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

Primary Purpose

HIV Infections, Herpes Genitalis

Status

Completed

Phase

Phase 2

Locations

Uganda

Study Type

Interventional

Intervention

Acyclovir

Placebo

About this trial

This is an interventional treatment trial for HIV Infections focused on measuring AIDS, HIV Disease Progression, Quality of Life, HIV Viral Load, Genital Ulcers, HIV, Treatment Naive

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:

Concurrent malignancy or any other disease state requiring cytotoxic chemotherapy
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
Active HSV-2 disease as suggested by painful genital ulcer disease at time of screening or enrollment
Current use of antiretroviral medications or Preventing Mother-to-Child Transmission (PMTCT) use of antiretrovirals within the previous 6 months
Significant cardiac, pulmonary, kidney, rheumatologic, gastrointestinal, or CNS disease as detectable on routine medical history, physical examination, or screening laboratory studies.
Psychiatric illness that, in the opinion of the PI, might interfere with the study compliance.
Active substance abuse or history of prior substance abuse that may interfere with protocol compliance or patient safety.
CD4+ count less than 300 or more than 400 cells/microliter.

Sites / Locations

Rakai Health Sciences Program, Uganda Virus Research Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Acyclovir 400mg tablet twice daily

Placebo tablet twice daily

Arm Description

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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.

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.

Toxicity of Acyclovir

Adherence to Acyclovir

Virologic and Immunologic Responses to ART in Those Who Progress to CD+4 Less Than 250cells/mL

Full Information

NCT ID

NCT00405821

First Posted

November 29, 2006

Last Updated

August 28, 2012

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborators

University of Washington, Johns Hopkins University, Translational Genomics Research Institute

1. Study Identification

Unique Protocol Identification Number

NCT00405821

Brief Title

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

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 Type

Interventional

2. Study Status

Record Verification Date

August 2012

Overall Recruitment Status

Completed

Study Start Date

November 2006 (undefined)

Primary Completion Date

October 2010 (Actual)

Study Completion Date

November 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborators

University of Washington, Johns Hopkins University, Translational Genomics Research Institute

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV Infections, Herpes Genitalis

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

440 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Acyclovir 400mg tablet twice daily

Arm Type

Active Comparator

Arm Title

Placebo tablet twice daily

Arm Type

Placebo Comparator

Intervention Type

Drug

Intervention Name(s)

Acyclovir

Intervention Description

400mg twice daily for 24 months

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo tablet twice daily for 24 months

Primary Outcome Measure Information:

Title

Progression to AIDS (CD4+ Less Than 250 Cells/Microliter or World Health Org Stage IV dx, Excluding Esophageal Candidiasis)

Description

Time Frame

2 years

Secondary Outcome Measure Information:

Title

Difference in Number of Episodes of Genital Ulcer Disease Between Arms

Description

We calculated incidence rate for each treatment arm for episodes of genital ulcer disease, and incidence rate ratio.

Time Frame

2 years

Title

HIV-1 Viral Load Difference Between Arms

Description

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.

Time Frame

baseline, 6 months, 12 months, 18 months, 24 months

Title

Toxicity of Acyclovir

Time Frame

2 years

Title

Adherence to Acyclovir

Time Frame

2 years

Title

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

INCLUSION CRITERIA: Documentation of HIV-1 infection, by either two positive ELISAs or two discrepant ELISAs with a confirmatory positive Western Blot Documentation of prior HSV-2 infection by Focus Kalon ELISA 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 All participants must be receiving Cotrimoxazole prophylaxis as part of standard care unless contraindicated Age at least 18 years and above Laboratory values (within 30 days prior to randomization) Aspartate transaminase (AST) no more than five times the upper limit of normal (ULN) Total bilirubin no more than 2 times ULN Creatinine no more than 2.0 mg/dL Platelet count at least 50 000/microliter Hemoglobin at least 8g/dL Written informed consent EXCLUSION CRITERIA: Concurrent malignancy or any other disease state requiring cytotoxic chemotherapy 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 Active HSV-2 disease as suggested by painful genital ulcer disease at time of screening or enrollment Current use of antiretroviral medications or Preventing Mother-to-Child Transmission (PMTCT) use of antiretrovirals within the previous 6 months Significant cardiac, pulmonary, kidney, rheumatologic, gastrointestinal, or CNS disease as detectable on routine medical history, physical examination, or screening laboratory studies. Psychiatric illness that, in the opinion of the PI, might interfere with the study compliance. Active substance abuse or history of prior substance abuse that may interfere with protocol compliance or patient safety. CD4+ count less than 300 or more than 400 cells/microliter.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Steven J Reynolds, MD

Organizational Affiliation

National Institute of Allergy and Infectious Diseases (NIAID)

Official's Role

Principal Investigator

Facility Information:

Facility Name

Rakai Health Sciences Program, Uganda Virus Research Institute

City

Kalisizo

State/Province

Rakai District

Country

Uganda

12. IPD Sharing Statement

Citations:

PubMed Identifier

11118375

Citation

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. doi: 10.1006/viro.2000.0667.

Results Reference

background

PubMed Identifier

14624374

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. doi: 10.1086/379333. Epub 2003 Oct 28.

Results Reference

background

PubMed Identifier

8017721

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. doi: 10.7326/0003-4819-121-2-199407150-00004.

Results Reference

background

PubMed Identifier

25904747

Citation

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.

Results Reference

derived

PubMed Identifier

22433279

Citation

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.

Results Reference

derived

Learn more about this trial

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

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