Terms used in these reports:
- RVR (Rapid virological response)= No virus detected at week 4
- eRVR(Extended rapid virological response) = No virus detected at week 4 and week 12
- EVR (Early Virological Response) — 2 log drop of HCV RNA after 12 weeks.
- cEVR = Complete Early Virological Response — No virus detected after 12 Weeks.
- SVR12 (Sustained virological response) = No virus detected at 12 weeks after completion of treatment.
- SVR24 = No virus detected at 24 weeks after completion of treatment.
The hepatitis C virus (HCV) NS3/4A protease inhibitor danoprevir (formerly RG7128) plus pegylated interferon/ribavirin produced high cure rates and many patients were eligible for shorter therapy, according to findings presented at the recent American Association for the Study of Liver Diseases Liver Meeting (AASLD 2011) in San Francisco.
Norah Terrault from the University of California at San Francisco presented final data from the ATLAS trial, which evaluated danoprevir plus pegylated interferon/ribavirin in previously untreated patients with genotype 1 chronic hepatitis C.
The analysis included 225 treatment-naive participants in North America, Europe, and Australia. A majority were men, nearly 90% were white, 10% were black, and the average age was 48 years. Patients had absent to moderate fibrosis (stage F0-F2) and HCV RNA 50,000 IU/mL or higher at baseline; 65% had hard-to-treat HCV subtype 1a and one-third had the favorable IL28B CC gene pattern.
Participants were randomly allocated to received danoprevir at doses of 300 mg three-times-daily (every 8 hours), 600 mg twice-daily, or 900 mg twice-daily, or else placebo, in combination with pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted ribavirin.
All patients used the triple regimen or placebo for 12 weeks, then continued on pegylated interferon/ribavirin alone for an additional 12 weeks. Those with extended rapid virological response (eRVR) at weeks 4 through 20 stopped all treatment at week 24, while the rest continued on pegylated interferon/ribavirin through week 48.
Results
Participants in all danoprevir arms were significantly more likely to experience virological response than those on standard therapy:
RVR at week 4: 74% in 300 mg danoprevir arm, 88% in 600 mg arm, 86% in 900 mg arm, and 7% in placebo arm;
- Extended RVR in danoprevir arms: 65%, 79%, and 18%, respectively;
- Sustained virological response at 24 weeks post-treatment: 68%, 85%, 76%, and 42%, respectively;
- Among patients in the danoprevir arms who achieved eRVR, the corresponding SVR rates were 87%, 96%, and 89%, respectively.
- Relapse rates were 18%, 8%, and 11% in the danoprevir arms, compared with 38% in the standard therapy arm.
- People with the favorable IL28B pattern did well regardless of regimen (SVR 81%, 95%, 85%, and 88%, respectively), but those with the unfavorable CT or TT patterns did much better in the danoprevir arms vs placebo (63%, 79%, 68%, and 25%, respectively).
- In all treatment arms, sustained response rates were higher for people with HCV subtype 1b (86%, 93%, 67%, and 33%, respectively) compared with 1a (57%, 79%, 78%, and 48%, respectively)
- 3 patients (1.4%) had danoprevir resistance mutations at baseline (D168E, D168D/E, or R155R/K), but all achieved undetectable viral load at week 12.
- 8 people (4%) had resistance-related viral breakthrough or partial response while on triple therapy.
- The most common side effects were fatigue and headache, reported by about half the participants in all treatment arms.
- Nausea, vomiting, and diarrhea occurred more often in the danoprevir arms compared with the standard therapy arm, mostly in the high-dose group.
- Anemia, neutropenia, and rash occurred with similar frequency across arms.
- The highest dose danoprevir arm (900 mg twice-daily) was stopped early due to elevated alanine aminotransferase (ALT), a potential indicator of liver toxicity
- 3 people in the 900 mg danoprevir arm and 1 in the 600 mg arm experienced grade 4 or severe ALT elevation, which resolved after drug discontinuation.
Based on these findings, the researchers concluded, "Response-guided therapy with danoprevir achieved high SVR24 rates" up to 85% vs 42% with pegylated interferon/ribavirin alone, representing a 43% improvement.
They added that 79% of participants in the 600 mg danoprevir arm -- the dose judged to have the best balance of efficacy and tolerability -- were eligible to stop treatment at week 24, and among this subgroup 96% achieved SVR.
Terrault noted that the ongoing Dauphine study is testing lower doses of danoprevir boosted with ritonavir (Norvir) -- an antiretroviral drug most often used to boost HIV protease inhibitors -- in an attempt to reduce overall drug exposure and minimize toxicity while maintaining potent antiviral activity.
