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bioRxiv · 10.1101/2024.04.15.589489

Modeling of HIV-1 prophylactic efficacy and toxicity with islatravir shows non-superiority for oral dosing, but promise as a subdermal implant

Kim, H.-y.·Zhang, L.·Hendrix, C. W.·Haberer, J. E.·von Kleist, M.
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Abstract

HIV prevention with pre-exposure prophylaxis (PrEP) constitutes a major pillar in fighting the ongoing epidemic. While daily oral PrEP adherence may be challenging, long-acting (LA-)PrEP in oral or implant formulations could overcome frequent dosing with convenient administration. The novel drug islatravir (ISL) may be suitable for LA-PrEP, but high doses have been associated with lymphopenia. We developed a mathematical model to predict ISL pro-drug levels in plasma and active intracellular ISL-triphosphate concentrations after oral vs. subdermal implant dosing. Using phase-II trial data, we simulated antiviral effects and estimated HIV risk reduction for multiple dosages and dosing frequencies. We then established non-toxic exposure thresholds and evaluated low-dose regimens. Our findings suggest that implants with 56-62 mg ISL offer safe, effective HIV risk reduction without being toxic. Oral 0.1 mg daily, 3-5 mg weekly, and 10 mg bi-weekly ISL provide comparable efficacy, but weekly and bi-weekly doses resulted in residual toxicity, while adherence requirements for daily dosing were similar to established oral PrEP regimen. Oral 0.5-1 mg on-demand provided > 90% protection, while not being suitable for post-exposure prophylaxis.

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Kim, H.-y., Zhang, L., Hendrix, C. W., Haberer, J. E., von Kleist, M.. 2024-04-19. Modeling of HIV-1 prophylactic efficacy and toxicity with islatravir shows non-superiority for oral dosing, but promise as a subdermal implant. https://doi.org/10.1101/2024.04.15.589489

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