A Dose-Escalating Study of Ro 31-8959 ( HIV Protease Inhibitor ) in Patients With HIV Disease.

To investigate the toxicity, antiviral activity, and pharmacokinetics in HIV-infected patients receiving 16 weeks of oral saquinavir mesylate ( Ro 31-8959 ) at one of two doses.

Cohorts of 16 patients receive 1 of 2 doses of Ro 31-8959 for 20 weeks. Administration of the higher dose will proceed only after 2-week safety data for the first eight patients on the lower dose has been reviewed.

Inclusion Criteria

Patients must have:

• Documented HIV infection.
• CD4 count 200 - 500 cells/mm3.
• No evidence of viral resistance.
• HIV RNA quantifiable by PCR.
• Negativity for HBsAg, HBeAg, and anti-HBc.

NOTE:

• Fifty percent of patients must have measurable p24 antigen levels (> 31 pg/ml).

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Active opportunistic infection requiring immediate treatment, such as tuberculosis, cytomegalovirus, cerebral toxoplasmosis, and Pneumocystis carinii pneumonia.
• Unable to maintain adequate oral intake.
• Clinically significant vomiting and/or diarrhea.
• Malignancy, visceral Kaposi's sarcoma, or lymphoma that will require systemic chemotherapy within the next 12 months.
• Unable to comply with protocol requirements, in the judgment of the investigator.
• Any grade 3 or worse laboratory or clinical abnormality.

Concurrent Medication:

Excluded:

• Antineoplastic agents.
• Concomitant or maintenance treatment with excluded experimental drugs and drugs with known nephrotoxic or hepatotoxic potential.

Concurrent Treatment:

Excluded:

• Radiation therapy other than local skin radiation therapy.

Patients with the following prior conditions are excluded:

• Unexplained temperature >= 38.5 C (101.5 F) persisting for 14 days or more within a 30-day period.
• Unexplained, chronic diarrhea persisting for 14 days or more within a 30-day period.

Prior Medication:

Excluded:

• Prior treatment with an HIV proteinase inhibitor.
• AZT within 30 days prior to study entry OR lasting more than 1 year.
• Other antiretroviral therapy (besides AZT) within 30 days prior to study entry OR lasting more than 14 days.
• Acute therapy for an opportunistic infection within 14 days prior to study entry.