An interferon-free regimen of faldaprevir, deleobuvir, and ribavirin proved to be effective in a phase II clinical trial involving 362 patients with previously untreated chronic hepatitis C virus genotype 1 infection, according to a report published in the New England Journal of Medicine.
The new combination therapy achieved sustained virologic response rates of 52%-69% 12 weeks after treatment was completed, reported Dr. Stefan Zeuzem of Johann Wolfgang Goethe University Medical Center, Frankfurt am Main (Germany), and his associates (N. Engl. J. Med. 2013;369:630-9).
Courtesy U.S. Department of Veterans Affairs
The new combination therapy achieved sustained virologic response rates of 52%-69% 12 weeks after treatment was completed.
Those sustained virologic response rates compare well with rates of 68%-75% reported in phase III trials of the regimen of pegylated interferon, ribavirin, and telaprevir or boceprevir that is the current standard of care, the investigators noted.
The new, interferon-free regimen may offer an advantage over the standard of care by avoiding interferon’s detrimental effects on white-cell and platelet counts, they said.
The open-label trial, sponsored by Boehringer Ingelheim, enrolled patients at 48 medical centers in Europe, Australia, and New Zealand. They were randomly assigned to one of five treatment groups with various dosages of the protease inhibitor faldaprevir and the nonnucleoside polymerase inhibitor deleobuvir, with or without the addition of daily ribavirin. Treatment intervals of 16, 28, and 40 weeks were tested.
The primary efficacy endpoint was a sustained virologic response (an undetectable plasma level of hepatitis C virus [HCV] RNA) 12 weeks after the completion of treatment. That endpoint was achieved in 52%-69% of patients with several combinations of faldaprevir, deleobuvir, and ribavirin, and with all treatment durations, Dr. Zeuzem and his colleagues said.
The treatment response rate was not affected by the duration of therapy in most groups. However, the relapse rate was markedly higher in the subgroup of patients with HCV genotype 1a who received only 16 weeks of therapy (41%), compared with those who received 28 weeks (0%) or 40 weeks (6%).
In contrast, relapse rates among patients with HCV genotype 1b were consistently low across all treatment durations, suggesting that 16 weeks of treatment may be sufficient for this subgroup of patients, the researchers said.
The groups who did not receive ribavirin showed high rates of both virologic breakthrough during treatment and relapse after treatment was completed. This has been reported in other studies of interferon-free regimens without ribavirin, and indicates that ribavirin is a necessary component of such regimens, they said.
There were small, nonsignificant differences in response rates according to the dosage of deleobuvir. However, the rate of premature discontinuation among patients who did not have a sustained virologic response 12 weeks after the completion of therapy was significantly higher among those who took deleobuvir three times per day (15%) than in those who took it twice per day (4%).
Adverse events were extremely common, affecting 94% of patients. Nine percent reported severe adverse events, including rash (six patients) and anemia (two patients).
Gastrointestinal effects (nausea, diarrhea, and vomiting) and dermatologic effects (pruritus, maculopapular rash, photosensitivity reaction, and dry skin) were the most frequently reported, and they were particularly common during the first week of treatment. That may be because patients received high loading doses at the start of therapy.
Jaundice also was reported and was attributed to increased levels of bilirubin. Faldaprevir is known to inhibit bilirubin metabolism and likely contributed to the 67 cases in the study.
"Substantial reductions in red-cell, white-cell, and platelet counts are the most prohibitive side effects of interferon-based treatments for HCV infection," but were uncommon in the study, Dr. Zeuzem and his associates said.
However, the study was limited because it didn’t include an interferon-receiving control group, and the finding regarding cell counts should be interpreted with caution, they added.
Boehringer Ingelheim funded the trial, monitored the study, collected data, performed the statistical analyses, and helped write the report.