Laurie Bouck

November 06, 2008

November 6, 2008 (San Francisco, California) — Two protease inhibitors improve the sustained virologic response (SVR) rate in hepatitis C patients when combined with the standard drug treatment, researchers for 2 separate studies said here at The Liver Meeting 2008, the 59th Annual Meeting of the American Association for the Study of Liver Diseases.

The first study analyzed the use of boceprevir to augment the combination of once-weekly peginterferon alfa-2b (1.5 µg/kg) plus daily ribavirin (400 to 1400 mg).

Data were obtained from 595 patients who participated in the HCV SPRINT-1 phase 2 study of boceprevir 800 mg 3 times a day. That study had 3 treatment groups and 1 control group.

One group received boceprevir after a 4-week lead-in of peginterferon alfa-2b plus daily ribavirin (800 to 1400 mg), then continued receiving all 3 medications for 24 weeks (n = 103) or 44 weeks (n = 103), for a total of 28 or 48 weeks, respectively. The other 2 treatment groups received all 3 medications for the duration of the study; daily ribavirin dose was either 800 to 1400 mg for 28 weeks (n = 107), or 800 to 1400 mg or 400 to 1000 mg for 48 weeks (n = 103).The control group received combination therapy without boceprevir but with daily ribavirin (800 to 1400 mg) for 48 weeks (n = 104).

The 48-week boceprevir lead-in group had the highest SVR rate; 74% of patients were hepatitis C virus (HCV) negative, compared with 38% in the boceprevir-free control group. Viral breakthrough with the triple therapy was more common without the boceprevir lead-in times.

The 4-week lead-in allows "the pegylated interferon and the ribavirin to get to steady-state levels," lead investigator Paul Kwo, MD, from Indiana University School of Medicine in Indianapolis, told Medscape Gastroenterology. Once you have partially reduced the virus, "you add boceprevir to further reduce it," he said. This lead-in strategy also seems to reduce viral resistance through mutations, he said.

The boceprevir groups did have a higher rate of adverse-event-related discontinuations — up to 19%, compared with 8% in the control group. These discontinuations were caused by adverse events related to peginterferon or ribavirin, which boceprevir might have aggravated, said Dr. Kwo. "I think this becomes a matter of being in the clinic and learning to manage the side effects of boceprevir in addition to [peginterferon] and ribavirin."

"I think that's going to be true for all the proteases," Dr. Kwo pointed out. "The second time around, you have more experience with them, and you should be able to have a better adherence rate to the medicine."

The second study, presented by Stefan Zeuzem, MD, from the Department of Internal Medicine at J.W. Goethe University Hospital in Frankfurt, Germany, analyzed the use of telaprevir plus once-weekly peginterferon alfa-2a (180 µg), with or without daily ribavirin (1000 or 1200 mg). Telaprevir was found to be effective in triple therapy for patients with HCV genotype 1.

The PROVE2 study, a 29-site European study, randomized 323 patients to receive various combinations of peginterferon, ribavirin, and telaprevir. The groups were as follows:

  • 82 patients received peginterferon alfa-2a plus daily ribavirin (1000 or 1200 mg), plus a placebo for 48 weeks (PR48 group)

  • 78 patients received peginterferon alfa-2a plus telaprevir 750 mg every 8 hours for 12 weeks (T12/P12 group)

  • 82 patients received peginterferon alfa-2a plus ribavirin plus telaprevir 750 mg every 8 hours for 12 weeks (T12/PR12 group)

  • 81 patients received peginterferon alfa-2a plus ribavirin plus telaprevir 750 mg every 8 hours for 12 weeks, followed by 12 weeks of just peginterferon alfa-2a and ribavirin (T12/PR24 group).



In the placebo (PR48) group, 48% achieved SVR at follow-up. In contrast, 68% of the 24-week triple-therapy (T12/PR24) group achieved SVR.

"I think the data look pretty good," session moderator T. Jake Liang, MD, from the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health in Bethesda, Maryland, told Medscape Gastroenterology. The SVR change is "an important improvement in the treatment response," he said. "We will have to see what the registration phase 3 trial shows," he said, but the phase 2 trial is probably "pretty indicative of what the larger trial could be."

Dr. Liang also thought that boceprevir was "another drug that potentially could be an important addition to the treatment mode for hepatitis C," although, he said, "I think we're going to have to wait for the registration trials and see what the outcome is." "Both of these drugs are the leading drugs at this point that we know appear to have increased efficacy over the standard therapy," he said.

Dr. Liang said it was hard to compare the 2 drugs and their studies directly, because the data from different studies are not always comparable.

Dr. Kwo is a member of advisory committees or review panels for Schering-Plough and Vertex; has received grant or research support from Indenex, Human Genome Sciences, Merck, Novartis, Schering-Plough, and Vertex; and has received speaking and teaching support from Novartis and Schering-Plough. Dr. Zeuzem has consulted for Tibotec, Vertex, and Roche; and has investigated off-label uses of telaprevir. Dr. Liang has disclosed no relevant financial relationships.

The Liver Meeting 2008: 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD): Abstracts LB16 and 243. Presented November 3 and 4, 2008.

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