A 12-week course of treatment with two direct-acting
antivirals in development by Merck plus
ribavirin cured 95% of people with hepatitis C who had experienced failure of a
previous treatment combination containing a protease inhibitor, Dr Xavier Forns of
the Hospital Clinic, University of Barcelona, told the International Liver
Congress in Vienna, Austria, on Thursday
Merck’s combination of direct-acting antivirals consists of
grazoprevir (a NS3/4 protease inhibitor) and elbasvir (an NS5A inhibitor). The
combination is being studied as a once-daily, single-tablet regimen, with or
without ribavirin. The two drugs are active against multiple genotypes of
The C-SALVAGE study was designed to investigate the efficacy
of grazoprevir/elbasvir in people with genotype 1 hepatitis C virus (HCV) monoinfection who
had failed to achieve a cure after a previous course of antiviral treatment containing
pegylated interferon and either telaprevir, boceprevir or simeprevir.
- decompensated cirrhosis
The later stage of
cirrhosis, during which the liver cannot perform some vital functions and
complications occur. See also ‘cirrhosis’ and ‘compensated cirrhosis’.
- direct-acting antiviral (DAA)
A drug which prevents hepatitis C from reproducing by blocking certain steps in its lifecycle.
Protease inhibitor (PI) activity after first PI failure is not
well understood. There is some evidence that resistance to protease inhibitors
persists, but until the C-SALVAGE study was carried out it was unclear to what
extent Merck’s protease inhibitor-based regimen might be successful in the
population of people who had failed to benefit from a first- or
second-generation protease inhibitor.
For Merck, it is important to establish that a regimen
containing grazoprevir can cure HCV in the vast majority of people who failed
to benefit from the first generation of protease inhibitors, telaprevir and
boceprevir, or the second-generation protease inhibitor. In the cases of people
previously treated with boceprevir and telaprevir, up to half of patients with
more advanced liver disease may have failed to achieve a cure, leaving a
substantial unmet need.
The study excluded participants with decompensated cirrhosis
or hepatocellular carcinoma (liver cancer), and people with HIV and
hepatitis C co-infection.
The study recruited 79 people, of whom 42% were women and 34%
had cirrhosis. Thirty-eight per cent had genotype 1a infection.
The majority of participants had received prior treatment
with telaprevir (54%); simeprevir treatment was less common (10%). Thirty per cent of
participants had experienced virological non-response or viral breakthrough
during protease inhibitor treatment. The remainder had experienced viral
breakthrough during the post-protease inhibitor period of pegylated interferon
treatment, or viral relapse after completion of all treatment.
A high frequency of resistance mutations associated with
prior protease inhibitor treatment was identified at baseline by sequencing of
the NS3 region of HCV. Of 73 study participants with sequencing data available, 41% had
at least one protease resistance mutation.
Overall, 96.2% of participants achieved a sustained
virologic response 12 weeks after completing treatment (SVR12), with no
substantial difference according to the protease inhibitor to which
participants were exposed previously.
All but one participant
completed the 12-week course of treatment; one person discontinued treatment
due to a serious adverse event. None of the five serious adverse events
reported during the study (bacterial pharyngitis, laryngeal squamous cell
carcinoma, asthma, appendicitis, and urinary tract infection) were considered
to be associated with the study drugs.
A total of 17.9% of participants had a ribavirin dose
reduction. In all cases these patients achieved SVR12.