The Safety and Effectiveness of Fozivudine Tidoxil in HIV-1 Infected Patients

To identify doses of fozivudine tidoxil that are well tolerated and produce measurable antiviral activity.

To identify the adverse event profile that defines the maximum tolerated dose. To characterize the single- and multiple-dose pharmacokinetics of fozivudine and its metabolites.

To correlate the adverse event profile and antiviral activity of fozivudine with pharmacokinetic parameters.

In this double-blind, dose-escalating study, patients receive fozivudine tidoxil at one of 5 dosage levels for 4 weeks and are randomized with respect to once- or twice-daily administration (cohorts 2 vs. 3 and 4 vs. 5). Within each cohort, 10 patients are randomized to the study drug and 2 to the placebo. At least 9 of the 12 patients enrolled in Cohort 1 must complete the entire 4-week course before Cohorts 2 and 3 are enrolled. At least 18 of these 24 patients must complete 2 weeks of the 4-week course before Cohorts 4 and 5 are enrolled.

Inclusion Criteria

Concurrent Medication:

Allowed:

Primary and secondary prophylaxis for opportunistic infection if stable and initiated at least 3 months prior to study drug administration.

Patients must have:

• HIV-positive status.
• One HIV RNA count > 10,000 copies/ml within 30 days prior to entry, with a second count at least 3-fold above or below the first value.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or symptoms are excluded:

• Active medical problems including chronic diarrhea and active opportunistic infections such as cryptococcosis, Pneumocystis carinii, histoplasmosis, etc..
• Malignancy for which systemic therapy or radiation therapy is expected to be required during the study.
• Any other disease or condition that would place a patient at undue risk or confound the results of the study.

Concurrent Medication:

Excluded:

Systemic therapy for malignancy.

Prior Medication:

Excluded:

• Zidovudine or any other nucleoside reverse transcriptase inhibitor.
• Immunomodulators within one month prior to study drug administration.
• Investigational drugs within 30 days prior to study drug administration.
• Systemic cytotoxic chemotherapy within 3 months prior to study drug administration.

Prior Treatment:

Excluded:

• Extended-field radiation therapy within 3 months prior to study drug administration.
• Blood transfusion within 2 weeks prior to study drug administration.