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

Michael Charlton, Gregory T. Everson, Steven L. Flamm, Princy Kumar, Charles Landis, Robert S. Brown, Michael W. Fried, Norah A. Terrault, Jacqueline G. O'Leary, Hugo E. Vargas, Alexander Kuo, Eugene R Schiff, Mark S. Sulkowski, Richard Gilroy, Kymberly D. Watt, Kimberly Brown, Paul Kwo, Surakit Pungpapong, Kevin M. Korenblat, Andrew J. MuirLewis Teperman, Robert J. Fontana, Jill Denning, Sarah Arterburn, Hadas Dvory-Sobol, Theo Brandt-Sarif, Phillip S. Pang, John G. McHutchison, K. Rajender Reddy, Nezam Afdhal

Research output: Contribution to journalArticle

491 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)649-659
Number of pages11
JournalGastroenterology
Volume149
Issue number3
DOIs
StatePublished - Sep 1 2015

Fingerprint

Ribavirin
Virus Diseases
Hepacivirus
Liver Diseases
Fibrosis
Therapeutics
Liver Transplantation
Liver
Genotype
sofosbuvir drug combination ledipasvir
Hepatitis
Chronic Hepatitis C
Infection
Tablets

Keywords

  • Decompensated Cirrhosis
  • Fibrosing Cholestatic Hepatitis
  • Hepatitis C Virus Infection
  • Liver Transplantation

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Charlton, M., Everson, G. T., Flamm, S. L., Kumar, P., Landis, C., Brown, R. S., ... Afdhal, N. (2015). Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients with Advanced Liver Disease. Gastroenterology, 149(3), 649-659. https://doi.org/10.1053/j.gastro.2015.05.010

Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients with Advanced Liver Disease. / Charlton, Michael; Everson, Gregory T.; Flamm, Steven L.; Kumar, Princy; Landis, Charles; Brown, Robert S.; Fried, Michael W.; Terrault, Norah A.; O'Leary, Jacqueline G.; Vargas, Hugo E.; Kuo, Alexander; Schiff, Eugene R; Sulkowski, Mark S.; Gilroy, Richard; Watt, Kymberly D.; Brown, Kimberly; Kwo, Paul; Pungpapong, Surakit; Korenblat, Kevin M.; Muir, Andrew J.; Teperman, Lewis; Fontana, Robert J.; Denning, Jill; Arterburn, Sarah; Dvory-Sobol, Hadas; Brandt-Sarif, Theo; Pang, Phillip S.; McHutchison, John G.; Reddy, K. Rajender; Afdhal, Nezam.

In: Gastroenterology, Vol. 149, No. 3, 01.09.2015, p. 649-659.

Research output: Contribution to journalArticle

Charlton, M, Everson, GT, Flamm, SL, Kumar, P, Landis, C, Brown, RS, Fried, MW, Terrault, NA, O'Leary, JG, Vargas, HE, Kuo, A, Schiff, ER, Sulkowski, MS, Gilroy, R, Watt, KD, Brown, K, Kwo, P, Pungpapong, S, Korenblat, KM, Muir, AJ, Teperman, L, Fontana, RJ, Denning, J, Arterburn, S, Dvory-Sobol, H, Brandt-Sarif, T, Pang, PS, McHutchison, JG, Reddy, KR & Afdhal, N 2015, 'Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients with Advanced Liver Disease', Gastroenterology, vol. 149, no. 3, pp. 649-659. https://doi.org/10.1053/j.gastro.2015.05.010
Charlton, Michael ; Everson, Gregory T. ; Flamm, Steven L. ; Kumar, Princy ; Landis, Charles ; Brown, Robert S. ; Fried, Michael W. ; Terrault, Norah A. ; O'Leary, Jacqueline G. ; Vargas, Hugo E. ; Kuo, Alexander ; Schiff, Eugene R ; Sulkowski, Mark S. ; Gilroy, Richard ; Watt, Kymberly D. ; Brown, Kimberly ; Kwo, Paul ; Pungpapong, Surakit ; Korenblat, Kevin M. ; Muir, Andrew J. ; Teperman, Lewis ; Fontana, Robert J. ; Denning, Jill ; Arterburn, Sarah ; Dvory-Sobol, Hadas ; Brandt-Sarif, Theo ; Pang, Phillip S. ; McHutchison, John G. ; Reddy, K. Rajender ; Afdhal, Nezam. / Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients with Advanced Liver Disease. In: Gastroenterology. 2015 ; Vol. 149, No. 3. pp. 649-659.
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abstract = "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.",
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author = "Michael Charlton and Everson, {Gregory T.} and Flamm, {Steven L.} and Princy Kumar and Charles Landis and Brown, {Robert S.} and Fried, {Michael W.} and Terrault, {Norah A.} and O'Leary, {Jacqueline G.} and Vargas, {Hugo E.} and Alexander Kuo and Schiff, {Eugene R} and Sulkowski, {Mark S.} and Richard Gilroy and Watt, {Kymberly D.} and Kimberly Brown and Paul Kwo and Surakit Pungpapong and Korenblat, {Kevin M.} and Muir, {Andrew J.} and Lewis Teperman and Fontana, {Robert J.} and Jill Denning and Sarah Arterburn and Hadas Dvory-Sobol and Theo Brandt-Sarif and Pang, {Phillip S.} and McHutchison, {John G.} and Reddy, {K. Rajender} and Nezam Afdhal",
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T1 - Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients with Advanced Liver Disease

AU - Charlton, Michael

AU - Everson, Gregory T.

AU - Flamm, Steven L.

AU - Kumar, Princy

AU - Landis, Charles

AU - Brown, Robert S.

AU - Fried, Michael W.

AU - Terrault, Norah A.

AU - O'Leary, Jacqueline G.

AU - Vargas, Hugo E.

AU - Kuo, Alexander

AU - Schiff, Eugene R

AU - Sulkowski, Mark S.

AU - Gilroy, Richard

AU - Watt, Kymberly D.

AU - Brown, Kimberly

AU - Kwo, Paul

AU - Pungpapong, Surakit

AU - Korenblat, Kevin M.

AU - Muir, Andrew J.

AU - Teperman, Lewis

AU - Fontana, Robert J.

AU - Denning, Jill

AU - Arterburn, Sarah

AU - Dvory-Sobol, Hadas

AU - Brandt-Sarif, Theo

AU - Pang, Phillip S.

AU - McHutchison, John G.

AU - Reddy, K. Rajender

AU - Afdhal, Nezam

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

AB - 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.

KW - Decompensated Cirrhosis

KW - Fibrosing Cholestatic Hepatitis

KW - Hepatitis C Virus Infection

KW - Liver Transplantation

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