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EASL 2017: Triple Combination Cures Most Hepatitis C Patients with Prior DAA Failure


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 3-drug combination being developed by Merck, researchers reported at the EASL International Liver Congress last month in Amsterdam.

Direct-acting antivirals (DAAs) have transformed treatment for chronic hepatitis C virus (HCV) infection, with cure rates approaching 100% for most patient groups. But better options are still needed for people who do not respond to a first attempt at interferon-free therapy and who may have drug-resistant virus.

Heiner Wedemeyer from 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 (formerly MK-8408) is a NS5A inhibitor. This combination previously demonstrated cure rates over 90% for people new to treatment and those who experienced prior failure of interferon-based therapy.

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 -- 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 1, 39% had 1, and 4% had 3 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 (100/450/60 mg) 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 3 doses of medication. 
  • The presence of resistance-associated substitutions -- including the Y93 NS5A RAS -- had no effect on treatment outcomes.
  • Presence of cirrhosis also had no apparent effect, as all cirrhotic patients who finished treatment were cured.
  • 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, diarrhea, rash, and itching, mostly mild or moderate.
  • 4 people who used ribavirin (9%) developed anemia.

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.



H Wedemeyer, D Wyles, R Reddy,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). EASL International Liver Congress. Amsterdam, April 19-23, 2017. Abstract PS-159.