HIV-1 prevention with ART and PrEP: mathematical modeling insights into resistance, effectiveness, and public health impact.

The development of, and globlal access to, effective antiretroviral medications revolutionized human immunodeficiency virus type 1 (HIV-1) care. In addition to their important life-saving treatment benefits, antiretrovirals have recently been demonstrated to be highly efficacious for HIV-1 prevention as well, when used as antiretroviral therapy (ART) to reduce the infectiousness of HIV-1–infected persons and pre-exposure prophylaxis (PrEP) for uninfected persons who have ongoing HIV-1 exposure. Antiretroviral-based prevention, both ART and PrEP, are among the most promising strategies for reducing the number of new HIV-1 infections globally. Consequently, policymakers are weighing the costs, benefits, and risks of public health implementation of ART and PrEP for HIV-1 prevention. One potential risk of both ART and PrEP is the selection and transmission of HIV-1 variants that are resistant to one or more antiretroviral medications, which can result in HIV-1 treatment failure with associated morbidity and mortality and increased costs (of more complex secondand third-line treatment regimens); thus, there has been considerable speculation about the potential risks of resistance from both ART and PrEP. In this issue of the Journal of Infectious Diseases, Abbas et al present a mathematical model to estimate the number of HIV-1 infections averted and the number of acquired and transmitted HIV-1 cases of resistance in a setting similar to South Africa and under several scenarios about coverage of ART and PrEP [1]. For PrEP, the authors assumed use of combination emtricitabine-tenofovir, for which efficacy has been demonstrated [2–4]. For ART, the authors modeled first-line regimens containing the same antiretrovirals and assumed that second-line drugs were not available, given limited availability of second-line medications in many resource-limited settings. A number of additional scenarios were analyzed, including having ART initiation at CD4 lymphocyte cell counts at either <200 or <350 cells/μL, reflecting evolving international guidelines on clinical benefits of earlier ART initiation, and allowing for “inappropriate” PrEP use by persons that are already infected with HIV-1, either through PrEP initiation occurring during unrecognized seronegative acute HIV-1 infection or PrEP initiation by persons with undocumented, chronic HIV-1 infection, which could occur if HIV-1 testing is not conducted prior to initiation or through “black market” availability of PrEP. The authors used optimistic scenarios for ART retention and PrEP effectiveness; notably, the model assumed general distribution of PrEP rather than risk-targeted delivery. Not surprisingly, the results of this mathematical modeling article underscore that population-level coverage and effectiveness (which is dependent on adherence) are the main determinants of the number of infections averted with both ART and PrEP, and that implementation of a combination of ART and PrEP prevents more infections in a population than a program that delivers exclusively either ART or PrEP. More interestingly, the model analysis also suggests that HIV-1 drug resistance in a population would be largely driven by ART, not PrEP, in all scenarios modeled, as a result of insufficient ART adherence or lack of viral load monitoring in ART programs, leading to selection of resistant variants during incomplete viral suppression. The model also finds that the population prevalence of resistance as a direct Received 13 February 2013; accepted 14 February 2013; electronically published 9 April 2013. Correspondence: Connie Celum, MD, MPH, International Clinical Research Center, Dept of Global Health, University of Washington, Box 359927, 325 Ninth Ave, Seattle, WA 98104 ([email protected]). The Journal of Infectious Diseases 2013;208:189–91 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jit154