Trial to Study the Effect of Dose of Herpes Simplex Virus-2 (HSV-2) Suppressive Therapy on HSV and HIV

Study Overview
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Brief Summary
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To compare the effect of high-dose valacyclovir (1 gram orally twice daily) versus standard-dose acyclovir (400 mg orally twice daily) on the frequency of genital HSV reactivation and on plasma HIV-1 levels among HSV-2/HIV-1 co-infected individuals. The investigators hypothesize that high-dose valacyclovir will result in greater reduction in plasma HIV-1 and genital HSV reactivation.

Detailed Description
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We propose to conduct a randomized, open-label, cross-over study of 38 individuals who are HIV-1 seropositive and HSV-2 seropositive. Both men and women will be recruited for the study. Participants must not be on antiretroviral therapy and must not be planning to initiate antiretroviral therapy during the anticipated study period. Participants will be randomized 1:1 to receive acyclovir 400 mg twice daily or valacyclovir 1000 mg twice daily. After 12 weeks on the initial treatment, each participant will be crossed over to the alternative treatment arm for 12 weeks. The treatment periods will be separated by a 2-week washout period. During the first four weeks of each treatment period (i.e. weeks 1-4 and weeks 15-18), participants will provide self-collected genital swabs daily for HSV DNA quantification. Each week during the entire study period plasma samples will be collected from participants for HIV-1 RNA quantification. Open-label acyclovir and valacyclovir will be used for this trial, as the primary outcome measures (genital HSV and plasma HIV-1) are unlikely to be influenced by knowledge of treatment assignment. However, laboratory staff performing plasma HIV-1 and genital HSV measurements will not be aware of treatment assignment. Optional Sub-Study A: Sub-study A will be offered to study participants. The purpose of sub-study A is to measure the effect of valacyclovir twice daily on plasma HIV-1 replication.

Official Title
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A Randomized, Open-label, Crossover Trial of the Effect of Dosing of Daily HSV-2 Suppressive Therapy on HSV Reactivation and Plasma HIV-1 Levels Among HIV-1/ HSV-2 Co-infected Persons

Conditions
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Genital Herpes, HIV Infection

Intervention / Treatment
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* Drug: valacyclovir
* Drug: acyclovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older Documented HIV-1 seropositive Not on HIV-1 antiretroviral therapy nor planning to initiate antiretroviral therapy during the study period Detectable HIV-1 plasma viral load HSV-2 seropositive as determined by western blot Not intending to move out of the area for the duration of study participation Willing and able to provide independent written informed consent Willing and able to undergo clinical evaluations Willing and able to take study drug as directed Willing and able to adhere to follow-up schedule Exclusion Criteria: Known history of adverse reaction to acyclovir, valacyclovir, or famciclovir Planned open label use of acyclovir, valacyclovir, or famciclovir History of evidence of CMV disease Known medical history of seizures Known renal insufficiency, defined as serum creatinine greater than 1.5 mg/dl AST or ALT greater than 3 times upper limit of normal Hematocrit less than 30 % Neutropenia, defined as absolute neutrophil count less than 1000 Thrombocytopenia, defined as platelet count less than 75,000 History of thrombotic microangiopathy For women, pregnancy as confirmed by a urine pregnancy test Any other condition which, in the opinion of the principal investigator, may compromise the ability to follow study procedures and complete the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard-dose acyclovir<br>acyclovir 400 mg orally twice daily for 12 weeks. | Drug: acyclovir<br>* acyclovir 400 mg orally twice daily for 12 weeks.<br>* Other names: Zovirax;|
| Experimental: High-dose valacyclovir<br>valacyclovir 1000 mg orally twice daily for 12 weeks. | Drug: valacyclovir<br>* valacyclovir 1000 mg orally twice daily for 12 weeks.<br>* Other names: Valtrex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Quantity of HIV-1 RNA in Plasma While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir. | Weekly measurements of plasma HIV-1 RNA on each drug were compared. The primary analysis was of the average difference in plasma HIV-1 RNA on valacyclovir and acyclovir as determined by a linear mixed model. The median of the average per-participant plasma HIV-1 RNA levels on valacyclovir and valacyclovir is also listed. | 26 weeks (12 weeks per drug intervention) | 
| The Genital HSV Shedding Rate While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir. | HSV DNA quantitated from daily self-collected genital swabs for the first four weeks of each drug intervention. The shedding rate was determined by the combined number of swabs with HSV detected divided by the combined number of swabs collected from participants, multiplied by 100. | The first four weeks of each intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Effect of Valacyclovir 1 Gram Twice Daily Compared to Acyclovir 400 mg Twice Daily on the Percentage of Days With Genital Herpes Lesions. | The percentage of days with genital herpes lesions was determined by the combined diary days in which genital lesions were recorded divided by the combined number of diary days for participants in the first four weeks of each drug intervention, multiplied by 100. | 26 weeks (12 weeks per drug intervention) | 
| The Effect of Valacyclovir 1 g Twice Daily Compared With Acyclovir 400 mg Twice Daily on the Quantity of Genital HSV Detected During Shedding Episodes. | HSV DNA was quantitated from daily self-collected genital swabs for the four weeks of each drug intervention. The quantity of genital HSV DNA present, when HSV DNA was detected, was compared. | The first four weeks of each intervention | 
| Sub-Study: To Evaluate the Kinetics of Plasma HIV-1 Decline Over the First Three Days of High-dose Valacyclovir Administration. | Plasma HIV-1 RNA was measured one day prior to, at initiation, and at 6, 24, 48, and 72 hours after initiating valacyclovir. Measurements at 24, 48, and 72 hours were used to determine the rate of HIV-1 RNA decline. | 72 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Herpes Simplex Virus Type 2, Human Immunodeficiency Virus, Treatment Naive