Abstract
Pre-exposure prophylaxis (PrEP) is considered one of the five “pillars” by UNAIDS to reduce HIV transmission. Moreover, it is a tool for female self-protection against HIV, making it highly relevant to sub-Saharan regions, where women have the highest infection burden. To date, Truvada is the only medication for PrEP. However, the cost of Truvada limits its uptake in resource-constrained countries. Similarly, several currently investigated, patent-protected compounds may be unaffordable in these regions. We set out to explore the potential of the patent-expired antiviral efavirenz (EFV) as a cost-efficient PrEP alternative. A population pharmacokinetic model utilizing data from the ENCORE1 study was developed. The model was refined for metabolic autoinduction. We then explored EFV cellular uptake mechanisms, finding that it is largely determined by plasma protein binding. Next, we predicted the prophylactic efficacy of various EFV dosing schemes after exposure to HIV using a stochastic simulation framework. We predicted that plasma concentrations of 11, 36, 1287 and 1486ng/mL prevent 90% sexual transmissions with wild type and Y181C, K103N and G190S mutants, respectively. Trough concentrations achieved after 600 mg once daily dosing (median: 2017 ng/mL, 95% CI:445–9830) and after reduced dose (400 mg) efavirenz (median: 1349ng/mL, 95% CI: 297–6553) provided complete protection against wild-type virus and the Y181C mutant, and median trough concentrations provided about 90% protection against the K103N and G190S mutants. As reduced dose EFV has a lower toxicity profile, we predicted the reduction in HIV infection when 400 mg EFV-PrEP was poorly adhered to, when it was taken “on demand” and as post-exposure prophylaxis (PEP). Once daily EFV-PrEP provided 99% protection against wild-type virus, if ≥50% of doses were taken. PrEP “on demand” provided complete protection against wild-type virus and prevented ≥81% infections in the mutants. PEP could prevent >98% infection with susceptible virus when initiated within 24 h after virus exposure and continued for at least 9 days. We predict that 400 mg oral EFV may provide superior protection against wild-type HIV. However, further studies are warranted to evaluate EFV as a cost-efficient alternative to Truvada. Predicted prophylactic concentrations may guide release kinetics of EFV long-acting formulations for clinical trial design.
Highlights
The ambitious goals formulated by UNAIDS are to end AIDS by 2030 (UNAIDS, 2017)
Based on an initial computational assessment of potential candidates (Duwal et al, 2019), we focus on the patent-expired nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV), which is successfully used in HIV treatment, in resource-constrained settings, where it costs as little as 0.1US$ per day
Truvada-based Pre-exposure prophylaxis (PrEP) is being implemented in a number of countries (AVAC, 2019), there are two major limitations to its optimal use: (i) its costs (Keller and Smith, 2011), and (ii) its sensitivity to poor medication adherence (Haberer et al, 2015)
Summary
The ambitious goals formulated by UNAIDS are to end AIDS by 2030 (UNAIDS, 2017). Ending AIDS heavily relies on strategies to reduce the number of new HIV infections from an estimated 2.1 million in 2014 (UNAIDS, 2015) to 500,000 cases by 2020 and to fewer than 200,000 by 2030 (UNAIDS, 2016). While a vaccine would be the ideal tool for the purpose, intrinsic difficulties have so far precluded the development of an effective vaccine against HIV. Despite these setbacks, the development of about 30 antiviral compounds to stop HIV replication has been an overwhelming success (Gulick, 2018) in HIV research.
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