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

Primary Purpose

Herpes Simplex Type II

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
TDF
Placebo Vaginal Gel
Vaginal TFV Gel
Placebo Tablets
Sponsored by
University of Washington
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Herpes Simplex Type II

Eligibility Criteria

18 Years - 50 Years (Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Washington Virology Research Clinic

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

No Intervention

Experimental

Experimental

Placebo Comparator

Arm Label

Run-in Phase

Study Drug Phase: TDF

Study Drug Phase: Vaginal TFV Gel

Study Drug Phase: Double Placebo

Arm Description

Women will first participate in a run-in phase with twice daily swabbing.

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.

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.

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.

Outcomes

Primary Outcome Measures

HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo
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

Within-person Changes in Log-copy Numbers of HSV
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.
Genital Lesion Rate
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.
Asymptomatic Shedding (Shedding on Days Without Genital Lesions)
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.

Full Information

First Posted
September 14, 2011
Last Updated
February 14, 2023
Sponsor
University of Washington
Collaborators
CONRAD, Gilead Sciences
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1. Study Identification

Unique Protocol Identification Number
NCT01448616
Brief Title
Effect of Tenofovir on Genital Herpes Simplex Virus (HSV) Shedding
Official Title
Effect of Tenofovir on Genital HSV Shedding: a Randomized, Double-blind, Placebo-controlled Clinical Trial
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Completed
Study Start Date
February 2012 (undefined)
Primary Completion Date
June 2015 (Actual)
Study Completion Date
June 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Washington
Collaborators
CONRAD, Gilead Sciences

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Herpes Simplex Type II

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
73 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Run-in Phase
Arm Type
No Intervention
Arm Description
Women will first participate in a run-in phase with twice daily swabbing.
Arm Title
Study Drug Phase: TDF
Arm Type
Experimental
Arm Description
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.
Arm Title
Study Drug Phase: Vaginal TFV Gel
Arm Type
Experimental
Arm Description
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.
Arm Title
Study Drug Phase: Double Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
TDF
Other Intervention Name(s)
Tenofovir disoproxil fumarate (TDF) oral tablets
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo Vaginal Gel
Other Intervention Name(s)
Placebo gel
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Vaginal TFV Gel
Other Intervention Name(s)
Tenofovir 1% Vaginal Gel
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo Tablets
Other Intervention Name(s)
Oral placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo
Description
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.
Time Frame
Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase
Secondary Outcome Measure Information:
Title
Within-person Changes in Log-copy Numbers of HSV
Description
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.
Time Frame
Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase
Title
Genital Lesion Rate
Description
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.
Time Frame
Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase
Title
Asymptomatic Shedding (Shedding on Days Without Genital Lesions)
Description
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.
Time Frame
Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anna Wald, MD, MPH
Organizational Affiliation
University of Washington
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Washington Virology Research Clinic
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
26265463
Citation
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.
Results Reference
derived
PubMed Identifier
26044291
Citation
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.
Results Reference
derived

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

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