The Tolerance of HIV-Infected Patients With Herpes Group Virus Infections to Oral Doses of FIAU
Condition: Herpes Simplex; HIV Infections; Hepatitis B
MeSH terms: Infections; Communicable Diseases; Hepatitis B; Virus Diseases; Herpes Simplex; Hepatitis
Study type: Interventional
Phase: Phase 2

Summary: 
      To determine the tolerance of HIV-infected patients to TID oral doses of FIAU syrup at 4
      different dose levels. To determine the peak and trough blood levels of FIAU and its
      metabolites during two weeks of oral dosing with FIAU.

      The pyrimidine nucleoside analog FIAC and its primary deaminated uracil metabolite FIAU are
      highly and specifically active compounds in vitro against several herpes group viruses,
      particularly herpes simplex virus (HSV) types 1 and 2, varicella zoster (VZV), and
      cytomegalovirus (CMV), as well as hepatitis B virus (HBV). Since FIAU is the primary
      metabolite of FIAC and the administration of FIAU simplifies the metabolism of FIAC, it is
      anticipated from clinical studies of FIAC that FIAU will be tolerated at least as well as
      FIAC. A single-dose, pharmacokinetic (blood level) study showed that FIAC, when taken orally,
      is readily absorbed into the bloodstream, and most of it is converted to FIAU. Daily oral
      doses are expected to provide concentrations of FIAU exceeding the in vitro minimum
      inhibitory concentration for nearly all the herpes group viruses.
    

Detailed description: 
      The pyrimidine nucleoside analog FIAC and its primary deaminated uracil metabolite FIAU are
      highly and specifically active compounds in vitro against several herpes group viruses,
      particularly herpes simplex virus (HSV) types 1 and 2, varicella zoster (VZV), and
      cytomegalovirus (CMV), as well as hepatitis B virus (HBV). Since FIAU is the primary
      metabolite of FIAC and the administration of FIAU simplifies the metabolism of FIAC, it is
      anticipated from clinical studies of FIAC that FIAU will be tolerated at least as well as
      FIAC. A single-dose, pharmacokinetic (blood level) study showed that FIAC, when taken orally,
      is readily absorbed into the bloodstream, and most of it is converted to FIAU. Daily oral
      doses are expected to provide concentrations of FIAU exceeding the in vitro minimum
      inhibitory concentration for nearly all the herpes group viruses.

      HIV-infected patients with Karnofsky scores at least 80 (with or without documented recurrent
      herpes group infections) are successively entered into consecutively studied, escalating dose
      cohorts. There are a total of 4 dose cohorts of FIAU and each patient takes the required
      amount of FIAU syrup every 8 hours, 1 hour prior to or 3 hours after meals, for a total of 14
      days. Entry of new patients at the next higher dose is based on results of tolerance and
      safety data for prior cohort when all 10 have received 14 days of therapy and at least 7 have
      met all of the tolerance criteria. Although not formally randomized due to the sequential
      nature of the study and serious medical condition of the patients, every attempt to avoid
      bias in assigning a patient to a dose is made. Patients are entered starting with the first
      dose cohort. Upon meeting the enrollment and tolerance criteria for dose escalation, up to 5
      patients with a history of chronic HBV infection and surface antigen positive at their
      screening visit are added to the end of each dose cohort. Plasma samples are taken to
      determine peak and trough levels of FIAU at Days 1, 3, 7, and 14 or at last visit. Patients
      with ongoing active infections are followed by culture (HSV, VZV and CMV) or test (HBV) at
      Days 1, 3, 7, and 14. Antiemetic therapy with Reglan, Compazine, and Trilafon is given
      concomitantly at the discretion of the investigator and tolerance determined with antiemetic
      therapy ongoing. Patients are advised to avoid heavy exercise within 24 hours of any
      laboratory tests.
    

Intervention name(s): Fialuridine
Intervention type(s): Drug
Intervention MeSH terms: Fialuridine
Primary purpose: Treatment
Keywords: AIDS-Related Opportunistic Infections; Pyrimidine Nucleosides; Herpesviridae Infections; Drug Evaluation; Antiviral Agents; Hepatitis B