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

Study Description

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Brief 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.

Condition or disease	Intervention/treatment	Phase
HIV Infections; Herpes Genitalis	Drug: Acyclovir; Drug: Placebo	Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	440 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Randomized, Double-Blind, Placebo-Controlled Trial of Acyclovir Prophylaxis Versus Placebo Among HIV-1/HSV-2 Co-Infected Individuals in Uganda
Study Start Date :	November 2006
Actual Primary Completion Date :	October 2010
Actual Study Completion Date :	November 2010

Arms and Interventions

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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

Outcome Measures

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Primary Outcome Measures :

1. 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)

Secondary Outcome Measures :

1. 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. 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.
3. Toxicity of Acyclovir [ Time Frame: 2 years ]
4. Adherence to Acyclovir [ Time Frame: 2 years ]
5. 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 ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 65 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

• 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.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

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

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

University of Washington

Johns Hopkins University

Translational Genomics Research Institute

Investigators

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

More Information

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Publications:

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.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Redd AD, Newell K, Patel EU, Nalugoda F, Ssebbowa P, Kalibbala S, Frank MA, Tobian AA, Gray RH, Quinn TC, Serwadda D, Reynolds SJ. Decreased monocyte activation with daily acyclovir use in HIV-1/HSV-2 coinfected women. Sex Transm Infect. 2015 Nov;91(7):485-8. doi: 10.1136/sextrans-2014-051867. Epub 2015 Apr 22.

Reynolds SJ, Makumbi F, Newell K, Kiwanuka N, Ssebbowa P, Mondo G, Boaz I, Wawer MJ, Gray RH, Serwadda D, Quinn TC. Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2: a randomised, double-blind placebo-controlled trial. Lancet Infect Dis. 2012 Jun;12(6):441-8. doi: 10.1016/S1473-3099(12)70037-3. Epub 2012 Mar 19.

Responsible Party:	Steven Reynolds, Scientific Director NIH-Uganda ICER, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT00405821 History of Changes
Other Study ID Numbers:	999907032; 07-I-N032 ( Other Identifier: NIAID Intramural IRB )
First Posted:	November 30, 2006
Results First Posted:	September 28, 2012
Last Update Posted:	September 28, 2012
Last Verified:	August 2012

Keywords provided by Steven Reynolds, National Institutes of Health Clinical Center (CC):

AIDS; HIV Disease Progression; Quality of Life; HIV Viral Load	Genital Ulcers; HIV; Treatment Naive

Additional relevant MeSH terms:

Herpes Genitalis; Herpes Simplex; HIV Infections; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases	Immunologic Deficiency Syndromes; Immune System Diseases; Herpesviridae Infections; DNA Virus Infections; Genital Diseases, Male; Genital Diseases, Female; Acyclovir; Antiviral Agents; Anti-Infective Agents