Back HCV Treatment AASLD 2012: Danoprevir and Mericitabine Work for Prior Non-responders, Hep C Patients with Cirrhosis

AASLD 2012: Danoprevir and Mericitabine Work for Prior Non-responders, Hep C Patients with Cirrhosis


The experimental hepatitis C drugs danoprevir and mericitabine, with or without pegylated interferon and ribavirin, showed good safety and efficacy in previously treated patients, according to findings from the MATTERHORN study presented at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting this week in Boston. Another analysis from the same trial showed good outcomes for people with liver fibrosis.

The advent of direct-acting drugs that target various steps of the hepatitis C virus (HCV) lifecycle have brought about a new era of treatment. Many combination regimens are currently under study, with a focus on difficult-to-treat patients who did not do well on the old standard of care, including non-responders to prior interferon-based therapy and people with advanced liver disease. The ultimate goal is all-oral, interferon-free regimens that are easy to use and cause minimal toxicity.

Jordan Feld from Toronto Western Hospital Liver Centre and colleagues evaluated the safety and efficacy of different combination regimens containing the second-generation HCV protease inhibitor danoprevir, the nucleoside HCV polymerase inhibitor mericitabine, ribavirin, and for some participants, pegylated interferon alfa-2a (Pegasys). Danoprevir is boosted with a small amount of ritonavir (Norvir) to reach higher levels in the body.

The MATTERHORN study enrolled 379 chronic hepatitis C patients with HCV genotype 1 who were either partial responders (at least a 2 log drop in HCV RNA by treatment week 12, but still detectable at the end of treatment)or null responders (less than a 2 log drop by week 12) to prior interferon-based treatment.

Approximately 70% of participants were men, most were white, and the average age was about 50 years. The study included people with HCV genotypes 1a or 1b, but those with harder-to-treat 1a were not assigned to interferon-free therapy.

About one-quarter of participants had advanced liver fibrosis (equivalent to Metavir stage F3), but all had biopsies or FibroScan measurements within the past 2 years showing no cirrhosis. (People with cirrhosis are being studied in a separate trial known as RUSHMORE.) Very few had the favorable IL28B CC gene pattern associated with better interferon response.

Prior partial responders were randomly allocated to 3 treatment arms, all for 24 weeks:

  • Interferon-free triple therapy with 100 mg twice-daily danoprevir boosted with 100 mg ritonavir, 1000 mg twice-daily mericitabine, and 1000-1200 mg/day ribavirin;
  • Triple therapy with danoprevir, mericitabine, and 180 mcg once-weekly pegylated interferon alfa-2a;
  • Quadruple therapy with all 4 drugs.

Prior null responders received either interferon-free triple therapy for 24 weeks, the quadruple regimen for 24 weeks, or the quadruple regimen with a pegylated interferon/ribavirin "tail" continuing through 48 weeks (the latter group is still undergoing treatment).

Researchers reported rates of sustained virological response, or continued undetectable HCV viral load (< 25 IU/mL), at weeks 4 and 12 after completion of treatment, known as SVR4 and SVR12. Sustained response at weeks 12 and 24 is considered a cure.


  • Among the 23 genotype 1b participants assigned to interferon-free triple therapy, the virological response rate at the end of treatment was 87%.
  • The relapse rate was high, however, resulting in SVR4 and SVR12 rates of 44% and 39%, respectively.
  • Among the 32 prior null responders taking the interferon-free regimen, the corresponding rates were 88%, 68%, and 55%.
  • Looking at the 49 prior partial responders with genotype 1a or 1b who received the boosted danoprevir/pegylated interferon/ribavirin triple regimen, as well as the 50 patients assigned to the quadruple regimen, both groups had an end-of-treatment response rate of 94%.
  • However, people in the triple therapy arm without mericitabine were significantly more likely to relapse after stopping therapy than those taking quadruple therapy.

o   SVR4: 67% vs 90%, respectively;

o   SVR12: 56% vs 86%, respectively.

  • Finally, among the 77 prior null responders with genotype 1a or 1b who received the quadruple regimen, the end-of-treatment response rate was 96%, SVR4 was 85%, and SVR12 was 84%.
  • Breaking the results down according to HCV subtype, people with genotype 1b had high SVR12 rates regardless of treatment:

o   Prior partial responders taking danoprevir/pegylated interferon/ribavirin triple therapy: 91%;

o   Partial responders taking the quadruple regimen: 96%;

o   Null responders on the quadruple combo: 100%.

  • Among genotype 1a participants, SVR12 response rates were lower across all arms.
  • Partial responders taking danoprevir/pegylated interferon/ribavirin were less than half as likely to achieve a cure as partial or null responders taking the quadruple regimen (30%, 75%, and 73%, respectively).
  • Viral breakthrough during treatment was uncommon across the board.
  • Relapse after finishing treatment was also uncommon among genotype 1b patients.
  • Relapse rate reached 67% for genotype 1a patients on the danoprevir/pegylated interferon/ribavirin triple regimen without mericitabine, and 23% even for those on the potent quadruple combo.
  • Participants with viral breakthrough or relapse had danoprevir resistance mutations, but not resistance to mericitabine.
  • Looking at drug safety, the most common adverse events were flu-like symptoms including fatigue, headache, muscle and joint aches, as well as gastrointestinal symptoms.
  • All side effects occurred less often in the interferon-free arm.
  • There were no adverse events uniquely associated with mericitabine.
  • Nevertheless, 9% of people taking the interferon-free regimen, 2% taking the triple regimen without mericitabine, and 4% on the quadruple combo reported severe adverse events.
  • No one in the interferon-free arm stopped treatment for this reason, however, compared with 4% and 2%, respectively, in the other arms.

The researchers concluded that 24 weeks of treatment with the quadruple regimen produced "high overall SVR12 rates" (84%-86%). Among people with HCV genotype 1b, boosted danoprevir plus pegylated interferon/ribavirin worked equally well with or without mericitabine for prior partial and null responders.

But for people with hard-to-treat genotype 1a, adding mericitabine raised the SVR12 rate from 30% to 75% for partial responders, with a similar 73% rate for null responders.

Given that mericitabine reduces the likelihood of post-treatment relapse with no extra toxicity, it would be interesting to see if it could be used instead of ribavirin (which causes anemia) in a triple regimen with boosted danoprevir and pegylated interferon.

[Editor's note: This report has been edited to correct the regimens used in the different treatment arms]

Advanced Fibrosis

Following Feld's presentation, Ira Jacobson from Weill Cornell Medical College showed results from a MATTERHORN sub-analysis looking at people with advanced liver fibrosis. As noted above, about one-quarter of study participants had advanced fibrosis (stage F3), but none had cirrhosis (F4).

In an analysis comparing 179 participants with absent (F0), mild (F1), or moderate (F2) fibrosis versus 52 people with advanced fibrosis, the researchers found that boosted danoprevir pharmacokinetics were similar regardless of the extent of fibrosis.

SVR12 rates were similar for partial responders taking boosted danoprevir/pegylated interferon/ribavirin (56% vs 57%, respectively) and partial or null responders taking the quadruple regimen (86% vs 82%, respectively).

Among partial or null responders using interferon-free triple therapy, patients with milder fibrosis had a somewhat lower SVR12 rate than those with advanced liver disease (43% vs 70%, respectively). This pattern was seen both for people with genotype 1b (90% vs 100%) and those with 1a (27% vs 40%). Overall, however, the researchers concluded that sustained response rates were "comparable."

But people with absent or moderate fibrosis had lower rates of most adverse events and laboratory abnormalities when compared with the advanced fibrosis group. Serious adverse events were 4 times more common (3% vs 12%), while discontinuation due to side effects was twice as common 2% vs 4%).

The RUSHMORE study looking at people with cirrhosis should shed more light on the influence of liver damage on the safety and effectiveness of danoprevir and mericitabine.



JJ Feld, IM Jacobson, DM Jensen, et al. Up to 100% SVR4 rates with ritonavir-boosted danoprevir (DNVr), mericitabine (MCB) and ribavirin (R) + peginterferon alfa-2a (40KD) (P) in HCV genotype 1-infected partial and null responders: results from the MATTERHORN study. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 81.

IM Jacobson, DM Jensen, S Pol, et al. Safety and efficacy of ritonavir-boosted danoprevir (DNVr), peginterferon α-2a (40KD) (P) and ribavirin (R) with or without mericitabine in HCV genotype (G)1-infected treatment-experienced patients with advanced hepatic fibrosis. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 82.