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

HIV Infections Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00405821
• Other study ID #: 999907032
• Secondary ID: 07-I-N032
• Status: Completed
• Phase: Phase 2
• First received: November 29, 2006
• Last updated: August 28, 2012
• Start date: November 2006
• Est. completion date: November 2010

Study information

• Verified date: August 2012
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUganda: Research Ethics CommitteeUganda: National Council for Science and Technology
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 440
• Est. completion date: November 2010
• Est. primary completion date: October 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

• 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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Herpes Genitalis
• HIV Infections

Intervention

Drug:
• Acyclovir
400mg twice daily for 24 months
• Placebo
Placebo tablet twice daily for 24 months

Locations

Country	Name	City	State
Uganda	Rakai Health Sciences Program, Uganda Virus Research Institute	Kalisizo	Rakai District

Sponsors (4)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Johns Hopkins University, Translational Genomics Research Institute, Phoenix, Arizona., University of Washington

Country where clinical trial is conducted

Uganda, 

References & Publications (3)

Moriuchi M, Moriuchi H, Williams R, Straus SE. Herpes simplex virus infection induces replication of human immunodeficiency virus type 1. Virology. 2000 Dec 20;278(2):534-40. — View Citation

Serwadda D, Gray RH, Sewankambo NK, Wabwire-Mangen F, Chen MZ, Quinn TC, Lutalo T, Kiwanuka N, Kigozi G, Nalugoda F, Meehan MP, Ashley Morrow R, Wawer MJ. Human immunodeficiency virus acquisition associated with genital ulcer disease and herpes simplex virus type 2 infection: a nested case-control study in Rakai, Uganda. J Infect Dis. 2003 Nov 15;188(10):1492-7. Epub 2003 Oct 28. — View Citation

Stein DS, Graham NM, Park LP, Hoover DR, Phair JP, Detels R, Ho M, Saah AJ. The effect of the interaction of acyclovir with zidovudine on progression to AIDS and survival. Analysis of data in the Multicenter AIDS Cohort Study. Ann Intern Med. 1994 Jul 15;121(2):100-8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression to AIDS (CD4+ Less Than 250 Cells/Microliter or World Health Org Stage IV dx, Excluding Esophageal Candidiasis)	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	No
Secondary	Difference in Number of Episodes of Genital Ulcer Disease Between Arms	We calculated incidence rate for each treatment arm for episodes of genital ulcer disease, and incidence rate ratio.	2 years	No
Secondary	HIV-1 Viral Load Difference Between Arms	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	No
Secondary	Toxicity of Acyclovir		2 years	Yes
Secondary	Adherence to Acyclovir		2 years	No
Secondary	Virologic and Immunologic Responses to ART in Those Who Progress to CD+4 Less Than 250cells/mL		6 months and 12 moths post ART initiation	No