HCV: Interferon-Free Regimen Works in Over 50% of Patients

Troy Brown

August 14, 2013

More than half (52% - 69%) of patients with hepatitis C virus (HCV) genotype 1 who received interferon-free treatment with faldaprevir combined with deleobuvir plus ribavirin had sustained virologic response 12 weeks after treatment completion, according to a phase 2b, randomized open-label trial of 362 patients.

Stefan Zeuzem, MD, from Johann Wolfgang Goethe University Medical Center in Frankfurt am Main, Germany, and colleagues report their findings in an article published in the August 15 issue of the New England Journal of Medicine.

HCV genotype 1 is the most prevalent and hard-to-cure genotype. Current treatment involves the use of protease inhibitors combined with pegylated interferon and ribavirin, which have high rates of adverse effects and discontinuation. Many patients also have contraindications to pegylated interferon. Faldaprevir is a protease inhibitor, and deleobuvir is a polymerase inhibitor.

In the current trial, investigators randomly assigned previously untreated patients to 1 of 5 groups: faldaprevir 120 mg once daily and deleobuvir 600 mg 3 times daily, plus ribavirin, for 16, 28, or 40 weeks (TID16W, TID28W, or TID40W, respectively); faldaprevir 120 mg once daily and deleobuvir 600 mg twice daily, plus ribavirin, for 28 weeks (BID28W); or faldaprevir 120 mg once daily and deleobuvir 600 mg 3 times daily, without ribavirin, for 28 weeks (TID28W-NR).

Among patients in the TID16W group, 59% achieved the primary end point of sustained virologic response 12 weeks after therapy completion as did 59% in the TID28W group, 52% in the TID40W group, 69% in the BID28W group, and 39% in the TID28W-NR group. There were no significant differences in sustained virologic response according to treatment duration or deleobuvir dosage.

Sustained virologic response rates were higher among those who received ribavirin compared with those who received the same regimen without ribavirin (59% in the TID28W group vs 39% in the TID28W-NR group; P = .03).

The investigators found that genotype 1b, IL28B CC genotype, female sex, ribavirin-containing treatment regimens, and normal baseline γ-glutamyl transferase levels were associated with a higher rate of sustained virologic response 12 weeks after therapy completion. They adjusted the analyses for age, sex, body mass index, presence or absence of cirrhosis or diabetes, baseline alanine aminotransferase and γ-glutamyl transferase levels, viral subtype, IL28B genotype, and baseline HCV RNA level.

After adjustment for IL28B genotype, sustained virologic response rates were higher among those with HCV genotype 1b infection compared with patients with HCV genotype 1a infection in all groups except the TID40W group (BID28W, P < .001; TID16W and TID28W-NR, P = .001; TID28W, P = .03; and TID40W, P = .38).

After adjustment for viral subtype, patients with the IL28B CC genotype had higher sustained response rates compared with those with non-CC genotypes in the BID28W and TID28W-NR groups (P = .05 and P = .02, respectively).

Of the 75 patients who had virologic breakthrough during the trial, 50 had HCV genotype 1a infection. Relapse occurred in 19% of those in the TID16W group, 2% of those in the TID28W group, 2% of those in the TID40W group, 0% of those in the BID28W group, and 10% of those in the TIDW-NR group.

Overall, 94% of patients experienced adverse events, 9% of which were severe. The most common adverse events were gastrointestinal and dermatologic: nausea, vomiting, diarrhea, rash, and photosensitivity.

"While it is important to show that responses in the 50% to 60% range can be obtained without interferon, it is unlikely that these drugs will have much impact in the near future," said Gary L. Davis, MD, director of general and transplant hepatology at Baylor University Medical Center, Baylor HealthCare System, Dallas, Texas, in an interview with Medscape Medical News.

"First, this is a phase 2b trial, and their phase 3 study is still ongoing," said Dr. Davis, who was not involved in the trial. "Second, these results are not really competitive with other interferon-free regimens in phase 3 or the combination of sufosbuvir and simeprevir (2 drugs that are likely to be approved by the end of the year; although these 2 drugs will not be approved as a combination, the phase 2 trial with this combination showed 100% [sustained virologic response])," Dr. Davis explained.

"Thus, [Boehringer Ingelheim's] strategy moving forward would probably be to add another drug to this regimen. In looking at clinicaltrials.gov, it appears that they are recruiting such a study now (includes PPI-668, an NS5A inhibitor like daclatasvir and GS5885). Finally, I am concerned about the amount of side effects and whether such a poorly tolerated regimen would ever be competitive," Dr. Davis added. "The poor response with genotype 1a is problematic, but again this might be overcome with PPI-668 in their new study."

The study was supported by Boehringer Ingelheim. The authors report a variety of relationships with pharmaceutical companies that make treatments for HCV, including consulting, expert testimony, board membership, employment, serving on speaker's bureaus, payment for development of educational presentations, and receipt of grant funding. A complete list can be found on the journal's Web site. Dr. Davis is on the Data Safety and Monitoring Boards for Gilead and BMS.

N Engl J Med. 2013;369:630-639.

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