Tuesday, 01 October 2013 00:00 Written by Liz Highleyman
Combining the second-generation hepatitis C virus (HCV) protease inhibitor danoprevir with pegylated interferon and ribavirin raised the sustained virological response rate to 85% for genotype 1 patients, without much increase in toxicity, according to a report in the October 2013 issue of Gastroenterology.
The advent of direct-acting antivirals has ushered in a new paradigm of treatment for chronic hepatitis C. While these new drugs will eventually be combined in all-oral regimens, many will first be used as add-ons to pegylated interferon and ribavirin.
Patrick Marcellin from Hôpital Beaujon in Clichy, France, and colleagues evaluated the safety and efficacy of response-guided therapy using danoprevir (formerly known as RG7227 and ITMN-191) plus pegylated interferon alfa-2a (Pegasys) and weight-based ribavirin.
This Phase 2 multinational trial included 237 previously untreated people with genotype 1 chronic hepatitis C. Most were white men.
Participants were randomly assigned to received danoprevir at doses of 300 mg every 8 hours, 600 mg every 12 hours, or 900 mg every 12 hours, or else placebo, for 12 weeks, along with pegylated interferon and ribavirin. Patients then continued on pegylated interferon/ribavirin alone, with treatment duration determined by early response.
Danoprevir recipients who experienced extended rapid virological response (eRVR), or undetectable HCV RNA (<15 IU/mL) during weeks 4-20, stopped all treatment at 24 week. Danoprevir recipients without eRVR, and all placebo recipients, stayed on pegylated interferon/ribavirin through 48 weeks.
The primary efficacy endpoint was sustained virological response (SVR), or continued undetectable HCV viral load at 24 weeks after completion of therapy.
- SVR rates were higher among people treated with danoprevir compared with placebo, varying by dose:
o 300 mg: 68%;
o 600 mg: 85%;
o 900 mg: 76%;
o Placebo: 42%.
- Post-treatment relapse rates were 18%, 8%, 11%, and 38%, respectively.
- 65% of participants in the 300 mg danoprevir arm and 79% in the 600 mg arm experienced eRVR.
- Among these patients, 87% in the 300 mg arm and 96% in the 600 mg arm went on to achieve SVR.
- Danoprevir was generally safe and well-tolerated.
- 7% to 8% of danoprevir recipients reported serious adverse events, compared with 19% of placebo recipients.
- 4 people taking danoprevir (1 in the 600 mg group and 3 in the 900 mg group) experienced reversible grade 4 increases in alanine aminotransferase (ALT), leading to early discontinuation of the 900 mg arm.
“The combination of danoprevir, peginterferon alfa-2a, and ribavirin leads to high rates of SVR in patients with HCV genotype 1 infection,” the study authors concluded. “Importantly, the majority of patients treated with danoprevir plus peginterferon alfa-2a/ribavirin achieved [eRVR] and were eligible for a shortened treatment regimen.”
Studies are underway using lower doses of danoprevir boosted with ritonavir in an effort to reduce overall danoprevir exposure while maintaining potent antiviral activity, they added.