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Twice-daily acyclovir to reduce HIV-1 transmission from HIV-1 / HSV-2 co-infected persons within HIV-1 serodiscordant couples: a randomized, double-blind, placebo-controlled trial
Presented by Connie Celum (United States).
C. Celum1,2,3, A. Wald2,3,4,5, J. Lingappa1,2,6, A. Magaret4,5, R. Wang1, N. Mugo1,7, A. Mujugira1, J. Baeten1,2, J. Mullins2, J. Hughes2, E. Bukusi1,7,8, C. Cohen9, E. Katabira10, A. Ronald11, J. Kiarie7, C. Farquhar2,3, G. John Stewart2, J. Makhema12, M. Essex13, E. Were14, K. Fife15, G. deBruyn16, G. Gray16, J. McIntyre16, R. Monongi17, S. Kapiga17,18, D. Coetzee19, S. Allen20, M. Inambao21, K. Kayitenkore22, E. Karita22, W. Kanweka23, S. Delany24, H. Rees24, B. Vwalika25, W. Stevens26, M. Campbell2, K. Thomas2, R. Coombs2,5, R. Morrow5, W. Whittington2, M.J. McElrath1,2, L. Barnes1, R. Ridzon27, L. Corey2,4,5, Partners in Prevention HSV-HIV Transmission Team
1University of Washington, Department of Global Health, Seattle, United States, 2University of Washington, Department of Medicine, Seattle, United States, 3University of Washington, Department of Epidemiology, Seattle, United States, 4Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Institute, Seattle, United States, 5University of Washington, Department of Laboratory Medicine, Seattle, United States, 6University of Washington, Department of Pediatrics, Seattle, United States, 7University of Nairobi and Kenyatta National Hospital, Department of Obstetrics & Ginecology, Nairobi, Kenya, 8Kenya Medical Research Institute, Center for Microbiology Research, Nairobi, Kenya, 9University of California San Francisco, Department of Obstetrics, Gynecology and Reproductive Sciences, San Francisco, United States, 10Makerere University, Infectious Disease Institute, Kampala, Uganda,
Background: Herpes simplex virus type 2 (HSV-2) is highly prevalent in HIV-1 infected persons, reactivates frequently, and is associated with increased HIV-1 concentrations in plasma and genital secretions. Suppressive HSV-2 therapy reduces plasma and genital HIV-1 levels, suggesting HSV-2 suppression could reduce HIV-1 transmission.
Methods: We enrolled 3408 African heterosexual HIV-1 serodiscordant couples from 14 African sites (Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, and Zambia). HIV-1/HSV-2 dually-infected partners had CD4 counts ≥250 cells/mm3 and were not taking antiretrovirals at enrollment; they were randomized to acyclovir 400 mg orally twice daily or matching placebo. Participants were followed monthly (HIV-1 infected partners) or quarterly (HIV-1 uninfected partners) for up to 24 months. Viruses were sequenced from seroconverting partnerships to determine genetic linkage.
Results: 67% of HIV-1 infected partners were female. At enrollment, median CD4 count was 462 and median plasma viral loads were 3.9 log10 and 4.3 log10 in female and in male HIV-infected partners, respectively. Retention at 24 months was 92% for HIV-1 infected and 84% for HIV-1 uninfected participants. Participants took 96.5% of study drug doses dispensed. Overall HIV-1 seroincidence was 2.8/100 person-years and 1.8/100 person-years for virologically-linked transmissions. Acyclovir significantly reduced the frequency of HSV-2 positive genital ulcers (HR 0.27; 95% CI 0.20-0.36, p< 0.001), and mean plasma HIV-1 concentrations by 0.25 log10 copies/mL (95% CI 0.22-0.29, p< 0.001). Of 84 linked HIV-1 transmissions, 41 and 43 occurred in the acyclovir and placebo arms, respectively (HR 0.92, 95% CI 0.60-1.41, p=0.70). Risk of HIV-1 transmission was strongly associated with plasma HIV-1 levels.
Conclusion: HSV-2 suppression among HIV-1/HSV-2 dually-infected persons reduced plasma HIV-1 RNA concentrations by 0.25 log10 and HSV-2 genital ulcers by 73%, but did not reduce risk of HIV-1 transmission to uninfected partners. Significantly greater effects on plasma HIV-1 concentrations is needed to reduce HIV-1 transmission to sexual partners.
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