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EASL 2015: Merck Hepatitis C Combination Achieves 90% Cure in Advanced Cirrhosis Patients

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A 12-week course of treatment with 2 direct-acting antivirals in development by Merck cured hepatitis C virus infection in 90% of people with very advanced cirrhosis and at imminent risk of liver failure, Ira Jacobson of Weill Cornell Medical College reported at the European Association for the Study of the Liver (EASL) 50th International Liver Congress this week in Vienna. The Phase 2 study looked at the use of the HCV protease inhibitor grazoprevir and the NS5A inhibitor elbasvir in people with Child-Pugh B cirrhosis.

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People with a Child-Pugh class B score have significantly impaired liver function and are at high risk for progression to decompensated cirrhosis. They also have a poor prognosis: on average, only about 60% of people with Child-Pugh B cirrhosis survive for more than 2 years once they reach this stage of liver damage. Effective treatment for patients at this stage of liver disease is especially urgent, but until the introduction of interferon-free combinations treatment responses were very poor in this group.

The C-SALT study was designed to evaluate the safety and efficacy of the once-daily single-tablet regimen of grazoprevir and elbasvir without ribavirin in people with HCV genotypes 1, 4, or 6. The study population was restricted to people with Child-Pugh B cirrhosis.

The study was divided into 2 phases: a Phase 2 study in which the pharmacokinetics of grazoprevir and elbasvir were assessed in cirrhotic patients in comparison to a non-cirrhotic control group of people with hepatitis C, alongside safety and efficacy assessments, and a Phase 3 study in which a larger number of cirrhotic patients will be treated. Results of the Phase 2 study were presented at the International Liver Congress.

Participants received grazoprevir and elbasvir for 12 weeks, without ribavirin. Grazoprevir was dosed at 50 mg for cirrhotic patients rather than the usual dose of 100 mg, owing to the potential for higher drug levels in people with seriously impaired liver function. Elbasvir was dosed at 50 mg once-daily as usual, but the drugs were administered separately rather than in a single fixed-dose pill.

The study enrolled 30 participants with Child-Pugh B cirrhosis and a control group of 10 hepatitis C patients without cirrhosis. All participants had HCV genotype 1 (90% of cirrhotics had genotype 1a, compared to 60% of non-cirrhotics). Among those with cirrhosis, 57% were male and all were white.

Patients had Child-Pugh B cirrhosis with a median MELD score of 9.5, indicating a moderate-to-high mortality risk.

The 12-week post-treatment sustained virological response (SVR12) results showed that this interferon- and ribavirin-free regimen was highly effective in this small pilot study. 95% of people with Child-Pugh B cirrhosis and 100% of non-cirrhotic control participants achieved SVR12. Two post-treatment viral relapses occurred, by weeks 4 and 8 respectively, and 1 patient died due to liver failure after achieving end-of-treatment viral suppression.

Analysis of outcomes according to Child-Pugh score showed that a Child Pugh B score of 7 or less was associated with an SVR12 rate of 95%, whereas a score of 9 or above was associated with an SVR12 rate of 50%.

Adverse events were no more frequent in the cirrhosis arm, with the exception of a higher frequency of grade 3 or 4 bilirubin elevations (13% vs 0%), which resolved after the completion of treatment.

4/24/15

Reference

I Jacobson, F Poordad, R Firpi-Morell, et al. Efficacy and Safety af Grazoprevir and Elbasvir in Hepatitis C Genotype 1-infected Patients with Child-Pugh Class B Cirrhosis (C-SALT Part A). 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract O008.