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

Primary Purpose

Genital Herpes, HIV Infection

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
valacyclovir
acyclovir
Sponsored by
University of Washington
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Genital Herpes focused on measuring Herpes Simplex Virus Type 2, Human Immunodeficiency Virus, Treatment Naive

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Washington Virology Research Clinic

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Standard-dose acyclovir

High-dose valacyclovir

Arm Description

acyclovir 400 mg orally twice daily for 12 weeks.

valacyclovir 1000 mg orally twice daily for 12 weeks.

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
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.
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.

Full Information

First Posted
September 7, 2007
Last Updated
May 4, 2018
Sponsor
University of Washington
Collaborators
GlaxoSmithKline
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1. Study Identification

Unique Protocol Identification Number
NCT00527618
Brief Title
Trial to Study the Effect of Dose of Herpes Simplex Virus-2 (HSV-2) Suppressive Therapy on HSV and HIV
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
December 2007 (undefined)
Primary Completion Date
March 2011 (Actual)
Study Completion Date
March 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Washington
Collaborators
GlaxoSmithKline

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Genital Herpes, HIV Infection
Keywords
Herpes Simplex Virus Type 2, Human Immunodeficiency Virus, Treatment Naive

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
28 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Standard-dose acyclovir
Arm Type
Active Comparator
Arm Description
acyclovir 400 mg orally twice daily for 12 weeks.
Arm Title
High-dose valacyclovir
Arm Type
Experimental
Arm Description
valacyclovir 1000 mg orally twice daily for 12 weeks.
Intervention Type
Drug
Intervention Name(s)
valacyclovir
Other Intervention Name(s)
Valtrex
Intervention Description
valacyclovir 1000 mg orally twice daily for 12 weeks.
Intervention Type
Drug
Intervention Name(s)
acyclovir
Other Intervention Name(s)
Zovirax
Intervention Description
acyclovir 400 mg orally twice daily for 12 weeks.
Primary Outcome Measure Information:
Title
The Quantity of HIV-1 RNA in Plasma While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir.
Description
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.
Time Frame
26 weeks (12 weeks per drug intervention)
Title
The Genital HSV Shedding Rate While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir.
Description
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.
Time Frame
The first four weeks of each intervention
Secondary Outcome Measure Information:
Title
The Effect of Valacyclovir 1 Gram Twice Daily Compared to Acyclovir 400 mg Twice Daily on the Percentage of Days With Genital Herpes Lesions.
Description
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.
Time Frame
26 weeks (12 weeks per drug intervention)
Title
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.
Description
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.
Time Frame
The first four weeks of each intervention
Title
Sub-Study: To Evaluate the Kinetics of Plasma HIV-1 Decline Over the First Three Days of High-dose Valacyclovir Administration.
Description
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.
Time Frame
72 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jared Baeten, MD, PhD
Organizational Affiliation
University of Washington
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Anna Wald, MD, MPH
Organizational Affiliation
University of Washington
Official's Role
Study Director
Facility Information:
Facility Name
University of Washington Virology Research Clinic
City
Seattle
State/Province
Washington
ZIP/Postal Code
98122
Country
United States

12. IPD Sharing Statement

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

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