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

NCT00194519 | Completed Phase 3 DMC

• 2 other identifiers: STUDY00000867Gates Foundation Grant #26469
• Study Type: interventional
• Target: 3,408
• Locations: 6 countries
• Sites: 10

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.

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

Outcome Measures

Primary Outcomes (1)

• Sequence-verified HIV-transmission from index to partner participant

  March 2009

Secondary Outcomes (6)

• Measure effect of viral load, gender and other factors on HIV transmission

  March 2009

• Assess adherence to acyclovir suppressive therapy

  March 2009

• Assess effect of twice daily acyclovir on the frequency of genital ulcers

  March 2009

• Assess effect of twice daily acyclovir on plasma HIV viral load

  March 2009

• Assess effects of twice daily acyclovir on the sexual behaviors

  March 2009

Study Arms (2)

Acyclovir

ACTIVE COMPARATOR

Drug: Generic acyclovir

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Generic acyclovir DRUG

400 mg twice-daily oral

Acyclovir

Placebo DRUG

twice-daily oral

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Of legal age to provide independent informed consent for research per local regulations and guidelines.
• 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.
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• University of Washington: lead
• Bill and Melinda Gates Foundation: collaborator

Study Sites (13)

Botswana-Harvard Partnership

Gabarone, Botswana

Location

Moi University - Indiana University

Eldoret, Kenya

Location

Kemri - Ucsf

Kisumu, Kenya

Location

University of Nairobi

Nairobi, Kenya

Location

Partners Study Thika Site

Thika, Kenya

Location

Projet San Francisco-Emory University

Kigali, Rwanda

Location

University of Cape Town

Cape Town, South Africa

Location

Perinatal HIV Research Unit, University of Witswatersrand

Johannesburg, South Africa

Location

Reproductive Health and HIV Research Unit

Johannesburg, South Africa

Location

Kilimanjaro Christian Medical College-Harvard University

Moshi, Tanzania

Location

Mulago Hospital - IDI

Kampala, Uganda

Location

Zambia-Emory HIV Research Project

Lusaka, Zambia

Location

Zambia-Emory HIV Research Project

Ndola/Kitwe, Zambia

Location

Related Publications (11)

• 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.

  PMID: 29108000 DERIVED

• 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.

  PMID: 23130818 DERIVED

• 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.

  PMID: 23061422 DERIVED

• 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.

  PMID: 22745608 DERIVED

• 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.

  PMID: 21406077 DERIVED

• 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.

  PMID: 21399681 DERIVED

• 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.

  PMID: 20153888 DERIVED

• 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.

  PMID: 20089951 DERIVED

• 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.

  PMID: 20042848 DERIVED

• 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.

  PMID: 20011596 DERIVED

• 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.

  PMID: 19404392 DERIVED

MeSH Terms

Conditions

HIV Infections; Herpes Genitalis; Sexually Transmitted Diseases; Coitus

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Herpes Simplex; Herpesviridae Infections; DNA Virus Infections; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Diseases, Male; Male Urogenital Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Sexual Behavior; Behavior

Study Officials

• Connie Celum, MD, MPH

  University of Washington

  PRINCIPAL INVESTIGATOR

• Jairam Lingappa, MD, PhD,

  University of Washington

  STUDY DIRECTOR

• Anna Wald, MD, MPH

  University of Washington

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof of Medicine & Global Health, Adjunct Prof of Epidemiology, School of Medicine: Global Health

Study Record Dates

• First Submitted: September 13, 2005
• First Posted: September 19, 2005
• Study Start: November 1, 2004
• Primary Completion: November 1, 2009
• Study Completion: March 1, 2010
• Last Updated: October 12, 2018

Record last verified: 2018-10

Locations

KE (4); ZA (2); TA (1); RW (1); BO (1); UG (1)