New hepatitis C drugs danoprevir and mericitabine are safe and effective for prior non-responders and people with cirrhosis

This article is more than 11 years old. Click here for more recent articles on this topic

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 Liver Meeting 2012 (the 63rd Annual Meeting of the American Association for the Study of Liver Diseases, or AASLD) this week in Boston. Another analysis from the trial showed good outcomes for people with advanced 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 few side-effects.

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



Thickening and scarring of connective tissue. Often refers to fibrosis of the liver, which can be caused by an inflammatory reaction to long-term hepatitis infection. See also ‘cirrhosis’, which is more severe scarring.

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

pegylated interferon

Pegylated interferon, also known as peginterferon, is a chemically modified form of the standard interferon, sometimes used to treat hepatitis B and C. The difference between interferon and peginterferon is the PEG, which stands for a molecule called polyethylene glycol. The PEG does nothing to fight the virus. But by attaching it to the interferon (which does fight the virus), the interferon will stay in the blood much longer. 

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.


The return of signs and symptoms of a disease after a patient has been free of those signs and symptoms. 

The MATTERHORN study enrolled 379 chronic hepatitis C patients with HCV genotype 1 who were either partial responders (at least a 2 log10 drop in HCV RNA by treatment week 12, but still detectable at the end of treatment) or null responders (less than a 2 log10 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 showing no cirrhosis. (People with cirrhosis are being studied in a separate trial known as RUSHMORE.) Very few had the favourable IL28B 'CC' gene pattern associated with better interferon response.

Prior partial responders were randomly assigned to three treatment arms, all for 24 weeks:

  • Interferon-free triple therapy with 100mg twice-daily danoprevir, 1000mg twice-daily mericitabine and 1000-1200mg/day ribavirin;
  • Triple therapy with danoprevir, mericitabine and 180mcg once-weekly pegylated interferon alfa-2a (Pegasys);
  • Quadruple therapy with all four 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 participants assigned to interferon-free triple therapy (all genotype 1b), 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%, respectively.

Looking at 49 people with genotype 1a or 1b who received the other triple regimen of boosted danoprevir/pegylated interferon/ribavirin, as well as the 50 people assigned to the quadruple regimen, both groups had a response rate of 94% at the end of treatment.

But people in the triple-therapy arm without mericitabine were significantly more likely to relapse after stopping treatment than those taking quadruple therapy. SVR4 rates were 67 and 90%, respectively, while SVR12 rates were 56 and 86%, respectively.

Finally, among the 77 participants 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: 91% for prior partial responders taking interferon-free triple therapy, 96% for partial responders taking the quadruple regimen and 100% for null responders on the quadruple combo.

Among genotype 1a participants, SVR12 response rates were lower across the board. But the most notable difference was that partial responders taking interferon-free therapy were less than half as likely to achieve a cure as partial or null responders taking the quadruple regimen (30, 75 and 73%, respectively).

Stated another way, viral breakthrough during treatment was uncommon across the board. Relapse after finishing treatment was also uncommon among genotype 1b patients, but the rate reached 67% for genotype 1a patients on the triple regimen without mericitabine, and 23% even for those on the potent quadruple regimen. Participants with viral breakthrough or relapse showed evidence of danoprevir resistance mutations but not resistance to mericitabine.

Turning to drug safety, the most common side-effects were flu-like symptoms including fatigue, headache, and muscle and joint aches, as well as gastrointestinal symptoms. All side-effects occurred less often with interferon-free therapy, and no adverse events were uniquely associated with mericitabine.

Nevertheless, 9% of people taking interferon-free therapy, 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 two arms.

The researchers concluded that 24 weeks of treatment with the quadruple regimen produced "high overall SVR12 rates" (84 to 86%). Among people with 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 anaemia) in a triple regimen with boosted danoprevir and pegylated interferon.

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 vs 52 people with advanced fibrosis, the researchers found that boosted danoprevir pharmacokinetics were similar regardless of fibrosis stage.

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, people 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 side-effects and laboratory abnormalities when compared with the advanced fibrosis group. Serious adverse events were four 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.


Feld J 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 Disease, Boston, abstract 81, 2012. 

Jacobson I et al. Safety and efficacy of ritonavir-boosted danoprevir (DNVr), peginterferon alfa-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 Disease, Boston, abstract 82, 2012.

View the abstracts on the conference website.