral gavage of ISL 3.9 mg/kg. Uninfected animals in stages 1–4 were then challenged as in stage 1 for each subsequent stage: receiving 3, 2 and 1 weekly dose of oral ISL, respectively, initiated 24 hours after inoculation and monitored for 7 weeks after the last dose. ISL, islatravir; PEP, post‐exposure prophylaxis; SIVmac251, simian immunodeficiency virus mac251.

Figure 2

(a) Plasma viral load through day 49 in rhesus macaques for untreated control animals in stage 1 and treated animals in stages 1–3 after SIVmac251 IV inoculation, followed by 2−4 weekly doses of ISL 3.9 mg/kg by oral gavage. Undetectable viral loads are displayed at the LLD (40 copies/ml). The coloured lines represent individual animals. (b) Plasma viral load through day 49 in infected rhesus macaques in stage 4 after SIVmac251 IV inoculation followed by a single dose of ISL 3.9 mg/kg by oral gavage. The coloured lines represent individual animals. ISL, islatravir; IV, intravenous; LLD, lower limit of detection; SIVmac251, simian immunodeficiency virus mac251.

Figure 3

(a) Mean weekly intracellular ISL‐TP concentration levels starting on day 7 in all four stages after 1−4 weekly oral doses of ISL 3.9 mg/kg. The arrows represent the timing of ISL dosing per stage. The figure includes data only if there were at least two measurements with quantifiable ISL‐TP at each specific time point for each stage. ISL‐TP was below the LLOQ in rhesus PBMCs from all animals 3 weeks after the last dose of ISL 3.9 mg/kg. (b) Comparison of rhesus ISL‐TP exposure to simulated exposure of ISL‐TP in humans after once‐daily oral dosing of ISL 0.25 mg, once‐weekly oral dosing of ISL 2 mg or a single dose of ISL 2 mg. Coloured lines and bands represent the simulated median and 95% prediction interval, respectively, for dosing in humans. The solid black line represents the observed mean concentrations with minimum and maximum concentrations represented in the error bars in stage 3 in macaques. ISL, islatravir; ISL‐TP, ISL‐triphosphate; IV, intravenous; LLOQ, lower limit of quantitation; PBMC, peripheral blood mononuclear cell; QD, once daily; QW, once weekly.