Abstract
Currently, there is no effective vaccine to halt HIV transmission. However, pre-exposure prophylaxis (PrEP) with the drug combination Truvada can substantially decrease HIV transmission in individuals at risk. Despite its benefits, Truvada-based PrEP is expensive and needs to be taken once-daily, which often leads to inadequate adherence and incomplete protection. These deficits may be overcome by next-generation PrEP regimen, including currently investigated long-acting formulations, or patent-expired drugs. However, poor translatability of animal- and ex vivo/in vitro experiments, and the necessity to conduct long-term (several years) human trials involving considerable sample sizes (N>1000 individuals) are major obstacles to rationalize drug-candidate selection. We developed a prophylaxis modelling tool that mechanistically considers the mode-of-action of all available drugs. We used the tool to screen antivirals for their prophylactic utility and identify lower bound effective concentrations that can guide dose selection in PrEP trials. While in vitro measurable drug potency usually guides PrEP trial design, we found that it may over-predict PrEP potency for all drug classes except reverse transcriptase inhibitors. While most drugs displayed graded concentration-prophylaxis profiles, protease inhibitors tended to switch between none- and complete protection. While several treatment-approved drugs could be ruled out as PrEP candidates based on lack-of-prophylactic efficacy, darunavir, efavirenz, nevirapine, etravirine and rilpivirine could more potently prevent infection than existing PrEP regimen (Truvada). Notably, some drugs from this candidate set are patent-expired and currently neglected for PrEP repurposing. A next step is to further trim this candidate set by ruling out compounds with ominous safety profiles, to assess different administration schemes in silico and to test the remaining candidates in human trials.
Highlights
Pre-exposure prophylaxis (PrEP) with Truvada can substantially decrease the risk of infection
Pre-exposure prophylaxis (PrEP) to prevent HIV infection has been assessed in people at high risk of sexual transmission
While the prophylactic efficacy after exposure to a single virus are moderately less than the direct effects of co-receptor antagonists Co-receptor antagonists (CRA) and integrase inhibitors InI respectively (Fig 2A), there is a profound difference for protease inhibitors, which do not seem to reduce HIV transmission unless their direct efficacy η exceeds 95%
Summary
Pre-exposure prophylaxis (PrEP) to prevent HIV infection (using drugs which are licensed for its treatment) has been assessed in people at high risk of sexual transmission. Major shortcomings of Truvada-based PrEP are its costs [4], a residual infection risk and the necessity for daily drug intake (which often leads to inadequate adherence). These deficits may be overcome by next-generation PrEP regimen, including patent-expired antivirals and long-acting formulations. Studies assessing next-generation PrEP regimen are underway [5], but rational selection of which agents to advance into PrEP trials based on their intrinsic pharmacology and mode of action has not been comprehensively or systematically undertaken. Studies have focussed on patent-protected compounds [6], which are likely unaffordable in resource-constrained settings [4] hit hardest by the epidemic
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