Background The Partners HSV-2/HIV-1 Transmission Study (Partners Study) is a phase III, placebo-controlled trial of daily acyclovir for genital herpes (HSV-2) suppression among HIV-1/HSV-2 co-infected persons to reduce HIV-1 transmission to their HIV-1 susceptible partners, which requires recruitment of HIV-1 serodiscordant heterosexual couples. We describe the baseline characteristics of this cohort. Methods HIV-1 serodiscordant heterosexual couples, in which the HIV-1 infected partner was HSV-2 seropositive, had a CD4 count ≥250 cells/mcL and was not on antiretroviral therapy, were enrolled at 14 sites in East and Southern Africa. Demographic, behavioral, clinical and laboratory characteristics were assessed. Results Of the 3408 HIV-1 serodiscordant couples enrolled, 67% of the HIV-1 infected partners were women. Couples had cohabitated for a median of 5 years (range 2–9) with 28% reporting unprotected sex in the month prior to enrollment. Among HIV-1 susceptible participants, 86% of women and 59% of men were HSV-2 seropositive. Other laboratory-diagnosed sexually transmitted infections were uncommon (<5%), except for Trichomonas vaginalis in 14% of HIV-1 infected women. Median baseline CD4 count for HIV-1 infected participants was 462cells/mcL and median HIV-1 plasma RNA was 4.2 log10 copies/mL. After adjusting for age and African region, correlates of HIV-1 RNA level included male gender (+0.24 log10 copies/mL; p<0.001) and CD4 count (？0.25 and ？0.55 log10 copies/mL for CD4 350–499 and >500 relative to <350, respectively, p<0.001). Conclusions The Partners Study successfully enrolled a cohort of 3408 heterosexual HIV-1 serodiscordant couples in Africa at high risk for HIV-1 transmission. Follow-up of this cohort will evaluate the efficacy of acyclovir for HSV-2 suppression in preventing HIV-1 transmission and provide insights into biological and behavioral factors determining heterosexual HIV-1 transmission. Trial Registration ClinicalTrials.gov NCT00194519
References
[1]
Corey L, Wald A, Celum CL, Quinn TC (2004) The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr 35: 435–445.
[2]
Mole L, Ripich S, Margolis D, Holodniy M (1997) The impact of active herpes simplex virus infection on human immunodeficiency virus load. J Infect Dis 176: 766–770.
[3]
Schacker T, Zeh J, Hu H, Shaughnessy M, Corey L (2002) Changes in plasma human immunodeficiency virus type 1 RNA associated with herpes simplex virus reactivation and suppression. J Infect Dis 186: 1718–1725.
[4]
Baeten JM, McClelland RS, Corey L, Overbaugh J, Lavreys L, et al. (2004) Vitamin A supplementation and genital shedding of herpes simplex virus among HIV-1-infected women: a randomized clinical trial. J Infect Dis 189: 1466–1471.
[5]
Mbopi-Keou FX, Legoff J, Gresenguet G, Si-Mohamed A, Matta M, et al. (2003) Genital shedding of herpes simplex virus-2 DNA and HIV-1 RNA and proviral DNA in HIV-1- and herpes simplex virus-2-coinfected African women. J Acquir Immune Defic Syndr 33: 121–124.
[6]
Zuckerman RA, Lucchetti A, Whittington WL, Sanchez J, Coombs RW, et al. (2007) Herpes simplex virus (HSV) suppression with valacyclovir reduces rectal and blood plasma HIV-1 levels in HIV-1/HSV-2-seropositive men: a randomized, double-blind, placebo-controlled crossover trial. J Infect Dis 196: 1500–1508.
[7]
Zuckerman RA, Celum C, e al (2009) Seminal HIV viral load in HIV-1/HSV-2 co-infected men. AIDS. In press.
[8]
Gray RH, Wawer MJ, Brookmeyer R, Sewankambo NK, Serwadda D, et al. (2001) Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 357: 1149–1153.
[9]
Abu-Raddad LJ, Magaret AS, Celum C, Wald A, Longini IM Jr, et al. (2008) Genital herpes has played a more important role than any other sexually transmitted infection in driving HIV prevalence in Africa. PLoS ONE 3: e2230.
[10]
Freeman EE, Orroth KK, White RG, Glynn JR, Bakker R, et al. (2007) Proportion of new HIV infections attributable to herpes simplex 2 increases over time: simulations of the changing role of sexually transmitted infections in sub-Saharan African HIV epidemics. Sex Transm Infect 83: Suppl 1i17–24.
[11]
Wald A (2004) Synergistic interactions between herpes simplex virus type-2 and human immunodeficiency virus epidemics. Herpes 11: 70–76.
[12]
Lingappa JR, Celum C (2007) Clinical and therapeutic issues for herpes simplex virus-2 and HIV co-infection. Drugs 67: 155–174.
[13]
Fideli US, Allen SA, Musonda R, Trask S, Hahn BH, et al. (2001) Virologic and immunologic determinants of heterosexual transmission of human immunodeficiency virus type 1 in Africa. AIDS Res Hum Retroviruses 17: 901–910.
[14]
Lingappa JR, Lambdin B, Bukusi EA, Ngure K, Kavuma L, et al. (2008) Regional Differences in Prevalence of HIV-1 Discordance in Africa and Enrollment of HIV-1 Discordant Couples into an HIV-1 Prevention Trial. PLoS ONE 3: e1411.
[15]
Centers for Disease Control and Prevention (November 2007) Couples HIV Counseling and Testing.
[16]
Ashley-Morrow R, Nollkamper J, Robinson NJ, Bishop N, Smith J (2004) Performance of focus ELISA tests for herpes simplex virus type 1 (HSV-1) and HSV-2 antibodies among women in ten diverse geographical locations. Clin Microbiol Infect 10: 530–536.
[17]
Huppert JS, Mortensen JE, Reed JL, Kahn JA, Rich KD, et al. (2007) Rapid antigen testing compares favorably with transcription-mediated amplification assay for the detection of Trichomonas vaginalis in young women. Clin Infect Dis 45: 194–198.
[18]
Glencross DK, Aggett HM, Stevens WS, Mandy F (2008) African regional external quality assessment for CD4 T-cell enumeration: development, outcomes, and performance of laboratories. Cytometry B Clin Cytom 74: Suppl 1S69–79.
[19]
Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C, et al. (2000) Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 342: 921–929.
[20]
Fleming DT, McQuillan GM, Johnson RE, Nahmias AJ, Aral SO, et al. (1997) Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 337: 1105–1111.
[21]
Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, et al. (2006) Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 20: 73–83.
[22]
Wald A, Link K (2002) Risk of human immunodeficiency virus infection in herpes simplex virus type 2-seropositive persons: a meta-analysis. J Infect Dis 185: 45–52.
[23]
Auvert B, Males S, Puren A, Taljaard D, Carael M, et al. (2004) Can highly active antiretroviral therapy reduce the spread of HIV?: A study in a township of South Africa. J Acquir Immune Defic Syndr 36: 613–621.
[24]
Lew J, Reichelderfer P, Fowler M, Bremer J, Carrol R, et al. (1998) Determinations of levels of human immunodeficiency virus type 1 RNA in plasma: reassessment of parameters affecting assay outcome. TUBE Meeting Workshop Attendees. Technology Utilization for HIV-1 Blood Evaluation and Standardization in Pediatrics. J Clin Microbiol 36: 1471–1479.
[25]
Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J, Sitta R, et al. (2005) Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med 2: e298.
[26]
Bailey RC, Moses S, Parker CB, Agot K, Maclean I, et al. (2007) Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet 369: 643–656.
[27]
Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, et al. (2007) Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet 369: 657–666.
[28]
Rottingen JA, Cameron DW, Garnett GP (2001) A systematic review of the epidemiologic interactions between classic sexually transmitted diseases and HIV: how much really is known? Sex Transm Dis 28: 579–597.
[29]
Celum C, Wald A, Hughes J, Sanchez J, Reid S, et al. (2008) Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet 371: 2109–2119.
[30]
Watson-Jones D, Weiss HA, Rusizoka M, Changalucha J, Baisley K, et al. (2008) Effect of Herpes Simplex Suppression on Incidence of HIV among Women in Tanzania. N Engl J Med 358: 1560–1571.
[31]
Mark KE, Wald A, Magaret AS, Selke S, Olin L, et al. (2008) Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. J Infect Dis 198: 1141–1149.
[32]
Rebbapragada A, Wachihi C, Pettengell C, Sunderji S, Huibner S, et al. (2007) Negative mucosal synergy between Herpes simplex type 2 and HIV in the female genital tract. Aids 21: 589–598.
[33]
Zhu J, Koelle DM, Cao J, Vazquez J, Huang ML, et al. (2007) Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J Exp Med 204: 595–603.
[34]
Zhu J, Woodward A, Klock A, Peng T, Johnston C, et al. (2009) Genital HSV-2 Infection Imprints a Marked Enrichment and Long Term Persistence of HIV Receptor Positive Cells in the Genital Tract., Keystone Symposia on Prevention of HIV/AIDS, Abstract #X3-123, Keystone, Colorado, March 2009:
[35]
Schacker T, Ryncarz AJ, Goddard J, Diem K, Shaughnessy M, et al. (1998) Frequent recovery of HIV-1 from genital herpes simplex virus lesions in HIV-1-infected men. JAMA 280: 61–66.
[36]
Albrecht MA, DeLuca NA, Byrn RA, Schaffer PA, Hammer SM (1989) The herpes simplex virus immediate-early protein, ICP4, is required to potentiate replication of human immunodeficiency virus in CD4+ lymphocytes. J Virol 63: 1861–1868.
[37]
Golden MP, Kim S, Hammer SM, Ladd EA, Schaffer PA, et al. (1992) Activation of human immunodeficiency virus by herpes simplex virus. J Infect Dis 166: 494–499.
[38]
Palu G, Benetti L, Calistri A (2001) Molecular Basis of the Interactions between Herpes Simplex Viruses and HIV-1. Herpes 8: 50–55.
[39]
Tremblay M, Gornitsky M, Wainberg MA (1989) Active replication of human immunodeficiency virus type 1 by peripheral blood mononuclear cells following coincubation with herpes viruses. J Med Virol 29: 109–114.
[40]
Baeten JM, Strick LB, Lucchetti A, Whittington WL, Sanchez J, et al. (2008) Herpes Simplex Virus (HSV)-Suppressive Therapy Decreases Plasma and Genital HIV-1 Levels in HSV-2/HIV-1 Coinfected Women: A Randomized, Placebo-Controlled, Cross-Over Trial. J Infect Dis 198: 1804–1808.
[41]
Dunne EF, Whitehead S, Sternberg M, Thepamnuay S, Leelawiwat W, et al. (2008) Suppressive acyclovir therapy reduces HIV cervicovaginal shedding in HIV- and HSV-2-infected women, Chiang Rai, Thailand. J Acquir Immune Defic Syndr 49: 77–83.
[42]
Nagot N, Ouedraogo A, Foulongne V, Konate I, Weiss HA, et al. (2007) Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med 356: 790–799.
[43]
Delany SC, Mlaba N, Akpomiemie G, Capovilla A, Stevens W, et al. (2008) Impact of aciclovir on genital and plasma HIV-1 RNA in HSV-2/HIV-1 co-infected women: a randomised placebo-controlled trial in South Africa. AIDS. In Press.
[44]
Ioannidis JP, Collier AC, Cooper DA, Corey L, Fiddian AP, et al. (1998) Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis of randomized individual patient data. J Infect Dis 178: 349–359.
[45]
Kempf MC, Allen S, Zulu I, Kancheya N, Stephenson R, et al. (2008) Enrollment and retention of HIV discordant couples in Lusaka, Zambia. J Acquir Immune Defic Syndr 47: 116–125.
[46]
de Walque D (2006) Discordant Couples - HIV infection among couples in Burkina Faso, Cameroon, Ghana, Kenya, and Tanzania. The World Bank.
[47]
Freeman EE, Glynn JR, Study Group on Heterogeneity of HIV Epidemics in African Cities (2004) Factors affecting HIV concordancy in married couples in four African cities. AIDS 18: 1715–1721.
[48]
Stephenson R, Barker J, Cramer R, Hall MA, Karita E, et al. (2008) The demographic profile of sero-discordant couples enrolled in clinical research in Rwanda and Zambia. AIDS Care 20: 395–405.
[49]
Morrill AC, Noland C (2006) Interpersonal issues surrounding HIV counseling and testing, and the phenomenon of "testing by proxy". J Health Commun 11: 183–198.
[50]
Tumwesigye E, Asiimwe S, Muganzi S, Achom M, Kabatesi D, et al. (2008) High HIV Prevalence among Males in Discordant Partnerships in a Full Access Door–Door VCT Program in Rural Uganda. 15th Congress on Retroviruses and Opportunistic Infections (CROI). Boston, Massachusetts.
[51]
Allen S, Karita E, Chomba E, Roth DL, Telfair J, et al. (2007) Promotion of couples' voluntary counselling and testing for HIV through influential networks in two African capital cities. BMC Public Health 7: 349.
[52]
Allen S, Lindan C, Serufilira A, Van de Perre P, Rundle AC, et al. (1991) Human immunodeficiency virus infection in urban Rwanda. Demographic and behavioral correlates in a representative sample of childbearing women. Jama 266: 1657–1663.
[53]
Allen S, Meinzen-Derr J, Kautzman M, Zulu I, Trask S, et al. (2003) Sexual behavior of HIV discordant couples after HIV counseling and testing. Aids 17: 733–740.
[54]
Bunnell RE, Nassozi J, Marum E, Mubangizi J, Malamba S, et al. (2005) Living with discordance: knowledge, challenges, and prevention strategies of HIV-discordant couples in Uganda. AIDS Care 17: 999–1012.
[55]
Guthrie BL, de Bruyn G, Farquhar C (2007) HIV-1-discordant couples in sub-Saharan Africa: explanations and implications for high rates of discordancy. Curr HIV Res 5: 416–429.
[56]
Allen S, Tice J, Van de Perre P, Serufilira A, Hudes E, et al. (1992) Effect of serotesting with counselling on condom use and seroconversion among HIV discordant couples in Africa. Bmj 304: 1605–1609.
