Herpes Genitalis, HIV Infections
Conditions
Keywords
AIDS, HIV Disease Progression, Quality of Life, HIV Viral Load, Genital Ulcers, HIV, Treatment Naive
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.
Interventions
DRUGAcyclovir
400mg twice daily for 24 months
DRUGPlacebo
Placebo tablet twice daily for 24 months
Sponsors
University of Washington
Johns Hopkins University
Translational Genomics Research Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression to AIDS (CD4+ Less Than 250 Cells/Microliter or World Health Org Stage IV dx, Excluding Esophageal Candidiasis) | 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
| Measure | Time frame | Description |
|---|---|---|
| Difference in Number of Episodes of Genital Ulcer Disease Between Arms | 2 years | 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 | 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. |
| Toxicity of Acyclovir | 2 years | — |
| Adherence to Acyclovir | 2 years | — |
| 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 | — |
Countries
Uganda
Participant flow
Recruitment details
440 HIV+ subjects recruited in rural Rakai, Uganda within the Rakai Health Sciences Program mobile medical clinic during May 2007 thru November 2008
Pre-assignment details
All subjects were randomized to study arm, and initiated study treatment at the time of enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Acyclovir 400mg Tablet Twice Daily | 220 |
| Placebo Tablet Twice Daily | 220 |
| Total | 440 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 5 | 7 |
| Overall Study | initiated ART | 9 | 8 |
| Overall Study | Lost to Follow-up | 7 | 7 |
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Acyclovir 400mg Tablet Twice Daily | Placebo Tablet Twice Daily | Total |
|---|---|---|---|
| Age, Customized 20-29 years | 46 participants | 44 participants | 90 participants |
| Age, Customized 30-39 years | 94 participants | 93 participants | 187 participants |
| Age, Customized 40-49 years | 54 participants | 53 participants | 107 participants |
| Age, Customized 50+ years | 26 participants | 30 participants | 56 participants |
| Sex: Female, Male Female | 150 Participants | 161 Participants | 311 Participants |
| Sex: Female, Male Male | 70 Participants | 59 Participants | 129 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 219 / 220 | 218 / 220 |
| serious Total, serious adverse events | 75 / 220 | 85 / 220 |
Outcome results
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)
Time frame: 2 years
Population: Intention to treat analysis of all subjects randomized on the trial meeting the primary endpoint
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acyclovir 400mg Tablet Twice Daily | Progression to AIDS (CD4+ Less Than 250 Cells/Microliter or World Health Org Stage IV dx, Excluding Esophageal Candidiasis) | 95 participants |
| Placebo Tablet Twice Daily | Progression to AIDS (CD4+ Less Than 250 Cells/Microliter or World Health Org Stage IV dx, Excluding Esophageal Candidiasis) | 110 participants |
Comparison: Intent-to-treat analysis used Cox proportional hazards (CPH) models, adjusting for baseline log10 viral load (VL), CD4 cell count, gender and age to assess the risk of disease progressionp-value: <0.0595% CI: [0.58, 0.99]Regression, Cox
Secondary
Adherence to Acyclovir
Time frame: 2 years
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.
Time frame: 2 years
Population: We conducted monthly clinical assessment for GUD on all randomized subjects during their entire follow-up period on this trial. The number of episodes of GUD is shown below.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acyclovir 400mg Tablet Twice Daily | Difference in Number of Episodes of Genital Ulcer Disease Between Arms | 27 episodes |
| Placebo Tablet Twice Daily | Difference in Number of Episodes of Genital Ulcer Disease Between Arms | 47 episodes |
Comparison: Null hypothesis is no difference by treatment arm in rate of GUD.p-value: <0.0595% CI: [0.19, 0.48]rate ratio with 95% CI
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.
Time frame: baseline, 6 months, 12 months, 18 months, 24 months
Population: We measured viral load at baseline and at 6 monthly follow-up visits during 24 months of follow-up for all subjects randomized on this study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Acyclovir 400mg Tablet Twice Daily | HIV-1 Viral Load Difference Between Arms | -0.061 log10 (copies/mL) |
| Placebo Tablet Twice Daily | HIV-1 Viral Load Difference Between Arms | 0.402 log10 (copies/mL) |
Comparison: Null hypothesis is no difference in annual rate of change in log10 viral load by arm.p-value: 0.0595% CI: [-0.731, -0.194]t-test, 2 sided
Secondary
Toxicity of Acyclovir
Time frame: 2 years
Secondary
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