Combination therapy with the second-generation protease inhibitor danoprevir yielded high rates of sustained virologic response in hepatitis C.
Moreover, a large portion of patients also demonstrated an extended rapid virologic response up to 20 weeks, reported Dr. Patrick Marcellin and his colleagues in the October issue of Gastroenterology.
Dr. Marcellin, of the Hôpital Beaujon in Clichy, France, and his coinvestigators looked at 225 treatment-naive adults with hepatitis C virus (HCV) genotype 1 infection, including those who had a serum RNA level of 50,000 IU/mL or more.
Exclusion criteria included advanced fibrosis or cirrhosis, anemia, poorly controlled diabetes, or body mass index less than 18 kg/m2 or greater than 36 kg/m2.
The goal of this phase II, randomized, placebo-controlled study (ATLAS) was to evaluate the efficacy of treatment with danoprevir plus peginterferon alfa-2a/ribavirin for 12 weeks, compared with peginterferon alfa-2a/ribavirin alone.
Patients were randomized to one of three doses of oral danoprevir or placebo: 300 mg every 8 hours, 600 mg every 12 hours, or 900 mg every 12 hours.
All doses and placebo were given with standard combination HCV therapy, including subcutaneous peginterferon alfa-2a 180 mg/week plus oral ribavirin (1,000 mg/day for patients with a body weight less than 75 kg or 1,200 mg/day for patients weighing 75 kg or more).
At week 12, treatment with danoprevir or placebo was stopped, and peginterferon alfa-2a/ribavirin was continued for a total duration of 24 or 48 weeks, according to patient response.
Dr. Marcellin found that by week 1, mean decreases in HCV RNA ranged from 3.95 to 4.28 log10 IU/mL in the danoprevir groups, compared with 0.77 log10 IU/mL in the placebo group.
By week 2, according to the investigators, more than half of the danoprevir patients and none of the placebo recipients had achieved undetectable HCV RNA levels.
Indeed, broken down by dose, the researchers calculated that 74% of the danoprevir 300-mg group achieved a rapid virologic response (undetectable serum HCV RNA at week 4), with 65% maintaining an extended rapid virologic response (eRVR), defined as an undetectable HCV RNA that lasted from weeks 4 through 20.
Among the patients taking 600-mg doses, 88% achieved an RVR, with 79% maintaining an eRVR at week 20.
Finally, 86% of patients in the 900-mg treatment group achieved an RVR, although only 18% reached an eRVR.
Patients with an eRVR stopped all treatment at 24 weeks.
"Relapse occurred in 18%, 8%, and 11% of patients treated with danoprevir 300 mg, 600 mg, and 900 mg, respectively, versus 38% in the placebo group," the authors wrote.
Looking at the side-effect profile, Dr. Marcellin reported that fatigue, headache, nausea, insomnia, myalgia, and chills were the most common adverse events for both the treatment and placebo groups.
They also observed reversible, grade 4 elevations in alanine aminotransferase (ALT) levels between weeks 6 and 12 in 2% of danoprevir-treated patients, including three in the 900-mg cohort and one in the 600-mg cohort.
Treatment was discontinued, and serum ALT levels returned to within 1.5 times the upper limit of normal within a month for all four patients, the authors added.
"Notwithstanding the low incidence of reversible ALT elevations observed with high-dose danoprevir in this trial, danoprevir also appears to have a better tolerability profile than either boceprevir or telaprevir, as evidenced by the lower incidence of rash and anemia among danoprevir-treated patients compared with placebo recipients," concluded the investigators.
Indeed, they pointed to other studies showing that coadministration of low-dose ritonavir, another protease inhibitor, "significantly inhibits danoprevir reactive metabolite formation, proposed to be associated with ALT elevations."
"Studies to further evaluate the efficacy and safety of danoprevir in different patient groups are ongoing," the researchers said.
Dr. Marcellin and his fellow investigators reported financial relationships with numerous pharmaceutical companies, including Roche, the maker of danoprevir, which also funded this study.
