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.
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
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
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.
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.
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
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%,
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%.
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.
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