Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease.

By M. Charlton, G. Everson, S. Flamm, Princy N. Kumar, C. Landis, Robert S. Brown, M. Fried, N. Terrault, J. O’Leary, H. Vargas and 30 more. Gastroenterology, 2015

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BACKGROUND & AIMS There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. METHODS In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85%-88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. CONCLUSION The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.

Subfields: Emergency Medicine, Hepatology, Infectious Diseases

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Citations in the corpus

EASL Recommendations on Treatment of Hepatitis C 2018. (2018, background): “Several studies have demonstrated acceptably high SVR rates, equivalent in Child-Pugh B and C patients, in individuals with decompensated cirrhosis, together with an effect of therapeutic viral clearance on liver function, with significant improvements in bilirubin, albumin and international normali”
EASL Clinical Practice Guidelines: Liver transplantation. (2016, methodology): “The combination of sofosbuvir and ledipasvir with RBV for 12 or 24 weeks was assessed in genotype 1 and 4 patients with compensated (Child-Pugh A) or decompensated (Child-Pugh B and C, up to 12 points) cirrhosis [30].”
Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. (2016, background): “Different studies have shown rates of sustained virological response (SVR) around 95–97% in compensated cirrhosis [1–3] and 85–90% in patients with more advanced liver disease including those awaiting liver transplantation [4,5].”