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.