Effect of Tenofovir on Genital Herpes Simplex Virus (HSV) Shedding

Study Description

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Brief Summary:

The investigators propose a randomized, double blind, placebo-controlled, cross-over trial to evaluate the effect of oral and topical (vaginal gel) tenofovir on genital herpes simplex virus (HSV) shedding among herpes simplex virus type-2 (HSV-2) seropositive, human immunodeficiency virus (HIV) seronegative women. The investigators hypothesize that tenofovir will reduce genital HSV shedding compared to placebo.

Condition or disease	Intervention/treatment	Phase
Herpes Simplex Type II	Drug: TDF; Drug: Placebo Vaginal Gel; Drug: Vaginal TFV Gel; Drug: Placebo Tablets	Phase 4

Detailed Description:

The investigators propose a randomized, double-blind, placebo-controlled, cross-over study of 55 adult, healthy women who are HSV-2 seropositive and HIV-1 seronegative. Women will first participate in a run-in phase with twice daily swabbing. Following 4 weeks of swabbing, participants will be randomized 2:2:1 to one of three groups: 1) oral tenofovir and placebo gel, 2) oral placebo and tenofovir gel, or 3) oral placebo and placebo gel. Participants will begin treatment and swab the genital region twice daily for 5 more weeks. Study drug will be administered daily.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	73 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	Triple (Participant, Care Provider, Investigator)
Primary Purpose:	Treatment
Official Title:	Effect of Tenofovir on Genital HSV Shedding: a Randomized, Double-blind, Placebo-controlled Clinical Trial
Study Start Date :	February 2012
Actual Primary Completion Date :	June 2015
Actual Study Completion Date :	June 2015

Arms and Interventions

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Arm	Intervention/treatment
No Intervention: Run-in Phase; Women will first participate in a run-in phase with twice daily swabbing.
Experimental: Study Drug Phase: TDF; Participants will take tenofovir disoproxil fumarate (TDF) tablets and apply a placebo vaginal gel. Participants will begin treatment and swab the genital region twice daily for 5 more weeks. Study drugs will be administered once daily.	Drug: TDF; Oral tenofovir will be administered as tablets. TDF (Viread®) tablets contain 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil. Study participants are instructed to take the one tablet, by mouth, once each day without regard to meals.; Other Name: Tenofovir disoproxil fumarate (TDF) oral tablets Drug: Placebo Vaginal Gel; Study participants are instructed to insert one dose (the entire contents of one applicator) of product into the vagina once each day. They are instructed to insert their gel as close to the same time each day as possible. The placebo gel (known as the 'universal' placebo gel) is formulated to minimize any possible effects — negative or positive — on study endpoints.; Other Name: Placebo gel
Experimental: Study Drug Phase: Vaginal TFV Gel; Participants will take oral placebo tablets and apply a tenofovir 1% (TFV) vaginal gel. Participants will begin treatment and swab the genital region twice daily for 5 more weeks. Study drugs will be administered once daily.	Drug: Vaginal TFV Gel; Tenofovir 1% gel (w/w) is a gel formulation of tenofovir. Study participants are instructed to insert one dose (the entire contents of one applicator) of product into the vagina once each day. They are instructed to insert their gel as close to the same time each day as possible.; Other Name: Tenofovir 1% Vaginal Gel Drug: Placebo Tablets; TDF placebo tablets are film-coated and contain denatonium benzoate, a bittering agent, in addition to other inactive ingredients. Study participants are instructed to take the one tablet, by mouth, once each day without regard to meals.; Other Name: Oral placebo
Placebo Comparator: Study Drug Phase: Double Placebo; Participants will take oral placebo tablets and apply a placebo vaginal gel. Participants will begin treatment and swab the genital region twice daily for 5 more weeks. Study drugs will be administered once daily.	Drug: Placebo Vaginal Gel; Study participants are instructed to insert one dose (the entire contents of one applicator) of product into the vagina once each day. They are instructed to insert their gel as close to the same time each day as possible. The placebo gel (known as the 'universal' placebo gel) is formulated to minimize any possible effects — negative or positive — on study endpoints.; Other Name: Placebo gel Drug: Placebo Tablets; TDF placebo tablets are film-coated and contain denatonium benzoate, a bittering agent, in addition to other inactive ingredients. Study participants are instructed to take the one tablet, by mouth, once each day without regard to meals.; Other Name: Oral placebo

Outcome Measures

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Primary Outcome Measures :

1. HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo [ Time Frame: Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase ]
   The within-person changes in rate of HSV shedding during study drug administration (treatment phase) compared with the rate of HSV shedding during lead-in observation phase in the same participants. We evaluated only weeks 2-5 of HSV shedding during the treatment phase in comparison with the 4 weeks of the lead-in phase. We excluded the first week of samples from the treatment phase in order to allow for physiologic run-in of the treatment. This is analyzed separately for each treatment arm and not compared between arms.

Secondary Outcome Measures :

1. Within-person Changes in Log-copy Numbers of HSV [ Time Frame: Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase ]

   The within-person changes in mean log-copy numbers of HSV shed during treatment phase (oral TDF, vaginal TFV, or double placebo) compared with the lead-in (observation) phase in the same participants. Each treatment arm is analyzed separately without comparison between arms.

   We evaluated only weeks 2-5 of HSV shedding during the treatment phase in comparison with the 4 weeks of the lead-in phase. We excluded the first week of samples from the treatment phase in order to allow for physiologic run-in of the treatment.

2. Genital Lesion Rate [ Time Frame: Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase ]

   The within person change in proportion of days with lesions between the lead-in (observational) and study drug (treatment) phase for each arm separately. No between arm comparisons were performed. We include intent to treat with all randomized participants as well as per protocol (persons receiving study drug for at least 30 days with 90% or better reported compliance per returned product counts).

   We evaluated only weeks 2-5 of HSV shedding during the treatment phase in comparison with the 4 weeks of the lead-in phase. We excluded the first week of samples from the treatment phase in order to allow for physiologic run-in of the treatment.

3. Asymptomatic Shedding (Shedding on Days Without Genital Lesions) [ Time Frame: Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase ]

   Within person changes in shedding on days without lesions between the lead-in (observational) phase and the study drug (treatment) phase. Each arm is evaluated separately and no inter arm comparisons are made.

   We evaluated only weeks 2-5 of HSV shedding during the treatment phase in comparison with the 4 weeks of the lead-in phase. We excluded the first week of samples from the treatment phase in order to allow for physiologic run-in of the treatment.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 50 Years (Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Women age 18-50
• HSV-2 seropositive by the University of Washington (UW) Western blot
• History of recurrent genital herpes, with more than 4 recurrences but less than 10 in the last year or, if currently on suppressive therapy, with more than 4 recurrences but less than 10 in the year prior to starting suppressive therapy
• HIV negative
• General good health
• Willing to not use antiviral therapy (other than the study drug) for the duration of the study
• Willing to obtain a swab from genital secretions twice daily for the duration of the study
• Willing to use effective birth control
• Able to provide written informed consent at screening and enrollment

Exclusion Criteria:

• HIV positive or at high risk for HIV acquisition (intravenous drug user or HIV+ sex partner)
• Hepatitis B (HepB) antigen (Ag) positive, or at high risk for HepB acquisition and not vaccinated
• Have a history of adverse reaction to tenofovir and/or adefovir
• Immunosuppressive medications, except for intranasal or topical (not high potency) steroids.
• Any kidney disease, or renal insufficiency, defined as serum creatinine >1.5 mg/dl. Participants with a prior history of a single episode of pyelonephritis will be eligible.
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times upper limit of normal
• Pregnancy, as confirmed by a urine pregnancy test, planning to become pregnant during the course of the trial, or breast-feeding.
• Serious medical conditions or active infections
• Any other conditions that in the judgment of the investigator would preclude successful completion of the clinical trial.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Washington
University of Washington Virology Research Clinic
Seattle, Washington, United States, 98104

Sponsors and Collaborators

University of Washington

CONRAD

Gilead Sciences

Investigators

Principal Investigator:	Anna Wald, MD, MPH	University of Washington

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Johnston C, Harrington R, Jain R, Schiffer J, Kiem HP, Woolfrey A. Safety and Efficacy of Combination Antiretroviral Therapy in Human Immunodeficiency Virus-Infected Adults Undergoing Autologous or Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies. Biol Blood Marrow Transplant. 2016 Jan;22(1):149-56. doi: 10.1016/j.bbmt.2015.08.006. Epub 2015 Aug 8.

Bender Ignacio RA, Perti T, Magaret AS, Rajagopal S, Stevens CE, Huang ML, Selke S, Johnston C, Marrazzo J, Wald A. Oral and Vaginal Tenofovir for Genital Herpes Simplex Virus Type 2 Shedding in Immunocompetent Women: A Double-Blind, Randomized, Cross-over Trial. J Infect Dis. 2015 Dec 15;212(12):1949-56. doi: 10.1093/infdis/jiv317. Epub 2015 Jun 4.

Responsible Party:	Anna Wald, Professor, University of Washington
ClinicalTrials.gov Identifier:	NCT01448616 History of Changes
Other Study ID Numbers:	41250-J
First Posted:	October 7, 2011
Results First Posted:	January 12, 2016
Last Update Posted:	January 12, 2016
Last Verified:	December 2015

Additional relevant MeSH terms:

Herpes Simplex; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Skin Diseases, Viral; Skin Diseases, Infectious; Skin Diseases; Tenofovir	Antiviral Agents; Anti-Infective Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Retroviral Agents; Anti-HIV Agents