Abstract
BackgroundFour clinical trials have shown that oral and topical pre-exposure prophylaxis (PrEP) based on tenofovir may be effective in preventing HIV transmission. The expected reduction in HIV transmission and the projected prevalence of drug resistance due to PrEP use vary significantly across modeling studies as a result of the broad spectrum of assumptions employed. Our goal is to quantify the influence of drug resistance assumptions on the predicted population-level impact of PrEP.MethodsAll modeling studies which evaluate the impact of oral or topical PrEP are reviewed and key assumptions regarding mechanisms of generation and spread of drug-resistant HIV are identified. A dynamic model of the HIV epidemic is developed to assess and compare the impact of oral PrEP using resistance assumptions extracted from published studies. The benefits and risks associated with ten years of PrEP use are evaluated under identical epidemic, behavioral and intervention conditions in terms of cumulative fractions of new HIV infections prevented, resistance prevalence among those infected with HIV, and fractions of infections in which resistance is transmitted.ResultsPublished models demonstrate enormous variability in resistance-generating assumptions and uncertainty in parameter values. Depending on which resistance parameterization is used, a resistance prevalence between 2% and 44% may be expected if 50% efficacious oral PrEP is used consistently by 50% of the population over ten years. We estimated that resistance may be responsible for up to a 10% reduction or up to a 30% contribution to the fraction of prevented infections predicted in different studies.ConclusionsResistance assumptions used in published studies have a strong influence on the projected impact of PrEP. Modelers and virologists should collaborate toward clarifying the set of resistance assumptions biologically relevant to the PrEP products which are already in use or soon to be added to the arsenal against HIV.
Highlights
Several randomized clinical trials demonstrated that if used adequately, pre-exposure prophylaxis (PrEP) products in the form of daily pills or topical gels could be partially effective in preventing HIV acquisition for men who have sex with men [1], heterosexual men and women [2,3], and serodiscordent couples [4]. These encouraging results were not confirmed in two other trials [5,6], Truvada became the first drug approved for PrEP use in US [7]
We identify conditions under which drug resistance may cause an increase in the projected number of prevented infections due to PrEP use
Summary of resistance assumptions from the review of published PrEP models The resistance parameters used in the published modeling studies demonstrate enormous variability in assumptions and uncertainty in values
Summary
Several randomized clinical trials demonstrated that if used adequately, pre-exposure prophylaxis (PrEP) products in the form of daily pills (oral PrEP) or topical gels (vaginal microbicides) could be partially effective in preventing HIV acquisition for men who have sex with men [1], heterosexual men and women [2,3], and serodiscordent couples [4]. These encouraging results were not confirmed in two other trials [5,6], Truvada (emtricitabine/tenofovir disoproxil fumarate) became the first drug approved for PrEP use in US [7].
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