Published: Oct 16, 2013
By Cole Petrochko, Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania
- The addition of danoprevir to the combination peginterferon alfa-2a and ribavirin in a randomized study led to high rates of sustained virologic response in patients with hepatitis C virus genotype 1 infection.
- Note, however, that some of the patients receiving high doses of danoprevir had grade 4 increases in alanine aminotransferase.
The addition of danoprevir to peginterferon and ribavirin therapy for hepatitis C increased patients' sustained virologic response, researchers found.
In a phase II trial of danoprevir as an add-on therapy for peginterferon alfa-2a and ribavirin, sustained virologic response was achieved in 68% of those who received 300 mg of the drug, 85% of those who received 600 mg, and 76% in those who received 900 mg, versus 42% in those who received placebo, according to Patrick Marcellin, MD, PhD, of Hôpital Beaujon in Clichy, France, and colleagues.
Serious adverse events were also less common among those treated with danoprevir, with 7% to 8% of those who received drug treatment experiencing serious adverse events versus 19% of those who received placebo, they wrote online in the October issue of Gastroenterology.
Danoprevir is a second-generation protease inhibitor. A pilot trial in 2009 showed that danoprevir combination treatment with mericitabine was associated with dramatic decreases in viral load at 13 days.
The clinical trial randomized 225 treatment-naive hepatitis C genotype 1 patients to one of three danoprevir treatment groups -- 300 mg every 8 hours, 600 mg every 12 hours, or 900 mg every 12 hours -- or to placebo with peginterferon alfa-2a and ribavirin for 12 weeks.
After week 12, patients continued treatment with peginterferon alfa-2a and ribavirin for an additional 12 to 36 weeks. Those who experienced extended rapid virologic response -- defined as undetectable hepatitis C virus (HCV) RNA at weeks 4 to 20 -- discontinued therapy after 24 total weeks.
Efficacy endpoints included sustained undetectable viral load at 23 weeks of untreated follow-up, virologic response rates over time, relapse rates, and sustained virologic response in those who had an extended rapid virologic response. Researchers also looked at response based on HCV RNA analysis through serum measures every few weeks through week 48 of treatment, as well as at weeks 4, 12, and 24 of untreated follow-up.
Patients were mostly white (84% to 88%), had a mean age of 47 to 50, and had HCV RNA levels of 800,000 IU/mL or greater.
After the first week of drug treatment, mean HCV RNA decreases ranged from 3.95 to 4.28 log10 IU/mL versus 0.77 log10 IU/mL with placebo treatment, and mean maximum reductions occurred after 4 to 6 weeks of drug treatment "and were sustained throughout the first 24 weeks of treatment in danoprevir-treated patients," the investigators reported.
Compared with placebo, danoprevir treatment increased on-treatment virologic response rates and sustained virologic response, and decreased relapse rates.
Investigators also found:
- Among those who experienced extended rapid virologic response, sustained virologic response was achieved in 87% of those receiving 300 mg of danoprevir and in 96% of those receiving 600 mg.
- Relapse occurred in 18%, 8%, and 11% of those treated with 300 mg, 600 mg, and 900 mg of danoprevir, respectively, versus 38% of those receiving placebo.
- There was also a "consistently higher sustained virologic response rate" among drug-treated patients with IL28B CC genotype disease.
Types of adverse events were similar between drug versus placebo treatment groups, and common events included fatigue, headache, nausea, insomnia, myalgia, and chills. Incidence of nausea, diarrhea, and vomiting "increased in a dose-related manner" among drug recipients.
Neutropenia occurred in 6% to 13% of danoprevir group participants versus 10% of placebo recipients. Hemoglobin of <10 g/dL and <8.5 g/dL occurred in 19-24% and 1-4% of participants, respectively, versus 35% and 6% of those who received placebo.
Four patients given danoprevir (one in the 600-mg group and three in the 900-mg group) had reversible, grade 4 increases in alanine aminotransferase, which led to early discontinuation of the 900-mg arm of the study.
The study was limited by a low number of black patients, exclusion of patients with advanced fibrosis and cirrhosis, and randomization that did not stratify for IL28B genotype or HCV subgenotype.
The study was supported by F. Hoffmann-La Roche.
The authors received support from Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tiboted, MSD, AbbVie, Boehringer Ingelheim, Pfizer, Allos BioPharma, Merck, Genentech, Hyperion, Bayer, Bristol-Myers Squibb, Kadmon, Idenix, Salix, Sundise, Genfit, Astellas, GlaxoSmithKline, Medtronic, Santaris, Rottapharm-Madaus, Achillion, MSD Austria, Janssen Austria, BMS Austria, and Roche Austria.
Primary source: Gastroenterology
Source reference: Marcellin P, et al "Randomized controlled trial of danoprevir plus peginterferon alfa-2a and ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection" Gastroenterology 2013; 145: 790-800; DOI: 10.1053/j.gastro.2013.06.051.