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

Study Overview
=================
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.

Official Title
-----------------
Effect of Tenofovir on Genital HSV Shedding: a Randomized, Double-blind, Placebo-controlled Clinical Trial

Conditions
-----------------
Herpes Simplex Type II

Intervention / Treatment
-----------------
* Drug: TDF
* Drug: Placebo Vaginal Gel
* Drug: Vaginal TFV Gel
* Drug: Placebo Tablets


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Run-in Phase<br>Women will first participate in a run-in phase with twice daily swabbing. | |
| Experimental: Study Drug Phase: TDF<br>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<br>* 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.<br>* Other names: Tenofovir disoproxil fumarate (TDF) oral tablets;Drug: Placebo Vaginal Gel<br>* 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.<br>* Other names: Placebo gel;|
| Experimental: Study Drug Phase: Vaginal TFV Gel<br>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<br>* 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.<br>* Other names: Tenofovir 1% Vaginal Gel;Drug: Placebo Tablets<br>* 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.<br>* Other names: Oral placebo;|
| Placebo Comparator: Study Drug Phase: Double Placebo<br>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<br>* 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.<br>* Other names: Placebo gel;Drug: Placebo Tablets<br>* 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.<br>* Other names: Oral placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase | 
| 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. | Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase | 
| 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. | Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase |