Phase III Results of Second-Generation HIV Protease Inhibitor Reported

Phase III clinical trial data for the human immunodeficiency virus (HIV) protease inhibitor amprenavir (Agenerase) suggest that the drug may be potent and generally well-tolerated in combination with lamivudine (Epivir) and zidovudine (AZT [Retrovir]). These data, presented at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), support the role of amprenavir in front-line combination antiretroviral therapy.

In this study, amprenavir in combination wwith lamivudine and zidovudine was significantly better at reducing the amount of HIV in blood, compared to the combination of lamivudine and zidovudine alone. Further analysis showed that 59% of patients receiving the three-drug regimen had a viral load below the limit of detection of an investigational ultrasensitive assay.

"In this trial, Agenerase appears to provide a significant amount of virus suppression when given in combination with two reverse transcriptase inhibitors," said Dr. Jeffrey Goodgame, lead investigator for the study and associate professor at the University of Central Florida. "Data generated in smaller studies have supported the potential clinical utility of Agenerase in a number of different regimens, including dual protease inhibitor combinations."

Amprenavir is a second-generation protease inhibitor that is now being made available in the United States to certain patients through an early access program.

A Potent Inhibitor of HIV

"Though preliminary, we believe these data are consistent with those generated in smaller phase II studies, which have suggested that Agenerase is a potent inhibitor of HIV," said Lynn Smiley,MD, vice president of antiviral clinical research at Glaxo Wellcome, developer of the new protease inhibitor. "We are pleased and encouraged by these early results as they support the clinical utility of regimens containing Agenerase."

The data reported by Dr. Goodgame are from protocol 3001, an ongoing double-blind, placebo-controlled, international, multicenter study comparing the safety, tolerance, viral load reduction, and CD4 lymphocyte response of amprenavir + lamivudine + zidovudine vs lamivudine + zidovudine. An interim analysis of 16-week data showed that 88% (65 of 74) of patients in the treatment arm containing amprenavir achieved viral loads below the limit of detection of standard assays (< 400 copies/mL), as compared with 19% of patients in the lamivudine + zidovudine arm patients. The study also showed that 59% (52 of 88) of patients receiving triple therapy with amprenavir achieved a viral load below the limit of detection of an investigational ultrasensitive assay (< 50 copies/mL) at 16 weeks (intent-to-treat analysis, collected data only). Preliminary data also suggested that amprenavir is not associated with significant increases in cholesterol or triglyceride at 16 weeks.

An additional, more conservative, intent-to-treat analysis, in which patients who withdrew from the study prematurely were considered treatment failures, indicated that 59% (66 of 112) of patients receiving triple therapy with amprenavir achieved a viral load below 400 copies/mL at 16 weeks, compared to 17% (19 of 109) of patients in the two-drug combination. Intent-to-treat analyses are the basis on which investigational anti-HIV drugs are reviewed by the FDA, and are considered to offer an expectation of a regimen’s success in a population. However, as-treated analyses (which evaluate only those patients who remain on the study medication through the entire study period) are preferred by many physicians, as they provide a more practical expectation of a regimen’s success in individual patients who can be kept on a particular therapy over time. Each analysis provides a different useful perspective.

Most Common Adverse Events

The most commonly reported adverse events in the amprenavir arm were mild to moderate and transient. They included nausea, vomiting, fatigue, gaseous symptoms, headache, and circumoral paresthesia. Of the patients assigned to the amprenavir arm who actually started but later discontinued therapy, 13 discontinued therapy due to nausea or other gastrointestinal (GI) symptoms, two due to anemia, and two due to rash. Of the patients assigned to the two-drug arm who discontinued therapy, the causes for discontinuation were GI symptoms in two patients, rash in one patient, and anemia in one patient.

The study involved 232 patients who had not been treated previously for HIV. After week 16, patients with plasma HIV RNA levels above the 400-copy/mL limit were allowed to switch therapies, which included adding open-label amprenavir and changing other therapies in the regimen. Assessments of antiviral activity and safety will continue until the last subject completes 48 weeks on the study.

A progressive early access program is making amprenavir available to patients in three protocols, including two for patients who have not responded to a protease inhibitor-containing regimen. Physicians who are interested in enrolling patients in the program can call 1-800-248-9757 for more information. Patients must have their physicians call if they are interested in being enrolled.