The Anti-HIV Effects of Saquinavir Soft Gelatin Capsules Versus Indinavir in Patients Who Have Used Saquinavir Hard Gelatin Capsules for One Year

To determine, in HIV-infected patients, whether switching to a new soft gelatin capsule formulation of saquinavir or to indinavir following prolonged use of the original hard capsule formulation of saquinavir results in an acute decrease in plasma HIV RNA.

Resistance to anti-HIV agents occurs with increasing duration of use. In vitro studies have shown that cross-resistance occurs among protease inhibitors, although no clinical trials have been conducted to examine antiretroviral activity with sequential use of protease inhibitors or to determine whether saquinavir resistance can be overcome with higher concentrations of the drug.

Resistance to anti-HIV agents occurs with increasing duration of use. In vitro studies have shown that cross-resistance occurs among protease inhibitors, although no clinical trials have been conducted to examine antiretroviral activity with sequential use of protease inhibitors or to determine whether saquinavir resistance can be overcome with higher concentrations of the drug.

Patients who are currently receiving hard capsule saquinavir are randomized to continue receiving hard capsule saquinavir or to switch to soft gelatin capsule saquinavir or indinavir. At week 8, patients receiving the hard capsule formulation will switch to open-label indinavir for weeks 8-24. Patients on the other two arms will remain on their assigned regimen for the entire 24 weeks unless they have no virologic response by week 8, in which case they will be crossed-over to open-label therapy with the alternative drug (i.e., either soft gelatin capsule saquinavir or indinavir).

AS PER AMENDMENT 12/23/96: Viral RNA from weeks 16 and 24 will be assayed in batch after week 24. Patients who exhibit an antiviral response based on this assay will be allowed to continue their current drug assignment for a total of 12 months.

AS PER AMENDMENT 5/7/97: Based on an interim analysis performed after 72 patients had completed 8 weeks of therapy, the study was closed as of March 7, 1997. Patients currently enrolled may stop their participation in the trial and seek other anti-retroviral therapies or may continue on study. Patients on hard capsule saquinavir who remain on study will be switched to indinavir at 8 weeks. Patients on soft gel capsule saquinavir may switch immediately to indinavir or, when results of HIV RNA and CD4 cell counts are available, may choose to switch to indinavir or remain on soft gel capsule saquinavir. Patients receiving indinavir will continue that agent. Follow-up for all patients will end on 7/4/97.

Eligibility Criteria:
Inclusion Criteria

Concurrent Medication:

Required:

* PCP prophylaxis if CD4 count \<= 200 cells/mm3.

Allowed:

* Intralesional therapy for KS.
* Vitamins.
* Nucleoside RT inhibitors, provided regimen remains stable for first 8 weeks of study.

Concurrent Treatment:

Allowed:

* Acupuncture.
* Visualization techniques.

Patients must have:

* HIV infection.
* Prior hard capsule saquinavir at 1800 mg/day for more than 1 year.

Prior Medication:

Allowed:

* Prior saquinavir.
* Prior antiretrovirals, excluding protease inhibitors other than saquinavir.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

* Psychological condition or medical instability that would interfere with study evaluation or procedures.

AS PER AMENDMENT 5/7/97:

* Active tuberculosis.

Concurrent Medication:

Excluded:

* Protease inhibitors other than study drugs.
* Non-nucleoside RT inhibitors.
* Interferon.
* Interleukins.
* GM-CSF.
* HIV vaccines.
* Systemic cytotoxic chemotherapy.
* Investigational drugs other than study medications.
* Rifabutin.
* Rifampin.
* Midazolam.
* Triazolam.
* Ketoconazole.
* Delavirdine.
* Cisapride.
* Terfenadine.
* Astemizole.

AS PER AMENDMENT 5/7/97:

* Nevirapine.

Patients with the following prior conditions are excluded:

* Unexplained fever \> 38.5 C for any 7 days within 30 days prior to study entry.
* Diarrhea persisting for 15 days within 30 days prior to study entry.

Prior Medication:

Excluded:

* Any prior protease inhibitor other than saquinavir.

Excluded within the past 2 months.

* Change in antiretroviral regimen.
* Systemic chemotherapy for KS.

Excluded within the past month:

* Non-nucleoside RT inhibitors.
* Interferons.
* Interleukins.
* HIV vaccines.
* Experimental therapies.

Excluded within the past 2 weeks:

* Rifabutin.
* Cisapride.
* Terfenadine.
* Astemizole.
* Midazolam.
* Triazolam.
* Oral ketoconazole.
* Delavirdine.
* Acute therapy for infection or other medical illness.

Active substance abuse that would interfere with study evaluation or procedures.