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

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.

• 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.