Using Plasma Viral Load to Guide Antiretroviral Therapy Initiation to Prevent HIV-1 Transmission

et al. (2012) Using Plasma Viral Load to Guide Antiretroviral Therapy Initiation to Prevent HIV-1 Transmission. PLoS ONE 7(11): e51192. doi:10.1371/journal.pone.0051192 Using Plasma Viral Load to Guide Antiretroviral Therapy Initiation to Prevent HIV-1 Transmission Pamela M. Murnane 0 James P. Hughes 0 Connie Celum 0 Jairam R. Lingappa 0 Nelly Mugo 0 Carey Farquhar 0 James Kiarie 0 Anna Wald 0 Jared M. Baeten 0 for the Partners in 0 Prevention HSV/HIV Transmission Study Team" 0 Chiyu Zhang, Institut Pasteur of Shanghai, Chinese Academy of Sciences, China 0 1 Department of Epidemiology, University of Washington, Seattle, Washington, United States of America, 2 Department of Global Health, University of Washington, Seattle, Washington, United States of America, 3 Department of Biostatistics, University of Washington, Seattle, Washington, United States of America, 4 Department of Medicine, University of Washington, Seattle, Washington, United States of America, 5 Department of Pediatrics, University of Washington, Seattle, Washington, United States of America, 6 Department of Obstetrics & Gynaecology, University of Nairobi, Nairobi, Kenya, 7 Department of Obstetrics & Gynaecology, Kenyatta National Hospital , Nairobi , Kenya , 8 Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America, 9 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, Washington, United States of America, 10 Public Health Sciences and Clinical Research Divisions FHCRC, Seattle , Washington , United States of America Background: Current WHO guidelines recommend antiretroviral therapy (ART) initiation at CD4 counts #350 cells/mL. Increasing this threshold has been proposed, with a primary goal of reducing HIV-1 infectiousness. Because the quantity of HIV-1 in plasma is the primary predictor of HIV-1 transmission, consideration of plasma viral load in ART initiation guidelines is warranted. Methods: Using per-sex-act infectivity estimates and cross-sectional sexual behavior data from 2,484 HIV-1 infected persons with CD4 counts .350 enrolled in a study of African heterosexual HIV-1 serodiscordant couples, we calculated the number of transmissions expected and the number potentially averted under selected scenarios for ART initiation: i) CD4 count ,500 cells/mL, ii) viral load $10,000 or $50,000 copies/mL and iii) universal treatment. For each scenario, we estimated the proportion of expected infections that could be averted, the proportion of infected persons initiating treatment, and the ratio of these proportions. Results: Initiating treatment at viral load $50,000 copies/mL would require treating 19.8% of infected persons with CD4 counts .350 while averting 40.5% of expected transmissions (ratio 2.0); treating at viral load $10,0000 copies/mL had a ratio of 1.5. In contrast, initiation at CD4 count ,500 would require treating 41.8%, while averting 48.4% (ratio 1.1). Conclusion: Inclusion of viral load in ART initiation guidelines could permit targeting ART resources to HIV-1 infected persons who have a higher risk of transmitting HIV-1. Further work is needed to estimate costs and feasibility. - Funding: This work was supported by the National Institutes of Health (R01 MH095507 and R01 AI083034) and the Bill and Melinda Gates Foundation (grant 26469). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. " Membership of the Partners in Prevention HSV/HIV Transmission Study Team is provided in the Acknowledgments. Antiretroviral therapy (ART) for treatment of HIV-1 infection has significant prevention benefits, reducing the risk of secondary HIV-1 transmission by over 90% [1,2]. Mathematical models suggest that providing ART to all HIV-1 infected persons and achieving sustained viral suppression could substantially reduce population-level HIV-1 incidence [3,4]. Earlier treatment is now recommended in many settings as a result of mounting evidence for treatment and prevention benefits of ART initiation early in the course of HIV-1 infection [5,6]. Guidelines for initiation of ART for HIV-1 infected persons have generally been based on CD4 T cell count and symptoms of advanced HIV-1 disease: current WHO guidelines recommend ART initiation for WHO clinical stage 3 and 4 infections and at CD4 counts #350 cells/mL regardless of stage [7]; the European AIDS Clinical Society recommends ART start at any CD4 count for symptomatic disease and consideration of ART at CD4 counts #500 cells/mL for asymptomatic infections; and in the United States guidelines now recommend universal ART, with a stronger recommendation for those with CD4 counts #500 cells/mL [5]. With limited health infrastructure and ART resource constraints in many settings, however, strategies are needed to target ART scale-up that maximizes clinical and prevention benefits. Plasma viral load is the primary predictor of HIV-1 transmission [8,9] and could be incorporated into ART initiation guidelines to target individuals with an increased risk of transmission [10]. We aimed to compare the potential prevention impact of early ART initiation guidelines (for infected persons with CD4 counts .350 cells/mL) based on high plasma viral load thresholds to guidelines based on CD4 counts #500 cells/mL. Data for this analysis were from the Partners in Prevention HSV/HIV Transmission Study, which was a randomized placebo-controlled trial of herpes simplex virus type-2 (HSV-2) suppression with acyclovir among 3381 heterosexual HSV-2/ HIV-1 co-infected individuals and their HIV-1 seronegative partners from 7 countries in southern and east Africa (Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, and Zambia). At enrollment, all HIV-1 infected participants had CD4 counts $250 cells/mL and were not yet on ART. The median CD4 count was 462 cells/mL (interquartile range 348631) and 68% were women. The primary outcome of the trial was virologically-linked HIV-1 transmission within the partnerships; acyclovir did not decrease the risk of HIV-1 transmission. The design, methods, and primary outcomes have been described previously [11]. For the present analysis, we used cross-sectional data on sexual behavior, CD4 count, and plasma viral load collected at the time of enrollment into the Partners in Prevention HSV/HIV Transmission Study for HIV-1 infected partners with CD4 counts .350 cells/mL. Sexual behavior data were from a standardized questionnaire that asked the number of sex acts with the HIV-1 uninfected partner with and without condoms in the prior month. We used enrollment data only, because our goal was to describe a population presenting to clinical care for consideration of early ART (i.e., at CD4 .350) and thus to minimize the potential impact on sexual behavior reporting as a result of partic (...truncated)