Herpes Simplex Type II
Conditions
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.
Interventions
DRUGTDF
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.
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.
DRUGVaginal 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.
DRUGPlacebo 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.
Sponsors
CONRAD
Gilead Sciences
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo | 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
| Measure | Time frame | Description |
|---|---|---|
| Within-person Changes in Log-copy Numbers of HSV | 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. |
| Genital Lesion Rate | 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. |
| Asymptomatic Shedding (Shedding on Days Without Genital Lesions) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Oral TDF + Vaginal Placebo Gel Participants randomized to receive 300mg Tenofovir Disaproxil Fumarate (TDF) 1 tab daily + the universal placebo vaginal gel (4ml) to be used daily. | 24 |
| Oral Placebo + Vaginal TFV Gel Participants randomized to receive matching oral placebo tab once daily + tenofovir (TFV) 1% vaginal gel (40mg in 4ml) to be used daily | 27 |
| Oral Placebo + Vaginal Placebo Gel Participants received matching oral tab and placebo gel both to be used daily | 13 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Lead-In (Observational Phase) | Collected <90% of required swabs | 6 | 0 | 0 | 0 |
| Lead-In (Observational Phase) | Collected no genital swabs | 3 | 0 | 0 | 0 |
| Study Drug (Treatment Phase) | Adverse Event | 0 | 1 | 1 | 0 |
| Study Drug (Treatment Phase) | Never initiated study drug | 0 | 0 | 1 | 2 |
| Study Drug (Treatment Phase) | Withdrawal by Subject | 0 | 1 | 2 | 2 |
Baseline characteristics
| Characteristic | Oral Placebo + Vaginal TFV Gel | Oral Placebo + Vaginal Placebo Gel | Oral TDF + Vaginal Placebo Gel | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 13 Participants | 24 Participants | 64 Participants |
| Age, Continuous | 36.7 years | 41.0 years | 39.1 years | 37.3 years |
| Region of Enrollment United States | 27 participants | 13 participants | 24 participants | 64 participants |
| Sex: Female, Male Female | 27 Participants | 13 Participants | 24 Participants | 64 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 73 | 12 / 24 | 11 / 27 | 3 / 13 |
| serious Total, serious adverse events | 0 / 73 | 0 / 24 | 0 / 27 | 0 / 13 |
Outcome results
Primary
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.
Time frame: Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase
Population: This is the intent-to-treat population (all randomized participants returning at least 1 swab in each phase of study)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oral TDF + Vaginal Placebo Gel | HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo | Lead-in Phase | 22.9 percentage of swabs positive (%) |
| Oral TDF + Vaginal Placebo Gel | HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo | Treatment Phase | 19.5 percentage of swabs positive (%) |
| Oral Placebo + Vaginal TFV Gel | HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo | Lead-in Phase | 13.8 percentage of swabs positive (%) |
| Oral Placebo + Vaginal TFV Gel | HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo | Treatment Phase | 12.0 percentage of swabs positive (%) |
| Oral Placebo + Vaginal Placebo | HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo | Treatment Phase | 20.4 percentage of swabs positive (%) |
| Oral Placebo + Vaginal Placebo | HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo | Lead-in Phase | 21.3 percentage of swabs positive (%) |
Comparison: For intent to treat analysis, difference between lead-in and treatment phase (within arm comparison)p-value: 0.08695% CI: [0.71, 1.01]Poisson GLME
Comparison: For intent to treat analysis, difference between lead-in and treatment phase (within arm comparison)p-value: 0.5495% CI: [0.75, 1.16]Poisson GLME
Comparison: For intent to treat analysis, difference between lead-in and treatment phase (within arm comparison)p-value: 0.4795% CI: [0.67, 1.22]Poisson GLME
Secondary
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.
Time frame: Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase
Population: All randomized participants are included in ITT analysis. Per protocol analysis includes persons receiving 30 or more days of study drug with \>90% adherence as documented by returned product counts.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oral TDF + Vaginal Placebo Gel | Asymptomatic Shedding (Shedding on Days Without Genital Lesions) | Lead-in Phase | 17.5 % days with asymptomatic shedding |
| Oral TDF + Vaginal Placebo Gel | Asymptomatic Shedding (Shedding on Days Without Genital Lesions) | Treatment Phase | 13.7 % days with asymptomatic shedding |
| Oral Placebo + Vaginal TFV Gel | Asymptomatic Shedding (Shedding on Days Without Genital Lesions) | Lead-in Phase | 7.6 % days with asymptomatic shedding |
| Oral Placebo + Vaginal TFV Gel | Asymptomatic Shedding (Shedding on Days Without Genital Lesions) | Treatment Phase | 8.2 % days with asymptomatic shedding |
| Oral Placebo + Vaginal Placebo | Asymptomatic Shedding (Shedding on Days Without Genital Lesions) | Lead-in Phase | 14.4 % days with asymptomatic shedding |
| Oral Placebo + Vaginal Placebo | Asymptomatic Shedding (Shedding on Days Without Genital Lesions) | Treatment Phase | 12.1 % days with asymptomatic shedding |
Comparison: Intent to Treatp-value: 0.0195% CI: [0.59, 0.92]Poisson GLME
p-value: 0.0995% CI: [0.9, 1.76]Poisson GLM
Comparison: Intent to treat analysisp-value: 0.4795% CI: [0.67, 1.22]Poisson GLM
Secondary
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.
Time frame: Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Oral TDF + Vaginal Placebo Gel | Genital Lesion Rate | Lead-in Phase | 11.8 percentage of days with lesions (%) |
| Oral TDF + Vaginal Placebo Gel | Genital Lesion Rate | Treatment Phase | 11.6 percentage of days with lesions (%) |
| Oral Placebo + Vaginal TFV Gel | Genital Lesion Rate | Lead-in Phase | 8.7 percentage of days with lesions (%) |
| Oral Placebo + Vaginal TFV Gel | Genital Lesion Rate | Treatment Phase | 7.1 percentage of days with lesions (%) |
| Oral Placebo + Vaginal Placebo | Genital Lesion Rate | Lead-in Phase | 13.6 percentage of days with lesions (%) |
| Oral Placebo + Vaginal Placebo | Genital Lesion Rate | Treatment Phase | 14.7 percentage of days with lesions (%) |
Comparison: Intent to treat analysisp-value: 0.995% CI: [0.7, 1.37]Poisson GLME
Comparison: Intent to treatp-value: 0.2595% CI: [0.54, 1.18]Poisson GLM
p-value: 0.8295% CI: [0.57, 1.57]Poisson GLM
Secondary
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.
Time frame: Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase
Population: Analysis is within person changes such that the observational group contributed to analyses of those persons in each treatment randomization group
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Oral TDF + Vaginal Placebo Gel | Within-person Changes in Log-copy Numbers of HSV | Treatment Phase | 4.11 log-copy number of HSV DNA shed |
| Oral TDF + Vaginal Placebo Gel | Within-person Changes in Log-copy Numbers of HSV | Lead-in Phase | 4.02 log-copy number of HSV DNA shed |
| Oral Placebo + Vaginal TFV Gel | Within-person Changes in Log-copy Numbers of HSV | Lead-in Phase | 4.47 log-copy number of HSV DNA shed |
| Oral Placebo + Vaginal TFV Gel | Within-person Changes in Log-copy Numbers of HSV | Treatment Phase | 4.40 log-copy number of HSV DNA shed |
| Oral Placebo + Vaginal Placebo | Within-person Changes in Log-copy Numbers of HSV | Lead-in Phase | 3.71 log-copy number of HSV DNA shed |
| Oral Placebo + Vaginal Placebo | Within-person Changes in Log-copy Numbers of HSV | Treatment Phase | 4.22 log-copy number of HSV DNA shed |
Comparison: Intent to treat analysisp-value: 0.1895% CI: [-0.4, 0.07]Linear Mixed Effects Model
Comparison: Intent to treat analysisp-value: 0.00895% CI: [-0.86, -0.13]Linear Mixed Effects Model
Comparison: Intent to treat analysisp-value: 0.4595% CI: [-0.27, 0.6]Linear Mixed Effects Model