WASHINGTON — A new protease inhibitor, tipranavir, was effective for controlling HIV infection in patients who had failed treatment with the standard protease inhibitors now on the U.S. market, in a phase III study with 620 patients.
Tipranavir's efficacy against HIV strains resistant to existing protease inhibitors (PI) was a welcome development, giving physicians a new way to treat patients no longer responding to standard combinations of antiretroviral drugs. Tipranavir is the first nonpeptidic, dihydropyrone PI. Results from prior studies showed that it retains activity against dozens of HIV isolates that are highly resistant to all PIs now available, including amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir.
“Tipranavir appears to be a very promising agent for patients with highly PI-resistant virus,” Joseph J. Eron Jr., M.D., commented at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. “Long-term success with tipranavir is likely to require coadministration with other drugs that are active against a patient's specific HIV-1 variant,” added Dr. Eron, director of the AIDS clinical trials unit at the University of North Carolina at Chapel Hill.
The study was sponsored by Boehringer Ingelheim Pharmaceuticals Inc., which makes tipranavir. Last October, the company submitted a license application to the Food and Drug Administration based on the results from this study and results from a second phase III study that have not yet been reported. Tipranavir is currently available to U.S. patients through a compassionate-use program.
The study enrolled patients who had a viral load of more than 1,000 copies/mL of HIV RNA, who had already been treated with at least two PI-based regimens of antiretroviral drugs, and who had received drugs from at least three classes of antiretroviral drugs (nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and PIs). The primary strain of HIV that infected each patient had to have at least one primary mutation that conferred resistance to PIs, but no more than two of the protease resistance-associated mutations.
Patients were randomized to either an optimized antiretroviral regimen that included a standard PI, or to an optimized regimen that included 500 mg tipranavir b.i.d plus 200 mg ritonavir b.i.d (a PI often added to a regimen to boost serum levels of the primary PI). About a third of all patients had the relatively new drug enfurvitide, an HIV fusion inhibitor, included in their regimen.
After 24 weeks of treatment, 41.5% of patients treated with tipranivir had at least a 1.0-log drop in their viral load, compared with baseline, the study's primary end point, compared with 22.3% of patients in the control arm—a statistically significant difference, reported Charles B. Hicks, M.D., associate director of the AIDS research and treatment center at Duke University in Durham, N.C.
The overall average drop in viral load among all patients was 0.88 log in the tipranavir group and 0.28 log in the control group. Viral load dropped to completely undetectable levels in 25.1% of patients in the tipranavir group, compared with 10% of those in the control group.
One additional analysis highlighted the improved responses of patients who were placed on two drugs that were active against their infection. Among the patients who received enfurvitide along with tipranivir, 32.8% had their viral load drop to an undetectable level, compared with 14.3% of patients in the control group who were treated with enfurvitide, Dr. Hicks said at the meeting, sponsored by the American Society of Microbiology.
The incidence of adverse events was similar in the two study groups, 22.8% among those treated with tipranavir and 18.1% among the control patients. The rate of elevations of liver enzymes or serum lipids was higher in patients treated with tipranavir, but these were mostly transient and asymptomatic. Two patients in the tipranavir group stopped treatment because of a rise in liver enzymes.
The results were a “proof of concept that in an advanced patient population treatment with tipranavir is superior to boosting another PI,” commented Michael S. Saag, M.D., professor of medicine at the University of Alabama, Birmingham.