Clinical trial NCT00194519: Herpes Simplex Virus Type 2 (HSV-2) Suppression to Prevent HIV Transmission
Official title: Phase III Randomized Placebo-Controlled Trial of HSV-2 Suppression to Prevent HIV Transmission Among HIV-Discordant Couples
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infection
Herpes Simplex, Genital
Sexually Transmitted Diseases
Keywords: HIV infection
HIV transmission
genital herpes
sexual intercourse
sexual transmitted infection
acyclovir
HIV Seronegativity
Treatment Naive
HIV-discordant couples
HIV serodiagnosis
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: Bill and Melinda Gates Foundation
First posted: 2005-09-19
Enrollment: 3408
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The University of Washington has received funding to conduct a proof-of-concept trial to assess the impact of suppression of genital herpes on HIV infectiousness. This study (the Partners in Prevention Study) will enroll HIV discordant heterosexual couples in which the HIV-infected partner is co-infected with herpes simplex virus type 2 (HSV-2) to test the efficacy of twice daily (bid) acyclovir (400 mg) given to the HIV-infected partner to prevent transmission to his/her HIV negative partner(s). This randomized, double-blind, placebo-controlled proof-of-concept trial will provide evidence for the efficacy of HSV-2 suppression with daily acyclovir on HIV transmission among HIV-discordant couples among whom the HIV-positive partner is also HSV-2 seropositive with CD4 \>250. The researchers hypothesis is that, by decreasing the frequency and amount of genital HIV shedding, standard doses of daily acyclovir 400 mg bid will reduce the rate of HIV transmission by 50% in HIV-discordant couples among whom the HIV-infected partner is HSV-2 positive.

Under the study protocol version 4.1.1, 3000 HIV-discordant heterosexual couples in which the HIV-positive partner is HSV-2 positive and has a CD4 count \>250 will be recruited; participants will be followed for up to 2 years. A 4% per year HIV incidence in the placebo arm is assumed.

The first study site began enrolling participants on 17 November 2005. As of September 2006, 14 sites in Eastern and Southern Africa had participated in recruiting the 2300 HIV-discordant couples enrolled to date.

Detailed description: Herpes simplex virus type-2 (HSV-2) is the primary cause of genital ulcers and one of the most prevalent sexually transmitted diseases worldwide. Consistently, over 30 studies have found HSV-2 infection to be a risk factor for HIV acquisition with an overall relative risk of 2.1 in the studies that demonstrated HSV-2 preceded HIV infection. A recent study of HIV-discordant couples from Rakai, Uganda, has shown that at all levels of HIV viral load in the HIV-positive partner, HSV-2 infection in the susceptible partner increased the per-contact risk of acquisition of HIV five-fold, and GUD in the HIV-source partner increased the per-contact risk of HIV transmission five-fold. As strong as these epidemiological data are, an intervention trial is required to define the clinical and public health significance of these findings.

This trial will directly answer the extent to which HSV-2 infection increases infectiousness of HIV/HSV-2 co-infected persons and the relative reduction in HIV transmission among HSV-2 seropositive persons treated with daily suppressive antiviral therapy. Acyclovir has an acceptable safety profile for widespread STD treatment and is inexpensive, well-tolerated, and episodic and long-term suppressive therapy has not been associated with increased acyclovir resistance. Given high HSV-2 seroprevalence in HIV-infected persons (70-80%) and high HIV incidence in populations with high prevalence of HSV-2 infection worldwide, this approach could have great public health importance by providing a safe, acceptable, and cost-effective method to reduce HIV transmission among HIV-infected persons who are also HSV-2 seropositive.

Sites that have enrolled couples in this study include: Johannesburg (2 sites) and Cape Town, South Africa; Gaborone, Botswana; Kitwe/Ndola and Lusaka, Zambia; Nairobi, Kisumu, Eldoret and Thika, Kenya; Moshi, Tanzania; Kampala, Uganda; and Kigali, Rwanda.

Eligibility criteria: Inclusion Criteria:

Potential index (HIV-infected) participants must meet the following criteria (by self-report, unless otherwise indicated) in order to be eligible for inclusion in the study:

* Of legal age to provide independent informed consent for research per local regulations and guidelines.
* Able and willing to provide written informed consent to be screened for and to take part in the study. (Note: Index participants who are not willing to provide genital tract specimens for HIV viral load quantitation, but are willing to undergo all other study procedures, will be considered eligible for inclusion in the study.)
* Part of a heterosexual couple in which one partner meets the study eligibility criteria for index participants and the other partner meets the study eligibility criteria for partner participants. Couples are defined as partners who are sexually active and plan to remain in the relationship for at least one year. Each site will develop appropriate criteria for determining whether a couple is likely to remain in the relationship (i.e., married, duration of partnership, cohabitation, have children).
* Has had vaginal intercourse with the partner participant at least three times in the last three months.
* Plans to maintain his/her relationship with the partner participant for the next 24 months.
* HIV-infected based on positive EIA.
* HSV-2-seropositive based on the Focus HSV-2 EIA (performed by study staff) with an index ratio of at least 3.5 or if Focus EIA IN 1.1-3.4, confirmed by HSV-2 WB dot-blot performed at the UW.
* CD4 cell count (performed by study staff) of at least 250 cells/mm3.
* No history of any clinical AIDS-defining diagnoses.
* Able and willing to provide adequate locator information for study retention purposes, as defined by local standard operating procedures.

Potential partner (HIV-uninfected at enrollment) participants must meet the following criteria (by self-report, unless otherwise indicated) in order to be eligible for inclusion in the study:

* Of legal age to provide independent informed consent for research per local regulations and guidelines.
* Able and willing to provide written informed consent to be screened for and to take part in the study.
* Part of a heterosexual couple in which one partner meets the study eligibility criteria for index participants and the other partner meets the study eligibility criteria for partner participants.
* Has had vaginal intercourse with the study partner at least three times in the last three months.
* Plans to maintain his/her relationship with the index participant for the next 24 months.
* HIV-uninfected based on negative HIV EIA tests.
* Able and willing to provide adequate locator information for study retention purposes, as defined by local standard operating procedures.

Exclusion Criteria:

Potential index (HIV-infected) participants who meet any of the following criteria (by self-report, unless otherwise indicated) will be excluded from the study:

* Current use of combination antiretroviral therapy
* Known history of adverse reaction to acyclovir.
* Known history of persistent genital ulcers unresponsive to episodic acyclovir therapy.
* Known plans to re-locate or travel away from the study site for more than two consecutive months during the next 24 months.
* Pregnant, based on participant self-report or urine testing performed by study staff. (Note: Self-reported pregnancy is adequate for exclusion from the study. A documented negative test performed by study staff is required for inclusion.)

Potential partner participants who meet any of the following criteria (by self-report, unless otherwise indicated) will be excluded from the study:

* Has had sexual intercourse with a partner other than the index participant in the last two months.
* Known plans to re-locate or travel away from the study site for more than two consecutive months during the next 24 months.

Primary outcomes:
measure: Sequence-verified HIV-transmission from index to partner participant
timeFrame: March 2009
Secondary outcomes:
measure: Measure effect of viral load, gender and other factors on HIV transmission
timeFrame: March 2009
measure: Assess adherence to acyclovir suppressive therapy
timeFrame: March 2009
measure: Assess effect of twice daily acyclovir on the frequency of genital ulcers
timeFrame: March 2009
measure: Assess effect of twice daily acyclovir on plasma HIV viral load
timeFrame: March 2009
measure: Assess effects of twice daily acyclovir on the sexual behaviors
timeFrame: March 2009
measure: Assess host immunologic and virologic determinants of HIV transmission
timeFrame: March 2009
Other outcomes:
Locations:
city: Gabarone
country: Botswana
facility: Botswana-Harvard Partnership
city: Eldoret
country: Kenya
facility: Moi University - Indiana University
city: Kisumu
country: Kenya
facility: Kemri - Ucsf
city: Nairobi
country: Kenya
facility: University of Nairobi
city: Thika
country: Kenya
facility: Partners Study Thika Site
city: Kigali
country: Rwanda
facility: Projet San Francisco-Emory University
city: Cape Town
country: South Africa
facility: University of Cape Town
city: Johannesburg
country: South Africa
facility: Perinatal HIV Research Unit, University of Witswatersrand
city: Johannesburg
country: South Africa
facility: Reproductive Health and HIV Research Unit
city: Moshi
country: Tanzania
facility: Kilimanjaro Christian Medical College-Harvard University
city: Kampala
country: Uganda
facility: Mulago Hospital - IDI
city: Lusaka
country: Zambia
facility: Zambia-Emory HIV Research Project
city: Ndola/Kitwe
country: Zambia
facility: Zambia-Emory HIV Research Project
Study officials:
affiliation: University of Washington
name: Connie Celum, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington
name: Jairam Lingappa, MD, PhD,
role: STUDY_DIRECTOR
affiliation: University of Washington
name: Anna Wald, MD, MPH
role: STUDY_CHAIR
References:
citation: Mackelprang RD, Bamshad MJ, Chong JX, Hou X, Buckingham KJ, Shively K, deBruyn G, Mugo NR, Mullins JI, McElrath MJ, Baeten JM, Celum C, Emond MJ, Lingappa JR; Partners in Prevention HSV/HIV Transmission Study and the Partners PrEP Study Teams. Whole genome sequencing of extreme phenotypes identifies variants in CD101 and UBE2V1 associated with increased risk of sexually acquired HIV-1. PLoS Pathog. 2017 Nov 6;13(11):e1006703. doi: 10.1371/journal.ppat.1006703. eCollection 2017 Nov.
citation: de Bruyn G, Magaret A, Baeten JM, Lingappa JR, Ndase P, Celum C, Wald A; Partners in Prevention HSV/HIV Transmission Study Team. Mortality in members of HIV-1 serodiscordant couples in Africa and implications for antiretroviral therapy initiation: results of analyses from a multicenter randomized trial. BMC Infect Dis. 2012 Oct 30;12:277. doi: 10.1186/1471-2334-12-277.
citation: Lingappa JR, Thomas KK, Hughes JP, Baeten JM, Wald A, Farquhar C, de Bruyn G, Fife KH, Campbell MS, Kapiga S, Mullins JI, Celum C; Partners in Prevention HSV/HIV Transmission Study Team. Partner characteristics predicting HIV-1 set point in sexually acquired HIV-1 among African seroconverters. AIDS Res Hum Retroviruses. 2013 Jan;29(1):164-71. doi: 10.1089/AID.2012.0206.
citation: Cohen CR, Lingappa JR, Baeten JM, Ngayo MO, Spiegel CA, Hong T, Donnell D, Celum C, Kapiga S, Delany S, Bukusi EA. Bacterial vaginosis associated with increased risk of female-to-male HIV-1 transmission: a prospective cohort analysis among African couples. PLoS Med. 2012;9(6):e1001251. doi: 10.1371/journal.pmed.1001251. Epub 2012 Jun 26.
citation: Mujugira A, Magaret AS, Baeten JM, Celum C, Lingappa J. Risk Factors for HSV-2 Infection among Sexual Partners of HSV-2/HIV-1 Co-Infected Persons. BMC Res Notes. 2011 Mar 15;4:64. doi: 10.1186/1756-0500-4-64.
citation: Campbell MS, Mullins JI, Hughes JP, Celum C, Wong KG, Raugi DN, Sorensen S, Stoddard JN, Zhao H, Deng W, Kahle E, Panteleeff D, Baeten JM, McCutchan FE, Albert J, Leitner T, Wald A, Corey L, Lingappa JR; Partners in Prevention HSV/HIV Transmission Study Team. Viral linkage in HIV-1 seroconverters and their partners in an HIV-1 prevention clinical trial. PLoS One. 2011 Mar 2;6(3):e16986. doi: 10.1371/journal.pone.0016986.
citation: Lingappa JR, Baeten JM, Wald A, Hughes JP, Thomas KK, Mujugira A, Mugo N, Bukusi EA, Cohen CR, Katabira E, Ronald A, Kiarie J, Farquhar C, Stewart GJ, Makhema J, Essex M, Were E, Fife KH, de Bruyn G, Gray GE, McIntyre JA, Manongi R, Kapiga S, Coetzee D, Allen S, Inambao M, Kayitenkore K, Karita E, Kanweka W, Delany S, Rees H, Vwalika B, Magaret AS, Wang RS, Kidoguchi L, Barnes L, Ridzon R, Corey L, Celum C; Partners in Prevention HSV/HIV Transmission Study Team. Daily acyclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial. Lancet. 2010 Mar 6;375(9717):824-33. doi: 10.1016/S0140-6736(09)62038-9. Epub 2010 Feb 12.
citation: Celum C, Wald A, Lingappa JR, Magaret AS, Wang RS, Mugo N, Mujugira A, Baeten JM, Mullins JI, Hughes JP, Bukusi EA, Cohen CR, Katabira E, Ronald A, Kiarie J, Farquhar C, Stewart GJ, Makhema J, Essex M, Were E, Fife KH, de Bruyn G, Gray GE, McIntyre JA, Manongi R, Kapiga S, Coetzee D, Allen S, Inambao M, Kayitenkore K, Karita E, Kanweka W, Delany S, Rees H, Vwalika B, Stevens W, Campbell MS, Thomas KK, Coombs RW, Morrow R, Whittington WL, McElrath MJ, Barnes L, Ridzon R, Corey L; Partners in Prevention HSV/HIV Transmission Study Team. Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. N Engl J Med. 2010 Feb 4;362(5):427-39. doi: 10.1056/NEJMoa0904849. Epub 2010 Jan 20.
citation: Baeten JM, Donnell D, Kapiga SH, Ronald A, John-Stewart G, Inambao M, Manongi R, Vwalika B, Celum C; Partners in Prevention HSV/HIV Transmission Study Team. Male circumcision and risk of male-to-female HIV-1 transmission: a multinational prospective study in African HIV-1-serodiscordant couples. AIDS. 2010 Mar 13;24(5):737-44. doi: 10.1097/QAD.0b013e32833616e0.
citation: Guthrie BL, Kiarie JN, Morrison S, John-Stewart GC, Kinuthia J, Whittington WL, Farquhar C. Sexually transmitted infections among HIV-1-discordant couples. PLoS One. 2009 Dec 14;4(12):e8276. doi: 10.1371/journal.pone.0008276.
citation: Lingappa JR, Kahle E, Mugo N, Mujugira A, Magaret A, Baeten J, Bukusi EA, Cohen CR, Katabira E, Ronald A, Kiarie J, Farquhar C, Stewart GJ, Makhema J, Essex M, Were E, Fife K, Debruyn G, Gray G, McIntyre J, Manongi R, Kapiga S, Coetzee D, Allen S, Inambao M, Kayitenkore K, Karita E, Kanweka W, Delany S, Rees H, Vwalika B, Coombs RW, Morrow R, Whittington W, Corey L, Wald A, Celum C; Partners HSV-2/HIV-1 Transmission Study Team. Characteristics of HIV-1 discordant couples enrolled in a trial of HSV-2 suppression to reduce HIV-1 transmission: the partners study. PLoS One. 2009;4(4):e5272. doi: 10.1371/journal.pone.0005272. Epub 2009 Apr 30.