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.
