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Triple combination cures most hepatitis C patients with prior DAA treatment failure

Liz Highleyman
02 May 2017

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 month 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.


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’.

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 anaemia.

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 concluded.


Wedemeyer H et al. Safety and efficacy of the fixed-dose combination regimen of MK- 3682/grazoprevir/ruzasvir in cirrhotic or non-cirrhotic patients with chronic HCV GT1 infection who previously failed a direct- acting antiviral regimen (C-SURGE). International Liver Congress, abstract PS-159, 2017.