A triple regimen of grazoprevir/elbasvir (Zepatier) plus sofosbuvir (Sovaldi) without ribavirin cured 96% of
previously untreated and 97% of treatment-experienced people with hepatitis C
virus (HCV) genotype 3 and liver cirrhosis, matching rates seen in easier-to-treat
patient groups, according to results from the C-ISLE study presented on Sunday at
the 2016 AASLD Liver Meeting in Boston.
The development of direct-acting antiviral (DAA)
agents has made treatment of chronic hepatitis C briefer, more convenient and
much more effective than interferon-based therapy. But better options are still
needed for the most difficult-to-treat patients, who still do not achieve the
near-100% sustained response rates seen in easier-to-treat groups.
Lower response rates are associated with HCV genotype
3, presence of liver cirrhosis, prior treatment failure and presence of DAA
resistance-associated variants (RAVs). Nearly a third of people with hepatitis
C worldwide have genotype 3 and it is associated with more rapid liver disease
A protein made in the liver, needed to maintain a balance of the fluids in the body. In a blood test, lower than normal levels of albumin and total protein may indicate liver damage or disease. If there is not enough albumin, fluid may accumulate in the abdomen (ascites).
- compensated cirrhosis
The earlier stage of
cirrhosis, during which the liver is damaged but still able to perform most of
its functions. See also ‘cirrhosis’ and ‘decompensated cirrhosis’.
- direct-acting antiviral (DAA)
A drug which prevents hepatitis C from reproducing by blocking certain steps in its lifecycle.
A non-invasive test, used instead of a biopsy, to measure the stiffness
or elasticity of the liver using an ultrasound probe.
Presenter Graham Foster of Queen Mary University in
London called treatment-experienced people with genotype 3 and cirrhosis the
"toughest of the tough." Currently approved regimens for this group
include sofosbuvir/velpatasvir (Epclusa)
with ribavirin for 12 weeks or sofosbuvir plus daclatasvir (Daklinza) with ribavirin for 12 or 24
weeks, but until recently DAA combinations with pegylated interferon were still
considered an option for these challenging patients.
The C-ISLE study evaluated a co-formulation of Merck's
grazoprevir (an HCV protease
inhibitor) and elbasvir (an NS5A inhibitor) plus Gilead Science’s sofosbuvir
(an NS5B polymerase inhibitor), taken with or without ribavirin for 8 to
16 weeks, for treatment-naive and treatment-experienced people with genotype 3
with compensated cirrhosis. Grazoprevir/elbasvir
is currently indicated only for genotypes 1 and 4. The earlier C-SWIFT study showed promising results for this intensified regimen, but it included
few people with genotype 3.
C-ISLE enrolled 100 participants. About two-thirds
were men, 69% were white, 29% were Asian and the average age was 53 years. Just
over half (53%) had previously used pegylated interferon/ribavirin and the mean
pre-treatment HCV RNA level was 6.2 log10 IU/ml. They had
compensated cirrhosis as indicated by FibroScan
(mean score 25.4 kPa) or liver biopsy. They had no history of hepatic
decompensation, but had albumin, bilirubin and platelet levels indicating
impaired liver function.
Participants in this open-label study were randomly
allocated to five treatment arms. Treatment-naive patients were randomised to
receive grazoprevir/elbasvir plus sofosbuvir either with ribavirin for 8 weeks
or without ribavirin for 12 weeks. Treatment-experienced patients were randomised
to receive grazoprevir/elbasvir plus sofosbuvir with or without ribavirin for
12 weeks, or without ribavirin for 16 weeks.
The primary endpoint was sustained virological
response, or continued undetectable HCV viral load at 12 weeks after completing
Among treatment-naive patients, SVR12 rates were 91%
for 8 weeks of grazoprevir/elbasvir plus sofosbuvir with ribavirin (with two
relapses) and 96% for 12 weeks of grazoprevir/elbasvir plus sofosbuvir without
ribavirin (with one non-virological failure).
Among treatment-experienced patients, SVR12 rates were
100% for 12 weeks of grazoprevir/elbasvir plus sofosbuvir without ribavirin,
94% for 12 weeks of grazoprevir/elbasvir plus sofosbuvir with ribavirin, and
94% for 16 weeks of grazoprevir/elbasvir plus sofosbuvir without ribavirin (with
one non-virological failure in each of the latter two arms).
However, when excluding the three participants who
discontinued treatment early for reasons other than virological failure (loss
to follow-up, withdrawal of consent and non-drug-related adverse event), the
cure rate was 100% for all but the 8-week regimen.
One of the two relapsers had various resistance-associated
variants (including the Y93H mutation) at baseline and at the time of treatment
failure, but the other had wild-type virus before and after treatment. The SVR12
rate was the same – 98% – for the half of patients that had pre-existing NS5A
RAVs and the half that did not.
Therapy was generally safe and well tolerated, with no
treatment discontinuations due to adverse events. The most frequently reported
adverse events were fatigue, nausea, and skin rash or itching. Side-effects
overall and serious adverse events were more common among people who used
ribavirin and those treated for a longer duration.
"High efficacy was
demonstrated in treatment-naive and treatment-experienced cirrhotic HCV
genotype 3-infected patients," the researchers concluded.
Everyone who completed
treatment with grazoprevir/elbasvir plus sofosbuvir without ribavirin
had a sustained response, Prof. Foster noted. Both virological failures were in
the 8-week arm with ribavirin, and one of these patients had the Y93H mutation.
However, all patients with Y93H who were treated for 12 weeks were cured.
While there has been concern
about liver-related adverse events in people with cirrhosis treated with HCV
protease inhibitors, no such problems were observed in this study. Prof. Foster
said he would be comfortable treating people with Child-Pugh class B cirrhosis,
which indicates significant compromise of liver function but not yet