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Triple combination cures most hepatitis C patients with prior DAA treatment failure
Liz Highleyman, 2017-04-28 09:20:00
Almost all people with genotype 1 hepatitis C who were
previously unsuccessfully treated with a course of interferon-free
direct-acting antiviral therapy achieved sustained response when retreated with
a three-drug combination being developed by Merck, researchers reported at the International
Liver Congress last week in Amsterdam.
Direct-acting antivirals (DAAs) have revolutionised
the treatment of chronic hepatitis C virus (HCV) infection, with cure rates
approaching 100% for most groups of patients. But better options are still
needed for people who do not respond to a first attempt at interferon-free
therapy and may have drug-resistant virus.
Heiner Wedemeyer of Hannover Medical School in
Germany presented findings from the phase 2 C-SURGE trial, which evaluated a once-daily
coformulation of grazoprevir, uprifosbuvir and ruzasvir in people who
relapsed after treatment with a DAA regimen containing an HCV NS5A inhibitor.
Attacking HCV at multiple different targets has a better
chance of overcoming resistance and maintaining viral suppression. Grazoprevir is
an HCV NS3 protease inhibitor, uprifosbuvir (formerly MK-3682) is a nucleotide NS5B polymerase
inhibitor, and ruzasvir is an NS5A inhibitor. This combination previously demonstrated cure rates over 90% for people new
to treatment and those with prior interferon-based therapy failure.
C-SURGE included 94 participants with HCV genotype 1,
mostly harder-to-treat subtype 1a. Most (80%) were men and the median age was
60 years. More than 40% had compensated cirrhosis; people with decompensated
liver disease were excluded.
Just over 60% were previously treated with
sofosbuvir/ledipasvir (Harvoni) for
at least 12 weeks, 15% had taken Harvoni
for only 8 weeks, which is shorter than the recommended treatment duration, and
24% had used grazoprevir/elbasvir (Zepatier)
for 12 weeks – that is, they had already used one of the drugs in the new coformulation.
Most participants had evidence of DAA resistance at
baseline. Over 80% had virus with NS5A resistance-associated substitutions
(RASs); 41% had one, 39% had two and 4% had three or more of these RASs. About
two-thirds (65%) had NS3 protease RASs and 55% had both NS5A and NS3 resistance.
Participants in this open-label study were randomly
assigned to receive once-daily grazoprevir/uprifosbuvir/ruzasvir (100/450/60mg)
either with ribavirin for 16 weeks or without ribavirin for 24 weeks. The primary
study endpoint was sustained virological response, or undetectable HCV RNA 12
weeks after the end of treatment (SVR12).
Cure rates were 98% using the 16-week regimen and 100% using the
24-week regimen in an intent-to-treat analysis. The single individual in the
16-week arm who did not achieve SVR12 left the study after taking only three
doses of medication. The presence of
cirrhosis and resistance-associated substitutions – including the Y93 NS5A RAS
– had no effect on treatment outcomes.
Treatment was generally safe and well tolerated. There
were no drug-related serious adverse events or discontinuations due to adverse
events. The most common events were fatigue, headache, diarrhoea, rash and
itching, mostly mild or moderate. Four people who used ribavirin (9%) developed
Grazoprevir/ruzasvir/uprifosbuvir with or without
ribavirin “was highly effective in genotype 1 participants who previously failed
an NS5A inhibitor-containing direct-acting antiviral regimen,” the researchers