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 regimens 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 regimens 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.