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HIV and Hepatitis.com Coverage of the
46th Annual Meeting of the European
Association for the Study of the Liver

March 30 - April 3, 2011, Berlin, Germany

Boosted Danoprevir Improves Response in Prior Null Responders

SUMMARY: Nearly 90% of genotype 1b prior non-responder hepatitis C patients treated with ritonavir-boosted danoprevir plus pegylated interferon/ribavirin experienced early virological response at week 12, but breakthrough reached 50% for those with genotype 1a.

By Liz Highleyman

Direct-acting antiviral drugs targeting various steps of the hepatitis C virus (HCV) lifestyle are expected to bring about a new treatment paradigm, especially for people with hard-to-treat HCV genotype 1 who did not achieve sustained virological response, or a cure, with a prior course of therapy. The need is especially urgent for prior null responders who did not experience significant decline in HCV viral load at any time during previous treatment.

As reported at the European Association for the Study of the Liver's International Liver Congress (EASL 2011) this month in Berlin, an international team of researchers evaluated the safety and efficacy Roche's HCV NS3/4A serine protease inhibitor candidate danoprevir (formerly known as RG7227 and ITMN-191) boosted with ritonavir (Norvir) added to standard therapy for prior null responders.

This analysis study included 24 chronic hepatitis C patients who did not achieve at least a 2 log reduction in HCV RNA by week 12 of prior treatment with pegylated interferon/ribavirin.

The larger study compared different doses of danoprevir or placebo plus standard therapy, but all prior null responders in this sub-analysis received open-label 100/100 mg danoprevir/ritonavir twice-daily plus pegylated interferon alfa-2a (Pegasys) and weight-adjusted ribavirin for 12 weeks, continuing on pegyalted interferon/ribavirin alone through week 48.

Most participants (79%) were men, 83% were white, and the mean age was 48 years. One-third had HCV genotype 1a and 67% had 1b. People with liver cirrhosis were excluded.

Results

At week 4, 38% of genotype 1a patients and 88% of genotype 1b patients experienced rapid virological response.
At week 12, 50% of genotype 1a patients achieved early virological response, with the rate remaining at 88% for those with genotype 1b.
By week 12, half of genotype 1a participants (4 out of 8) experienced viral breakthrough during treatment, compared with just 1 person (6%) with genotype 1b.
Enrollment of genotype 1a patients was halted due to these findings.
All participants experienced at least 1 adverse event, but none had serious adverse events or laboratory abnormalities.
The most common side effect was headache, reported by 63% of participants.
Viral breakthrough was associated with the R155K resistance mutation.

Based on these findings, the researchers concluded that danoprevir/ritonavir 100/100 mg twice-daily plus pegylated interferon/ribavirin "appears to be well tolerated and provides robust virological response" in genotype 1b prior null responders, with a low rate of virological breakthrough.

"In contrast," they continued, "relatively high rates of virological breakthrough were observed with genotype 1a null responders which may potentially be address by the addition of a second direct antiviral agent to increase the barrier to resistance.

They added that a new trial dubbed MATTERHORN will begin this year to evaluate boosted danoprevir plus the investigational HCV polymerase inhibitor mericitabine (RG7128) plus pegylated interferon/ribavirin in this difficult to treat patient population.

Investigator affiliations: Centre CAP; Saint Eloi Hospital, Montpellier, France; Auckland Clinical Studies, Auckland, New Zealand; Medical University of Warsaw, Warsaw, Poland; Roche, South San Francisco, CA; Roche, Welwyn, UK; Roche, Nutley, NJ.

4/19/11

Reference
R Rouzier, D Larrey, EJ Gane, et al. Activity of danoprevir plus low-dose ritonavir in combination with peginterferon alfa-2a (40KD) plus ribavirin in previous null responders. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 62.





 


 

 


 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



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