A Phase III, randomized, double-blind, placebo-controlled trial of acyclovir for the reduction of HIV acquisition among high risk HSV-2 seropositive, HIV-seronegative individuals
What is HPTN 039?
The presence of genital ulcers has been suggested as a potential risk factor for HIV acquisition since the start of the HIV epidemic. Numerous epidemiologic studies have supported the association of genital ulcers in general, and genital herpes in particular, with acquisition of HIV infection. Herpes simplex virus type 2 (HSV-2) is the most common cause of genital ulcers worldwide. This has been well documented in developed countries and has recently been shown in the developing world. HPTN 039 was a double-blind, placebo-controlled intervention trial of daily antiviral HSV-2 suppressive therapy for HIV prevention with a reasonable risk/benefit profile for participants. Although observational data indicate an increased risk of HIV infection among HSV-2 seropositive persons, a reduction in HIV infection due to daily HSV-2 suppression has not yet been tested or demonstrated. Participants in the placebo arm were provided with more than the standard of care for many U.S. settings, by provision of episodic antiviral treatment for symptomatic herpes outbreaks.
HPTN 039 was a Phase III, multi-site, randomized, double-blind, placebo-controlled trial that enrolled a total of 3,277 high-risk, HIV-negative, HSV-2 seropositive WSM and MSM over an accrual period of approximately 18 months. WSM were enrolled at study sites in Lusaka, Zambia, Johannesburg, South Africa, and Harare, Zimbabwe. MSM were enrolled at study sites in Lima, Iquitos, and Pucallpa, Peru; Seattle, WA, USA; New York City; NY, USA; and San Francisco, CA, USA. The study was the largest clinical trial to date to examine herpes suppression as a possible means of reducing the risk of HIV transmission.
In the final analysis of the study, which officially ended in November 2007, researchers found no evidence that twice-daily acyclovir prevents HIV infection among HSV-2 infected women and men who have sex with men. Specifically, there was a 3.9 percent HIV incidence rate (75 cases) among those participants who received acyclovir, while there was a 3.3 percent HIV incidence rate (64 cases) among those who received placebo. There was no statistically significant difference in HIV rates between those participants who received acyclovir and those who received placebo. Additionally, the study provided evidence that acyclovir reduces the occurrence of genital ulcers in HSV-2-infected individuals. The participants who received acyclovir experienced a 37 percent reduction in genital ulcer incidence.
Additional Information on the Study Results:
- NIAID Press Release
- Principal Investigator's Presentation at CROI 2008
- Lancet Article (June 21 2008)
Protocol Status: Concluded
Study Purpose: To determine the efficacy of twice daily acyclovir in preventing HIV infection among high risk HIV-negative, HSV-2 positive women and men who have sex with men (WSM, MSM)
Study Design: Phase III, multi-site, randomized, double-blind, placebo-controlled 2-arm trial of daily acyclovir
Study Population: High risk HIV-uninfected, HSV-2 positive WSM and MSM
Study Size: Total of 2820 to 3012 participants
Study Duration: Approximately 36 months total. Enrollment: 18 months. Follow-up: 18 months per participant
Treatment Regimen: Study participants will be randomized to one of two arms: Acyclovir 400 mg po bid Matching placebo po bid
Primary Objectives: To measure the efficacy of twice daily acyclovir suppressive therapy in preventing HIV infection among HSV-2 seropositive, HIV-negative WSM and MSM at high risk for HIV infection.
Secondary Objectives: To determine the effect of twice daily acyclovir suppressive therapy on reducing the occurrence and frequency of genital ulcers among HIV-negative HSV-2 seropositive persons. To assess adherence with twice daily acyclovir suppressive therapy among HIV-negative HSV-2 seropositive individuals.
HPTN 039 Publications
Celum C, Wald A, Hughes J, Sanchez J, Reid S, Delany-Moretlwe S, Cowan F, Casapia, M, Ortiz A, Fuchs J, Buchbinder S, Koblin B, Zwerski S, Rose S, Wang J, Corey L, HPTN 039 Protocol Team. 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. 2008, 371: 2109-19. PMCID:2650104
Reid SE, Dai JY, Wang J, Sichalwe BN, Akpomiemie G, Cowan FM, Delany-Moretlwe S, Baeten JM, Hughes JP, Wald A, Celum C. Pregnancy, Contraceptive Use, and HIV Acquisition in HPTN 039: Relevance for HIV Prevention Trials Among African Women. J Acquir Immune Defic Syndr. 2009, 53: 606-13 PMCID: 2845724
Fuchs J, Celum C, Wang J, Hughes J, Sanchez J, Cowan F, Reid S, Delany-Moretlwe S, Corey L, Wald A; HIV Prevention Trials Network 039 Protocol Team. Clinical and virologic efficacy of herpes simplex virus type 2 suppression by acyclovir in a multicontinent clinical trial. J Infect Dis. 2010, 201: 1164-8 PMCID: 2856478
Jacob ST, Baeten JM, Hughes JP, Peinado J, Wang J, Sanchez J, Reid SE, Delany-Moretlwe S, Cowan F, Fuchs JD, Koblin B, Griffith S, Wald A, Celum C. A Post-Trial Assessment of Factors Influencing Study Drug Adherence in a Randomized Biomedical HIV-1 Prevention Trial. AIDS Behav. 2010, 15: 897-904 PMCID: 3076532
Kim HN, Wang J, Hughes J, Coombs R, Sanchez J, Reid S, Delany-Moretlwe S, Cowan F, Fuchs J, Eshleman SH, Khaki L, McMahon MA, Siliciano RF, Wald A, Celum C. Effect of Acyclovir on HIV 1 Set Point among Herpes Simplex Virus Type 2 Seropositive Persons during Early HIV 1 Infection. J Infect Dis. 2010, 202: 734-8 PMCID: 2964878
Sánchez J, Sal Y Rosas VG, Hughes JP, Baeten JM, Fuchs J, Buchbinder SP, Koblin BA, Casapia M, Ortiz A, Celum C. Male circumcision and risk of HIV acquisition among men who have sex with men. AIDS. 2010, 25: 519-23 PMCID: 3120051
Watson-Jones D, Wald A, Celum C, Lingappa J, Weiss HA, Changalucha J, Baisley K, Tanton C, Hayes RJ, Marshak JO, Gladden RG, Koelle DM. Use of acyclovir for suppression of human immunodeficiency virus infection is not associated with genotypic evidence of herpes simplex virus type 2 resistance to acyclovir: analysis of specimens from three phase III trials. J Clin Microbiol. 2010, 48: 3496-503 PMCID: 2953087
Curlin ME, Cassis-Ghavami F, Magaret AS, Spies GA, Duerr A, Celum CL, Sanchez JL, Margolick JB, Detels R, McElrath MJ, Corey L. Serological immunity to adenovirus serotype 5 is not associated with risk of HIV infection: a case-control study. AIDS. 2011, 25: 153-8 PMCID: 3057418
Lu Y, Celum C, Wald A, Baeten JM, Cowan F, Delany-Moretlwe S, Reid SE, Hughes JP, Wilcox E, Corey L, Hendrix CW. Acyclovir achieves a lower concentration in African HIV-seronegative, herpes simplex virus 2-seropositive women than in non-African populations. Antimicrob Agents Chemother. 2012, 56: 2777-9 PMCID: 3346629