Multiscale, mechanistic pipeline to assess the prophylactic efficacy of anti- HIV compounds
Sulav Duwal (1), Vikram Sunkara (1,2), Laura Dickinson (3), Saye Khoo (3), Max von Kleist (1)
(1) Dep. of Mathematics and Computer Science, Freie Universität Berlin, Germany; (2) Zuse Intitute Berlin, Germany; (3) Institute of translational medicine, University of Liverpool
Objectives: While HIV-1 cannot be cured to date, pre-exposure prophylaxis (PrEP) has been suggested to halt the ongoing spread of HIV [1]. It requires that individuals take anti-retrovirals (ARVs) chronically, to avert infection in the case of exposure. Prophylaxis is the only method by which women can circumvent infection, however it can be anticipated that adherence levels are low in a roll-out and that individuals, unknowing of delays in the onset of drug action, may actually take the prophylaxis after exposure (PEP).
We developed a predictive mechanistic model for the efficacy of ARVs in the context of chronic PrEP, ‘PrEP on demand’ [2] and PEP. By coupling our model with drug-specific pharmacokinetics, we assess the mechanisms of prevention, the pharmacological limitations and opportunities for various prophylactic schedules using approved- and neglected drugs.
Methods: A technical difficulty was to estimate infection probabilities after viral challenge in a time-varying environment. We derived analytical solutions for the probability of virus clearance, depending on a constant, drug-class specific viral inhibition and fixed inoculum size. The latter was used to reduce the relevant state space of our stochastic model, where infection is reversible. We then develop an extrande algorithm, sampling the stochastic dynamics within the eradication polyhedron, considering the time- and dosing dependent efficacy of anti-retrovirals (ARVs). This allows proper PK-PD coupling to predict the stochastic endpoint (infection probability).
Results: We extend an existing framework [3], which allows integrating virus loads in the transmitter, mode of exposure and timing of viral challenge, with this time-dependent component to estimate the infection probability for unprotected sex for any particular ARV-prophylaxis. We observed drug-class specific prophylactic efficacies, with protease inhibitors exhibiting switch-like response profiles. Our simulations indicated that, unlike approved nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase inhibitors may be highly efficient, even when used in ‘PrEP on demand’ or PEP. Specifically, we study the efficacy of dolutegravir, including inter-individual PK variation [4].
Conclusions: Our findings warrant further clinical assessment, particularly since some NNRTIs are extremely cost-efficient and thus suitable for large-scale rollout in resource-constrained settings.
References:
[1] Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. R.M. Grant et al. New England Journal of Medicine, 363, 2587-2599, 2010
[2] On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. J.M. Molina, C. Capitant, B. Spire et al. New England Journal of Medicine, 373(23):2237-2246, 2015
[3] Multi-scale Systems-Pharmacology pipeline to assess the prophylactic efficacy of NRTIs against HIV-1. S. Duwal, V. Sunkara and M. von Kleist, CPT: Pharmacometrics & Systems Pharmacology, 5, 377, 2016
[4] Population Pharmacokinetics (PK) of Dolutegravir (DTG) Alone and Following Treatment Switch. Laura Dickinson, Margherita Bracchi, Emilie Elliot, Laura Else, Saye Khoo, David Back, Mark Nelson, Marta Boffito. Poster P094, HIV Drug Therapy, Glasgow 2016