Adding the second-generation HCV polymerase inhibitor
sofosbuvir (formerly GS-7977) to pegylated interferon plus ribavirin led to a
sustained response rate of 89% for treatment-naive patients with HCV genotype 1
in the NEUTRINO study, researchers reported at the International Liver Congress (EASL 2013) last week in Amsterdam. High rates
were also seen for the less common genotypes 4, 5 and 6.
While all-oral direct-acting antiviral (DAA) regimens
for chronic hepatitis C are eagerly anticipated, many patients with progressive
liver disease cannot afford to wait. Adding the approved HCV protease
inhibitors boceprevir (Victrelis) or
telaprevir (Incivo or Incivek) to interferon-based therapy can
shorten treatment and increase response, but these drugs have difficult dosing
regimens and come with side effects of their own. Several next generation DAAs
are easier to take and better tolerated.
Eric Lawitz from the University of Texas Health
Science Center and colleagues conducted an open-label, non-randomized phase 3
clinical trial to evaluated the safety and effectiveness of 400mg once-daily
sofosbuvir plus 180mcg/week pegylated interferon alfa-2a (Pegasys) plus
1,000-1,200mg/day weight-based ribavirin.
Glossary
- direct-acting antiviral (DAA)
A drug which prevents hepatitis C from reproducing by blocking certain steps in its lifecycle.
- IL28B
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
All participants were treated for 12 weeks, with no
response-guided therapy. The standard duration of pegylated
interferon/ribavirin alone is 48 weeks for people with genotype 1 and 24 weeks
for those with genotypes 2 or 3.
NEUTRINO enrolled 327 previously untreated chronic
hepatitis C patients with HCV genotypes 1, 4, 5 and 6. These genotypes have
traditionally been considered "hard to treat," but as several studies
at the congress showed, all may not be equally difficult, just as genotypes 2
and 3 are not equally "easy to treat".
Just over 60% of participants were men and the mean
age was 52 years. The study had broad inclusion criteria and enrolled "a good representation" of the U.S.
hepatitis C patient population, Lawitz said.
Looking at predictors of poorer treatment response,
17% were black and 70% had unfavourable (non-CC) IL28B gene variants. The mean
body mass index was 29 (with 30 being the cut-off for obesity) and 17% had
liver cirrhosis. People using opiate substitution therapy were included.
Most patients (89%) had HCV genotype 1, though the
proportions with subtypes 1a and 1b were not reported. Twenty-eight people, or
about 9%, had genotype 4 (most commonly found in the middle-east and Africa,
especially Egypt) while seven people, or about 2%, had genotypes 5 (found
mostly in South Africa) or 6 (found mostly in Asia).
By week 4 of treatment 99% of participants overall had
rapid virological response, and the same proportion still had undetectable HCV
RNA at the end of the 12-week course of treatment.
At 12 weeks post-treatment, 90% overall achieved
sustained virological response (SVR12), exceeding an estimated historical
control rate of 60% for similar patients using pegylated interferon/ribavirin
alone.
By genotype, 89% of people with genotype 1 achieved
SVR12, as did all but one patient with genotype 4 (96%) and all seven people
with genotypes 5 or 6 (100%). A subgroup analysis showed that HCV subtype 1b
had a lower response rate - contrary to most DAA studies, which find 1a harder
to treat - while genotypes 4, 5 and 6 were associated with better response.
Lawitz explained that in this population a disproportionate number of people
with subtype 1b had unfavourable IL28B variants.
Looking at other predictors, people with cirrhosis had
similar response rates as non-cirrhotics at weeks 4 and 12 on treatment (96%
and 100%, respectively), but falling to 80% at post-treatment week 12. Black
patients, people with IL28B non-CC variants, and people with higher baseline
viral load were somewhat less likely to achieve sustained response, but all achieved
SVR12 rates of at least 80%.
All virological failures were attributable to relapse,
with no viral breakthroughs during treatment. Genetic sequencing revealed no
S282T resistance mutations and no other NS5B substitutions causing reduced
susceptibility to sofosbuvir or ribavirin.
Treatment with triple therapy was generally safe and
well tolerated. Almost all participants (98%) completed the study, with seven
total early discontinuations, five (2%) of which were due to adverse events.
About one-third of participants experienced side-effects
- the most common being fatigue (59%), headache (36%) and nausea (34%) - but
serious adverse events were rare (1%). Looking at side-effects known to be associated
with other DAAs, 18% of patients experienced rash, 23% developed moderate
anaemia and 2% had severe anaemia.
Sofosbuvir + pegylated interferon + ribavirin for 12
weeks "resulted in 90% SVR12 rate," which was "statistically
superior to historical control SVR rate of 60%," the investigators
concluded. "Sofosbuvir was well tolerated without any additive effects of
sofosbuvir to the expected safety profile of [pegylated interferon +
ribavirin]."
Lawitz added that the sustained response rate of more
than 80% for cirrhotic patients "is
the highest reported in cirrhosis yet."
Since the
overall response rate with 12 weeks of therapy was so good, an audience member
asked if treatment could potentially be shortened even further. Lawitz replied
that a shorter regimen is "worth studying" in a clinical trial.
However, he noted, the study did not identify any on-treatment predictors (such
as early viral kinetics) to indicate which patients are likely to relapse.
Even though
this regimen still includes interferon and ribavirin, "from the patients'
point of view, 12 weeks is a major breakthrough," said EASL
Secretary-General Mark Thursz at a press conference to highlight hepatitis C
findings.
Results from the
NEUTRINO study were also published in the April 23, 2013, advance online
edition of the New England Journal of
Medicine.