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Herpes Simplex Virus Type 2 (HSV-2) Suppression to Prevent HIV Transmission

Primary Purpose

HIV Infection, Herpes Simplex, Genital, Sexually Transmitted Diseases

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Generic acyclovir
Placebo
Sponsored by
University of Washington
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for HIV Infection focused on measuring HIV infection, HIV transmission, genital herpes, sexual intercourse, sexual transmitted infection, acyclovir, HIV Seronegativity, Treatment Naive, HIV-discordant couples, HIV serodiagnosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Botswana-Harvard Partnership
  • Moi University - Indiana University
  • Kemri - Ucsf
  • University of Nairobi
  • Partners Study Thika Site
  • Projet San Francisco-Emory University
  • University of Cape Town
  • Perinatal HIV Research Unit, University of Witswatersrand
  • Reproductive Health and HIV Research Unit
  • Kilimanjaro Christian Medical College-Harvard University
  • Mulago Hospital - IDI
  • Zambia-Emory HIV Research Project
  • Zambia-Emory HIV Research Project

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Acyclovir

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Sequence-verified HIV-transmission from index to partner participant

Secondary Outcome Measures

Measure effect of viral load, gender and other factors on HIV transmission
Assess adherence to acyclovir suppressive therapy
Assess effect of twice daily acyclovir on the frequency of genital ulcers
Assess effect of twice daily acyclovir on plasma HIV viral load
Assess effects of twice daily acyclovir on the sexual behaviors
Assess host immunologic and virologic determinants of HIV transmission

Full Information

First Posted
September 13, 2005
Last Updated
October 9, 2018
Sponsor
University of Washington
Collaborators
Bill and Melinda Gates Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT00194519
Brief Title
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

2. Study Status

Record Verification Date
October 2018
Overall Recruitment Status
Completed
Study Start Date
November 2004 (undefined)
Primary Completion Date
November 2009 (Actual)
Study Completion Date
March 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Washington
Collaborators
Bill and Melinda Gates Foundation

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
3408 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Acyclovir
Arm Type
Active Comparator
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Generic acyclovir
Intervention Description
400 mg twice-daily oral
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
twice-daily oral
Primary Outcome Measure Information:
Title
Sequence-verified HIV-transmission from index to partner participant
Time Frame
March 2009
Secondary Outcome Measure Information:
Title
Measure effect of viral load, gender and other factors on HIV transmission
Time Frame
March 2009
Title
Assess adherence to acyclovir suppressive therapy
Time Frame
March 2009
Title
Assess effect of twice daily acyclovir on the frequency of genital ulcers
Time Frame
March 2009
Title
Assess effect of twice daily acyclovir on plasma HIV viral load
Time Frame
March 2009
Title
Assess effects of twice daily acyclovir on the sexual behaviors
Time Frame
March 2009
Title
Assess host immunologic and virologic determinants of HIV transmission
Time Frame
March 2009

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Connie Celum, MD, MPH
Organizational Affiliation
University of Washington
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jairam Lingappa, MD, PhD,
Organizational Affiliation
University of Washington
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Anna Wald, MD, MPH
Organizational Affiliation
University of Washington
Official's Role
Study Chair
Facility Information:
Facility Name
Botswana-Harvard Partnership
City
Gabarone
Country
Botswana
Facility Name
Moi University - Indiana University
City
Eldoret
Country
Kenya
Facility Name
Kemri - Ucsf
City
Kisumu
Country
Kenya
Facility Name
University of Nairobi
City
Nairobi
Country
Kenya
Facility Name
Partners Study Thika Site
City
Thika
Country
Kenya
Facility Name
Projet San Francisco-Emory University
City
Kigali
Country
Rwanda
Facility Name
University of Cape Town
City
Cape Town
Country
South Africa
Facility Name
Perinatal HIV Research Unit, University of Witswatersrand
City
Johannesburg
Country
South Africa
Facility Name
Reproductive Health and HIV Research Unit
City
Johannesburg
Country
South Africa
Facility Name
Kilimanjaro Christian Medical College-Harvard University
City
Moshi
Country
Tanzania
Facility Name
Mulago Hospital - IDI
City
Kampala
Country
Uganda
Facility Name
Zambia-Emory HIV Research Project
City
Lusaka
Country
Zambia
Facility Name
Zambia-Emory HIV Research Project
City
Ndola/Kitwe
Country
Zambia

12. IPD Sharing Statement

Citations:
PubMed Identifier
29108000
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. Erratum In: PLoS Pathog. 2019 Feb 11;15(2):e1007588.
Results Reference
derived
PubMed Identifier
23130818
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.
Results Reference
derived
PubMed Identifier
23061422
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.
Results Reference
derived
PubMed Identifier
22745608
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.
Results Reference
derived
PubMed Identifier
21406077
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.
Results Reference
derived
PubMed Identifier
21399681
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.
Results Reference
derived
PubMed Identifier
20153888
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.
Results Reference
derived
PubMed Identifier
20089951
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.
Results Reference
derived
PubMed Identifier
20042848
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.
Results Reference
derived
PubMed Identifier
20011596
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.
Results Reference
derived
PubMed Identifier
19404392
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.
Results Reference
derived

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Herpes Simplex Virus Type 2 (HSV-2) Suppression to Prevent HIV Transmission

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