Acyclovir to Treat Patients Co-infected With HIV and Herpes Viruses in Uganda

August 28, 2012 updated by: Steven Reynolds, National Institute of Allergy and Infectious Diseases (NIAID)

A Randomized, Double-Blind, Placebo-Controlled Trial of Acyclovir Prophylaxis Versus Placebo Among HIV-1/HSV-2 Co-Infected Individuals in Uganda

This study will determine whether acyclovir, a medicine used to treat herpes simplex virus 2 (HSV-2), can slow down the progression (worsening) of HIV disease in people with both HIV and HSV-2 infections. HSV-2 increases the amount of HIV virus in the blood of infected people and may make HIV progress faster. The study will evaluate:

"Whether people who take acyclovir can avoid antiretroviral treatment until later in their lives

"Whether people who take acyclovir get fewer genital ulcers

"How well people are able to take acyclovir and any side effects they experience from it

"Differences in the amount of HIV virus in the blood of patients who are and are not taking acyclovir, and how HIV/AIDS is different in these patients.

People 18 years of age and older living in the Rakai district of Uganda who are infected with both HIV (early stage disease) and HSV-2 may be eligible for this study. Participants are randomly assigned to take the study drug, acyclovir, or a placebo (look-alike pill with no active ingredient) daily for 2 years. During this time, they visit the clinic once a month for a routine physical examination. Patients who develop genital ulcers or complications of HIV are treated for the problem, and patients whose HIV disease progresses, requiring them to begin antiretroviral therapy, are treated accordingly.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Interventions that slow HIV-1 disease progression among persons with CD4+ counts above 250 cells/microliter could postpone the need for antiretroviral therapy (ART) and prolong life-expectancy for HIV-infected persons. Herpes simplex virus type 2 (HSV-2) has been shown to up-regulate HIV-1 replication at the cellular level. (1) This finding has been supported by clinical evidence that individuals who are HSV-2 seropositive at the time of HIV-1 seroconversion had higher HIV viral loads at 5 and 15 months post-seroconversion. (2) Earlier studies during the era of zidovudine (Retrovir) monotherapy showed a survival advantage when acyclovir (ACV, Zovirax) was added to the treatment of patients with HIV. (3) Acyclovir prophylaxis has been shown to decrease herpes simplex virus infections and varicella-zoster virus infections among HIV infected patients in a meta-analysis of randomized trials from North America and Europe. This analysis also found a reduced risk of mortality among patients treated with acyclovir. The potential of acyclovir to slow HIV-1 disease progression has not been assessed in a randomized trial in Africa where high rates of HSV-2 infection have been observed among HIV-1 infected individuals. This study proposes to assess the benefits of acyclovir prophylaxis among HIV-1 infected individuals dually infected with HSV-2 who are not on ART through a randomized double-blind placebo controlled trial.

Study Type

Interventional

Enrollment (Actual)

440

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Uganda
    • Rakai District
      • Kalisizo, Rakai District, Uganda
        • Rakai Health Sciences Program, Uganda Virus Research Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • INCLUSION CRITERIA:

    1. Documentation of HIV-1 infection, by either two positive ELISAs or two discrepant ELISAs with a confirmatory positive Western Blot
    2. Documentation of prior HSV-2 infection by Focus Kalon ELISA
    3. Absolute CD4+ T-cell count of greater than or equal to 300 and less than or equal to 400 cells/microliter within 30 days prior to randomization
    4. All participants must be receiving Cotrimoxazole prophylaxis as part of standard care unless contraindicated
    5. Age at least 18 years and above

    6. Laboratory values (within 30 days prior to randomization)

      1. Aspartate transaminase (AST) no more than five times the upper limit of normal (ULN)
      2. Total bilirubin no more than 2 times ULN
      3. Creatinine no more than 2.0 mg/dL
      4. Platelet count at least 50 000/microliter
      5. Hemoglobin at least 8g/dL
    7. Written informed consent

EXCLUSION CRITERIA:

  1. Concurrent malignancy or any other disease state requiring cytotoxic chemotherapy
  2. Symptomatic for significant HIV-related illnesses (WHO stage III or IV), such as opportunistic infections and malignancies other than mucocutaneous Kaposi's sarcoma. A history of AIDS defining opportunistic infections other than mucocutaneous Kaposi's sarcoma or candida or treated tuberculosis
  3. Active HSV-2 disease as suggested by painful genital ulcer disease at time of screening or enrollment
  4. Current use of antiretroviral medications or Preventing Mother-to-Child Transmission (PMTCT) use of antiretrovirals within the previous 6 months
  5. Significant cardiac, pulmonary, kidney, rheumatologic, gastrointestinal, or CNS disease as detectable on routine medical history, physical examination, or screening laboratory studies.
  6. Psychiatric illness that, in the opinion of the PI, might interfere with the study compliance.
  7. Active substance abuse or history of prior substance abuse that may interfere with protocol compliance or patient safety.
  8. CD4+ count less than 300 or more than 400 cells/microliter.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Acyclovir 400mg tablet twice daily
Drug: Acyclovir
400mg twice daily for 24 months
Placebo Comparator: Placebo tablet twice daily
Drug: Placebo
Placebo tablet twice daily for 24 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression to AIDS (CD4+ Less Than 250 Cells/Microliter or World Health Org Stage IV dx, Excluding Esophageal Candidiasis)
Time Frame: 2 years
Evaluate the effect of acyclovir prophylaxis vs placebo among HIV-1/HSV-2 co-infected individuals on the progression to AIDS (CD4+ less than 250 cells/microliter or World Health Org stage IV disease, excluding esophageal candidiasis)
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Difference in Number of Episodes of Genital Ulcer Disease Between Arms
Time Frame: 2 years
We calculated incidence rate for each treatment arm for episodes of genital ulcer disease, and incidence rate ratio.
2 years
HIV-1 Viral Load Difference Between Arms
Time Frame: baseline, 6 months, 12 months, 18 months, 24 months
We measured mean annual rate of change in log10 viral load (copies/mL) for each group. We assessed difference in annual rate of change in log10 viral load (copies/mL) between groups.
baseline, 6 months, 12 months, 18 months, 24 months
Toxicity of Acyclovir
Time Frame: 2 years
2 years
Adherence to Acyclovir
Time Frame: 2 years
2 years
Virologic and Immunologic Responses to ART in Those Who Progress to CD+4 Less Than 250cells/mL
Time Frame: 6 months and 12 moths post ART initiation
6 months and 12 moths post ART initiation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborators

Johns Hopkins University
University of Washington
Translational Genomics Research Institute

Investigators

  • Principal Investigator: Steven J Reynolds, MD, National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2006

Primary Completion (Actual)

October 1, 2010

Study Completion (Actual)

November 1, 2010

Study Registration Dates

First Submitted

November 29, 2006

First Submitted That Met QC Criteria

November 29, 2006

First Posted (Estimate)

November 30, 2006

Study Record Updates

Last Update Posted (Estimate)

September 28, 2012

Last Update Submitted That Met QC Criteria

August 28, 2012

Last Verified

August 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 999907032
  • 07-I-N032 (Other Identifier: NIAID Intramural IRB)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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