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Treatment of Key Populations and Unique Situations

Treatment of HCV in Persons with Cirrhosis

Lesson 4. Treatment of HCV in Persons with Cirrhosis

CME/CNE Earn CE credit for this module  PDF Share

Learning Objective Performance Indicators

  • Distinguish persons with compensated cirrhosis from those with decompensated cirrhosis
  • Summarize the impact of treating HCV in persons with cirrhosis
  • Provide appropriate HCV treatment options for persons with compensated cirrhosis
  • Discuss approaches to treatment of HCV in persons with decompensated cirrhosis
Last Updated: January 14th, 2021
Authors:
David H. Spach, MD
David H. Spach, MD
Professor of Medicine
Division of Allergy & Infectious Diseases
University of Washington
Disclosures: None
,
John D. Scott, MD
John D. Scott, MD
Assistant Director Hepatitis and Liver Clinic
Harborview Medical Center
Professor of Medicine
Division of Allergy & Infectious Diseases
University of Washington
Disclosures: Consulting: Gilead Sciences
Reviewer:
H. Nina Kim, MD
H. Nina Kim, MD
Professor of Medicine
Division of Allergy & Infectious Diseases
University of Washington
Disclosures: Grant to institution: Gilead Sciences
Table of Contents

Background

Introduction

Individuals with chronic hepatitis C virus (HCV) infection and cirrhosis have an increased risk of developing severe liver-related complications, including hepatic decompensation, hepatocellular cancer, and death. Accordingly, any person with chronic HCV infection who is diagnosed with compensated cirrhosis should be considered as a high priority for HCV treatment. For persons with chronic HCV infection and decompensated cirrhosis, the treatment plans and goals may need modifying if they are undergoing liver transplantation.

Distinguishing Compensated and Decompensated Cirrhosis

One important step in treating HCV in persons with cirrhosis is to determine whether the cirrhosis is compensated or decompensated.[1,2] The Child-Turcotte-Pugh score is an important component of determining the status of the cirrhosis and predicts morbidity and mortality.[3,4] The treatment approach and goals are divergent based on the classification of compensated versus decompensated cirrhosis. In particular, HCV protease inhibitor-based regimens are not recommended for use in persons with decompensated cirrhosis due to the risk of hepatotoxicity with some medications and lack of data with the others.[5]

  • Compensated Cirrhosis: In general, individuals with compensated cirrhosis have mild hepatic impairment (Child-Turcotte-Pugh class A) (Figure 1) and generally do not have clinical manifestations of decompensated disease, specifically jaundice, ascites, variceal hemorrhage, or hepatic encephalopathy.
  • Decompensated Cirrhosis: Individuals should be considered to have decompensated cirrhosis if they have moderate or severe liver disease (Child-Turcotte-Pugh class B or C, or a score of 7 or higher). Individuals with decompensated cirrhosis often have experienced one or more of the following: ascites, jaundice, variceal hemorrhage, or hepatic encephalopathy.[1,3] Individuals who have significant clinical improvement after experiencing one feature of hepatic decompensation should be evaluated on a case-by-case basis to determine whether they could be considered for treatment similar to patients with compensated cirrhosis. Even if they recover from the acute event, they are still considered having decompensated cirrhosis. 

Impact of Treating HCV in Persons with Cirrhosis

Multiple studies, most from the interferon era, have shown that successful treatment of HCV in persons with compensated cirrhosis will decrease the incidence of subsequent cirrhosis-related complications (Figure 2), including hepatic failure, hepatocellular carcinoma (Figure 3), and liver-related deaths.[6,7,8] Multiple studies have shown that persons with chronic HCV and cirrhosis have significant improvement in inflammatory grade and have improvement in fibrosis following HCV therapy and achievement of a sustained virologic response (SVR).[6,9] Several studies have shown substantial improvements in hepatic fibrosis following achievement of an SVR with DAA-based treatments.[10,11,12,13]

Treating HCV in Persons with Compensated Cirrhosis

HCV Treatment Goals in Persons with Compensated Cirrhosis

The most important immediate goal of treatment is to achieve a sustained virologic response (SVR), which is required before observing the subsequent benefit in liver-related and other outcomes. The next intermediate-term priority with therapy is to decrease the patient’s risk of developing hepatic decompensation. The long-term goals are to diminish the risk of developing HCV-related hepatocellular carcinoma and death.

HCV Treatment Data in Persons with Compensated Cirrhosis

The impact of cirrhosis on the response to therapy has changed over time with evolving treatment regimens. The following summary of clinical trials involving persons with compensated cirrhosis illustrates a significant improvement in SVR rates among patients with cirrhosis with regimens that include direct-acting agents.

Elbasvir-Grazoprevir

  • Integrated Analysis of Treatment in Persons with Compensated Cirrhosis: In this study, investigators performed an integrated analysis of 6 elbasvir-grazoprevir phase 2/3 clinical trials to determine SVR12 treatment responses in 402 study participants with HCV genotype 1, 4, or 6 and compensated cirrhosis.[14] Participants received treatment with elbasvir-grazoprevir, with or without weight-based ribavirin; the treatment duration was 12 weeks for treatment-naïve participants (n = 169) and 12, 16, or 18 weeks for treatment-experienced subjects (n = 233).[14] Notably, platelet counts less than 100,000 cells/mm3 and serum albumin less than 3.5 g/dL were present in only 25% and 6% of participants respectively. Overall, using an intent-to-treatment analysis, SVR12 occurred in 96% of treatment-naïve participants and ranged from 89 to 100% among treatment-experienced subjects.[14] Genotype 1a patients were most likely to experience viral relapse with the strongest predictor for treatment failure being the presence of baseline NS5A resistance-associated substitutions. Asymptomatic grade 3-4 increases in hepatic aminotransferase levels were observed in 2.3%.[14]

Glecaprevir-Pibrentasvir

  • Glecaprevir-Pibrentasvir in Cirrhosis: Pooled Analysis: The efficacy of glecaprevir-pibrentasvir for 12 or 16 weeks was evaluated in a pooled analysis of 308 adults with HCV genotypes 1, 2, 3, 4, 5, and 6 and compensated cirrhosis.[15] Cirrhosis status was determined by FibroScan in 70% of the study subjects and 41% were treatment-experienced with prior peginterferon-based therapy. Child-Turcotte-Pugh score was 5 in 86% of those enrolled. Using an intent-to-treat analysis, SVR12 was achieved in 96% (297/308) of the study participants.[15] The SVR12 rates by HCV genotype showed 94% with HCV genotype 1, 97% with genotype 3, and 100% with genotypes 2, 4, 5, or 6.[15] There were no DAA-associated serious adverse events and no grade 3-4 elevations in hepatic aminotransferase levels. Grade 3 hyperbilirubinemia developed in 3 study participants; this occurred without associated abnormalities in other liver parameters and it resolved without treatment discontinuation.[15]
  • EXPEDITION-8: In this single-arm trial, glecaprevir-pibrentasvir was administered for 8 weeks to 343 treatment-naïve adults with compensated cirrhosis and HCV genotypes 1, 2, 3, 4, 5, or 6.[16] By intent-to-treat analysis, the SVR12 response rates were 98% overall.[16] Among those enrolled, 67% (231 of 343) had genotype 1 HCV, suggesting that this shorter 8-week duration may be a reasonable option in this group. [16]

Ledipasvir-Sofosbuvir

  • ION-1: The ION-1 trial enrolled HCV treatment-naïve adults, with and without compensated cirrhosis, to receive 12 or 24 weeks of ledipasvir-sofosbuvir.[17] Among the subjects enrolled with compensated cirrhosis, 97% (63 of 65) achieved an SRV12; the results were similar with 12 or 24 weeks of therapy (Figure 4).[17] In this study, the addition of ribavirin did not significantly improve SVR12 rates.
  • ION-2: In this trial, treatment-experienced adults with HCV genotype 1 were treated with 12- or 24 weeks of ledipasvir-sofosbuvir, with or without ribavirin.[18] Among those individuals with cirrhosis, SVR12 rates were lower if they received ledipasvir-sofosbuvir for 12 weeks (86%) versus 24 weeks (100%) (Figure 5).[18] In this study, the addition of ribavirin did not significantly improve SVR12 rates.[18]
  • SIRIUS: In the SIRIUS trial, 155 treatment-experienced adults with HCV genotype 1 and compensated cirrhosis received 12 weeks ledipasvir-sofosbuvir plus ribavirin or 24 weeks of ledipasvir-sofosbuvir; the SVR12 rates were 96% for participants in the 12-week group and 97% in the 24-week group (Figure 6).[19] In a post-hoc analysis of 7 clinical trials, investigators analyzed data from 513 adults with HCV genotype 1 and compensated cirrhosis who received ledipasvir-sofosbuvir, with or without ribavirin.[20] The treatment-naïve subjects did equally well with either a 12- or 24-week treatment course, but treatment-experienced individuals had lower response rates with 12 compared with 24 weeks; ribavirin did not significantly improve SVR rates.[20]

Sofosbuvir-Velpatasvir

  • ASTRAL-1: The ASTRAL-1 trial enrolled treatment-naïve and treatment-experienced adults with genotype 1, 2, 4, 5, or 6 and individuals with compensated cirrhosis were not excluded.[21] The SVR12 rates with 12 weeks of sofosbuvir-velpatasvir treatment in participants with cirrhosis was 99% (120 of the 121), and these SVR12 rates were identical to those in participants without cirrhosis.[21] 
  • ASTRAL-2: In this randomized, placebo-controlled trial, participants with HCV genotype 2 received a 12-week treatment course with sofosbuvir-velpatasvir or sofosbuvir plus ribavirin.[22] Individuals with cirrhosis were not excluded.[22] All 19 participants with cirrhosis and HCV genotype 2 achieved an SVR12 with sofosbuvir-velpatasvir treatment.[22]
  • ASTRAL-3: The ASTRAL-3 study enrolled persons with HCV genotype 3 and among the 80 participants with cirrhosis who received sofosbuvir-velpatasvir, the SVR12 rates were 93% for treatment-naïve and 89% for treatment-experienced participants.[22]
  • Sofosbuvir-Velpatasvir in Patients with Compensated Cirrhosis and HCV Genotype 3 (Spain): Additional data from Spain suggest that persons with HCV genotype 3 and cirrhosis should undergo baseline NS5A resistance testing and those with pretreatment NS5A resistance-associated substitutions may benefit from the addition of ribavirin to reduce the risk of viral relapse.[23]

Sofosbuvir-Velpatasvir-Voxilaprevir

  • POLARIS-2: In this phase 3, active-comparator, open-labeled trial, 314 patients with chronic hepatitis C genotype 1, 2, or 3 with prior direct-acting antiviral (DAA) therapy without an NS5A inhibitor were randomized to receive either sofosbuvir-velpatasvir-voxilaprevir or sofosbuvir-velpatasvir for 12 weeks.[24] Compensated cirrhosis was present in 46% and prior sofosbuvir exposure in 80% of patients.[24] The overall sustained virologic response rates were 98% and 90% for the sofosbuvir-velpatasvir-voxilaprevir and sofosbuvir-velpatasvir arms respectively; among those participants with cirrhosis 98% (82 of 84) achieved an SVR12 in the sofosbuvir-velpatasvir-voxilaprevir arm compared with 86% (59 of 69) in the sofosbuvir-velpatasvir arm.[24] Virologic relapse was confirmed at week 4 for one sofosbuvir-velpatasvir-voxilaprevir patient and 14 sofosbuvir-velpatasvir participants, of whom 8 had genotype 3a.[24]

For individuals with compensated cirrhosis (Child-Turcotte-Pugh Class A), including those with hepatocellular carcinoma, the AASLD-IDSA HCV Guidance provides recommendations for initial treatment and retreatment (when prior therapy has failed).[25,26] Although the treatment recommendations for persons with and without cirrhosis have significant overlap, there are, in some instances, key differences in the recommended regimens, duration of therapy, or inclusion of ribavirin.[25,26] Thus, when treating HCV in persons with compensated cirrhosis, it should not be assumed the treatment is the same as those without cirrhosis and AASLD-IDSA treatment guidelines should be closely checked and followed.[25,26]

Treating HCV in Persons with Decompensated Cirrhosis

Definition of Decompensated Cirrhosis

Individuals with cirrhosis are considered to have decompensated cirrhosis if they score 7 or higher on the Child Pugh-Turcotte-Pugh score and/or develop any of the following complications: ascites, jaundice, variceal hemorrhage, or hepatic encephalopathy.[1,2,3]

HCV Treatment Goals in Persons with Decompensated Cirrhosis

The treatment of persons with decompensated cirrhosis (Child-Turcotte-Pugh class B or C) can be potentially challenging given the high rate of clinical events and complications that may occur in persons with decompensated cirrhosis.

  • Immediate Treatment Goal: The immediate treatment goal for individuals with decompensated cirrhosis differs based on candidacy for liver transplantation. For those who are not a candidate for liver transplantation, the short-term goal of therapy is to achieve an SVR, with the hope that some degree of liver decompensation will reverse as a result of therapy, which could then stabilize or improve their clinical condition.
  • Intermediate Treatment Goal: For persons with chronic HCV infection and decompensated cirrhosis who are candidates for liver transplantation, the intermediate goal of HCV therapy is to achieve virologic clearance of HCV prior to the liver transplantation. Individuals with detectable HCV at the time of liver transplantation will uniformly infect their new liver with HCV, which can reduce the life of the liver graft. The primary rationale for pretransplantation treatment of HCV is therefore to reduce the risk of HCV reinfection of the new liver and thus improve post-transplantation outcomes. Pretransplantation HCV treatment has been shown to be a cost-effective strategy in the United States.[27] In addition, for some pretransplantation individuals with decompensated cirrhosis, HCV treatment may prevent the need for a liver transplant.[28] In a European study that enrolled 103 persons with chronic HCV who were on an active liver transplant list due to decompensated cirrhosis, treatment with DAA therapy resulted in delisting of 19% at 60 weeks after treatment.[29]

HCV Treatment Data in Persons with Decompensated Cirrhosis

Limited data exist for hepatitis C treatment in patients with decompensated cirrhosis, primarily because of concerns related to treatment-related toxicity.

Ledipasvir-Sofosbuvir plus Ribavirin 

  • SOLAR-1: (Cohorts A and B): In Cohort A of the phase 2, SOLAR-1 study, investigators prospectively enrolled 108 adults with hepatitis C genotype 1 or 4 infection and decompensated liver disease (Child-Turcotte-Pugh class B or C).[30] A total of 108 participants were randomized to receive either a 12-week or 24-week course of ledipasvir-sofosbuvir plus ribavirin; the ribavirin dose started at 600 mg per day and then was titrated up as tolerated.[30] Overall, 65% of patients were HCV treatment experienced. Patients receiving the 12-week regimen had an SVR12 rate of 87%, which was similar to the SVR12 rate of 89% in the 24-week regimen; these data excluded 6 patients who underwent liver transplantation (Figure 8).[30] The results were similar in the Child-Turcotte-Pugh class B and C groups. Overall, the regimen of ledipasvir-sofosbuvir plus ribavirin was safe and well tolerated.
  • SOLAR-2: In a similar phase 2 trial (SOLAR 2), investigators evaluated 12 or 24 weeks of ledipasvir-sofosbuvir plus ribavirin in adults with HCV genotype 1 or 4 and advanced liver disease.[31] The study cohort A included adults with Child-Turcotte Pugh class A, B, and C who had not undergone liver transplantation.[31] In participants with Child-Turcotte Pugh class B, the SVR12 rates were 87% with 12 weeks of treatment and 96% with 24 weeks. For those with Child-Turcotte-Pugh class C, the SVR12 rates were 85% with 12 weeks of treatment and 78% with 24 weeks (Figure 9).[31]

Sofosbuvir-Based Regimens 

  • Sofosbuvir Plus Ribavirin in Decompensated Cirrhosis: In an open-label, nonrandomized, phase 2 trial, 50 adults with Child-Turcotte-Pugh cirrhosis and portal hypertension were randomized to receive immediate or deferred HCV treatment with sofosbuvir 400 mg once daily plus weight-based ribavirin 1,000 to 1,200 mg divided twice daily.[32] The immediate group received treatment for 48 weeks; the deferred group was observed during the first 24 weeks and then received 48 weeks of therapy.[32] Overall, 72% (33 of 46) of the participants achieved an SVR12. The results were better in those with Child-Turcotte-Pugh class A (78%) than in those with Child-Turcotte-Pugh class B (68%). For the 37 participants who had paired baseline and end-of-treatment hepatic venous gradient measurements, those who achieved an SVR12 had clinically meaningful reductions in portal pressure.[32]

Sofosbuvir-Velpatasvir

  • ASTRAL-4: The ASTRAL-4 trial was a randomized, open-label, phase 3 trial designed to examine the safety and efficacy of the fixed-dose combination of sofosbuvir-velpatasvir with or without ribavirin in adults with HCV genotype 1, 2, 3, 4, or 6 and decompensated cirrhosis.[33] Treatment-naïve and treatment-experienced individuals with Child-Pugh-Turcotte (CTP) class B disease were randomized to one of three arms: (1) sofosbuvir-velpatasvir for 12 weeks (n = 90), (2) sofosbuvir-velpatasvir plus ribavirin for 12 weeks (n=87), or (3) sofosbuvir-velpatasvir for 24 weeks (n = 90). All three regimens were highly efficacious among participants with HCV genotypes 1, 2, 4, and 6 (Figure 10).[33] Among participants with HCV genotype 3, the treatment groups without ribavirin had lower SVR12 rates (50%, 85% and 50% respectively).[33] The Model for End-Stage Liver Disease (MELD) scores improved over baseline in those with a baseline MELD score less than 15 (Figure 11) and in those with a baseline MELD score of 15 or greater (Figure 12).[33] 
  • Sofosbuvir-Velpatasvir in Patients with Decompensated Cirrhosis Study (Japan): Another open-label trial that enrolled patients with decompensated cirrhosis randomized 102 participants 1:1 to sofosbuvir-velpatasvir with or without ribavirin.[34] Most (77%) had CTP class B disease and 78% had HCV genotype 1 infection.[34] The SVR12 rates were the same 92% (47 of 51) in both groups.[34] Of 91 patients who achieved SVR, 26% demonstrated improvement in their CTP score from baseline to post-treatment week 12. Most adverse events were attributed to progression of liver disease or ribavirin toxicity.[34]
     

Guidance for HCV Treatment with Decompensated Cirrhosis

The AASLD-IDSA HCV Guidance addresses this group of patients in the section Unique Patient Populations: Patients with Decompensated Cirrhosis.[5] The key recommendation the guidance is that general management and treatment of all patients with decompensated cirrhosis should be performed by a medical practitioner highly experienced in managing persons with chronic HCV infection and decompensated cirrhosis. Accordingly, referral of these patients to an expert, ideally at a transplant center, is strongly recommended. Patients with decompensated cirrhosis include patients who may or may not be a candidate for liver transplantation and may include patients with hepatocellular carcinoma.

Summary Points

  • Treatment of HCV in persons with compensated cirrhosis (Child-Turcotte-Pugh class A) is a high priority because of the risk of developing severe liver-related complications. 
  • For persons with HCV-related cirrhosis, treatment of HCV is associated with significant reversal in hepatic fibrosis and reduced risk of developing hepatocellular carcinoma when an SVR occurs with therapy.
  • For persons with HCV and compensated cirrhosis, the regimen choice and duration is generally similar to those without cirrhosis, except for longer duration, and in select circumstances, the addition of ribavirin.
  • With use of HCV DAA treatment, individuals with HCV and compensated cirrhosis can have comparable SVR12 rates as those without cirrhosis, especially with adjustments in therapy duration when indicated.
  • Treatment of HCV is recommended in persons with decompensated cirrhosis who are eligible for liver transplantation, since the transplanted liver will become infected with HCV in all patients who have detectable HCV RNA levels at the time of liver transplantation. In addition, post-transplantation HCV infection is associated with an accelerated course of liver disease.
  • Treatment of HCV in persons with decompensated cirrhosis should be performed only by a medical provider who has experience in treating HCV in persons with decompensated cirrhosis.
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Citations

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  4. 4.D'Amico G, Morabito A, Pagliaro L, Marubini E. Survival and prognostic indicators in compensated and decompensated cirrhosis. Dig Dis Sci. 1986;31:468-75.
  5. 5.AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Unique populations: patients with decompensated cirrhosis.
  6. 6.van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308:2584-93.
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  10. 10.Chan J, Gogela N, Zheng H, et al. Direct-Acting Antiviral Therapy for Chronic HCV Infection Results in Liver Stiffness Regression Over 12 Months Post-treatment. Dig Dis Sci. 2018;63:486-492.
  11. 11.Kobayashi N, Iijima H, Tada T, et al. Changes in liver stiffness and steatosis among patients with hepatitis C virus infection who received direct-acting antiviral therapy and achieved sustained virological response. Eur J Gastroenterol Hepatol. 2018;30:546-551.
  12. 12.Singh S, Facciorusso A, Loomba R, Falck-Ytter YT. Magnitude and Kinetics of Decrease in Liver Stiffness After Antiviral Therapy in Patients With Chronic Hepatitis C: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018;16:27-38.e4.
  13. 13.Tada T, Kumada T, Toyoda H, et al. Improvement of liver stiffness in patients with hepatitis C virus infection who received direct-acting antiviral therapy and achieved sustained virological response. J Gastroenterol Hepatol. 2017;32:1982-8.
  14. 14.Jacobson IM, Lawitz E, Kwo PY, et al. Safety and Efficacy of Elbasvir/Grazoprevir in Patients With Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis. Gastroenterology. 2017;152:1372-1382.e2.
  15. 15.Gane E, Poordad F, Zadeikis N, et al. Safety and Pharmacokinetics of Glecaprevir/Pibrentasvir in Adults With Chronic Genotype 1-6 Hepatitis C Virus Infections and Compensated Liver Disease. Clin Infect Dis. 2019;69:1657-64.
  16. 16.Brown RS Jr, Buti M, Rodrigues L, et al. Glecaprevir/pibrentasvir for 8 weeks in treatment-naïve patients with chronic HCV genotypes 1-6 and compensated cirrhosis: The EXPEDITION-8 trial. J Hepatol. 2020;72:441-9.
  17. 17.Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370:1889-98.
  18. 18.Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370:1483-93.
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  20. 20.Reddy KR, Bourlière M, Sulkowski M, et al. Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: An integrated safety and efficacy analysis. Hepatology. 2015;62:79-86.
  21. 21.Feld JJ, Jacobson IM, Hézode C, et al. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med. 2015;373:2599-607.
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  24. 24.Jacobson IM, Lawitz E, Gane EJ, et al. Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials. Gastroenterology. 2017;153:113-22.
  25. 25.AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Initial treatment of HCV infection.
  26. 26.AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Retreatment of persons in whom prior therapy failed.
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  28. 28.Flemming JA, Kim WR, Brosgart CL, Terrault NA. Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy. Hepatology. 2017;65:804-12.
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  34. 34.Takehara T, Sakamoto N, Nishiguchi S, et al. Efficacy and safety of sofosbuvir-velpatasvir with or without ribavirin in HCV-infected Japanese patients with decompensated cirrhosis: an open-label phase 3 trial. J Gastroenterol. 2019;54:87-95.

Additional References

  • Akhtar E, Manne V, Saab S. Cirrhosis regression in hepatitis C patients with sustained virological response after antiviral therapy: a meta-analysis. Liver Int. 2015;35:30-6.
  • Benvegnù L, Chemello L, Noventa F, Fattovich G, Pontisso P, Alberti A. Retrospective analysis of the effect of interferon therapy on the clinical outcome of patients with viral cirrhosis. Cancer. 1998;83:901-9.
  • Bruno S, Shiffman ML, Roberts SK, Gane EJ, Messinger D, Hadziyannis SJ, Marcellin P. Efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in hepatitis C patients with advanced fibrosis and cirrhosis. Hepatology. 2010;51:388-97.
  • Burton JR Jr, O'Leary JG, Verna EC, et al. A US multicenter study of hepatitis C treatment of liver transplant recipients with protease-inhibitor triple therapy. J Hepatol. 2014;61:508-14.
  • Buti M, Agarwal K, Horsmans Y, et al. Telaprevir twice daily is noninferior to telaprevir every 8 hrs for patients with chronic hepatitis C. Gastroenterology. 2014;146:744-53.
  • Cardoso AC, Moucari R, Figueiredo-Mendes C, et al. Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis. J Hepatol. 2010;52:652-7.
  • Colombo M, Strasser S, Moreno C, et al. Sustained virological response with telaprevir in 1,078 patients with advanced hepatitis C: the international telaprevir access program. J Hepatol. 2014;61:976-83.
  • Conti F, Buonfiglioli F, Scuteri A, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol. 2016;65:727-733.
  • Crippin JS, McCashland T, Terrault N, Sheiner P, Charlton MR. A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation. Liver Transpl. 2002;8:350-5.
  • Curry MP, Forns X, Chung RT, et al. Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study. Gastroenterology. 2015;148:100-107.
  • Daniel KE, Said A. Considerations When Treating Hepatitis C in a Cirrhotic Transplant Candidate. Curr Gastroenterol Rep. 2018;20:20.
  • Dohmen K, Kawano A, Takahashi K, et al. The incidence and risk factors for the development of hepatocellular carcinoma after peginterferon plus ribavirin therapy for chronic hepatitis C. Hepatogastroenterology. 2013;60:2034-8.
  • Dufour JF, DeLellis R, Kaplan MM. Regression of hepatic fibrosis in hepatitis C with long-term interferon treatment. Dig Dis Sci. 1998;43:2573-6.
  • El-Sherif O, Jiang ZG, Tapper EB, et al. Baseline Factors Associated With Improvements in Decompensated Cirrhosis After Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection. Gastroenterology. 2018;154:2111-2121.e8.
  • European Association for Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2014;60:392-420.
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Figures

The Child-Turcotte-Pugh (CTP) classification system utilizes two clinical parameters (encephalopathy and ascites) and three laboratory values (bilirubin, albumin, and prothrombin time). Patients are classified as class A, B, or C based on their total points.
Figure 1. Child-Turcotte-Pugh Classification for Severity of Cirrhosis
The Child-Turcotte-Pugh (CTP) classification system utilizes two clinical parameters (encephalopathy and ascites) and three laboratory values (bilirubin, albumin, and prothrombin time). Patients are classified as class A, B, or C based on their total points.
Source: Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60:646-9.
Abbreviations: HCC = hepatocellular cancer<br /> In this international, multicenter study, 530 adults with chronic hepatitis C and advanced fibrosis or cirrhosis were followed after receiving interferon-based therapy. Patients who achieved SVR had substantially lower hepatic-related complications and lower mortality.
Figure 2. Clinical Events Related to HCV Treatment Response
Abbreviations: HCC = hepatocellular cancer
In this international, multicenter study, 530 adults with chronic hepatitis C and advanced fibrosis or cirrhosis were followed after receiving interferon-based therapy. Patients who achieved SVR had substantially lower hepatic-related complications and lower mortality.
Source: van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308:2584-93.
This study evaluated 345 individuals with chronic HCV and cirrhosis. Of the total 345 patients, 271 received treatment with an interferon-based regimen and 119 developed hepatocellular carcinoma over a median of 6.8 years’ follow-up. Treated patients had lower subsequent risk of developing HCC, particularly those who achieved an SVR.
Figure 3. Incidence of Hepatocellular Carcinoma Related to HCV Treatment in Adults with Cirrhosis
This study evaluated 345 individuals with chronic HCV and cirrhosis. Of the total 345 patients, 271 received treatment with an interferon-based regimen and 119 developed hepatocellular carcinoma over a median of 6.8 years’ follow-up. Treated patients had lower subsequent risk of developing HCC, particularly those who achieved an SVR.
Source: Shiratori Y, Ito Y, Yokosuka O, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med. 2005;142:105-14.
In the ION-1 trial, treatment-naïve adults received 12 or 24 weeks of ledipasvir-sofosbuvir and all of these treatment arms had very high SVR rates, regardless of the duration of therapy or the presence of cirrhosis. The addition of ribavirin to the regimen did not improve SVR rates (data not shown).
Figure 4. ION-1: Ledipasvir-Sofosbuvir in HCV Treatment-Naïve Adults with or without Cirrhosis
In the ION-1 trial, treatment-naïve adults received 12 or 24 weeks of ledipasvir-sofosbuvir and all of these treatment arms had very high SVR rates, regardless of the duration of therapy or the presence of cirrhosis. The addition of ribavirin to the regimen did not improve SVR rates (data not shown).
Source: Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370:1889-98.
In the ION-2 trial, treatment-experienced adults received 12 or 24 weeks of ledipasvir-sofosbuvir; individuals with cirrhosis had better SVR12 rates if they received 24 weeks of therapy. The addition of ribavirin to the regimen did not significantly improve SVR rates (data not shown).
Figure 5. ION-2: Ledipasvir-Sofosbuvir in HCV Treatment-Experienced Adults with or without Cirrhosis
In the ION-2 trial, treatment-experienced adults received 12 or 24 weeks of ledipasvir-sofosbuvir; individuals with cirrhosis had better SVR12 rates if they received 24 weeks of therapy. The addition of ribavirin to the regimen did not significantly improve SVR rates (data not shown).
Source: Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370:1483-93.
Treatment-experienced adults with genotype 1 HCV and compensated cirrhosis received either a 12-week course of ledipasvir-sofosbuvir and ribavirin or a 24-week course of ledipasvir-sofosbuvir. The SVR12 rates were similar in the two groups.
Figure 6. SIRIUS: Treatment of HCV Genotype 1 with Ledipasvir-Sofosbuvir in Adults with Cirrhosis
Treatment-experienced adults with genotype 1 HCV and compensated cirrhosis received either a 12-week course of ledipasvir-sofosbuvir and ribavirin or a 24-week course of ledipasvir-sofosbuvir. The SVR12 rates were similar in the two groups.
Bourlière M, Bronowicki JP, de Ledinghen V, et al. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS). Lancet Infect Dis. 2015;15:397-404.
This graph shows SVR12 rates with a 12- or 24-week course of ombitasvir-paritaprevir-ritonavir and dasabuvir plus ribavirin in adults with compensated cirrhosis. Results are shown based on prior treatment and prior treatment response.
Figure 7. TURQUOISE II: Treatment of HCV Genotype 1 with Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir plus Ribavirin in Adults with Compensated Cirrhosis
This graph shows SVR12 rates with a 12- or 24-week course of ombitasvir-paritaprevir-ritonavir and dasabuvir plus ribavirin in adults with compensated cirrhosis. Results are shown based on prior treatment and prior treatment response.
Source: Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;370:1973-82.
Abbreviations: LDV-SOF = ledipasvir-sofosbuvir; RBV = ribavirin </br>In Cohort A of this trial, adults with HCV genotype 1 or 4 and advanced liver disease (Child-Turcotte-Pugh class B or C) received either a 12- or 24-week course of ledipasvir-sofosbuvir and ribavirin. This graph shows similar results with 12- or 24 weeks of therapy with ledipasvir-sofosbuvir and ribavirin.
Figure 8. SOLAR-1: Treatment of HCV Genotype 1 or 4 with Ledipasvir-Sofosbuvir in Adults with Advanced Liver Disease
Abbreviations: LDV-SOF = ledipasvir-sofosbuvir; RBV = ribavirin
In Cohort A of this trial, adults with HCV genotype 1 or 4 and advanced liver disease (Child-Turcotte-Pugh class B or C) received either a 12- or 24-week course of ledipasvir-sofosbuvir and ribavirin. This graph shows similar results with 12- or 24 weeks of therapy with ledipasvir-sofosbuvir and ribavirin.
Source: Charlton M, Everson GT, Flamm SL, et al. Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology. 2015:149:649-59.
Abbreviations: LDV-SOF = ledipasvir-sofosbuvir; RBV = ribavirin </br>In Cohort A of this trial, adults with advanced liver disease (Child-Turcotte-Pugh B or C) received either a 12- or 24-week course of ledipasvir-sofosbuvir and ribavirin.
Figure 9. SOLAR-2: Treatment of HCV Genotype 1 or 4 with Ledipasvir-Sofosbuvir in Adults with Advanced Liver Disease
Abbreviations: LDV-SOF = ledipasvir-sofosbuvir; RBV = ribavirin
In Cohort A of this trial, adults with advanced liver disease (Child-Turcotte-Pugh B or C) received either a 12- or 24-week course of ledipasvir-sofosbuvir and ribavirin.
Source: Manns M, Samuel D, Gane EJ, et al. Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial. Lancet Infect Dis. 2016;16:685-97.
Abbreviations: SOF-VEL = sofosbuvir-velpatasvir; RBV = ribavirin </br>
Figure 10. ASTRAL 4: Sofosbuvir-Velpatasvir Treatment of HCV Genotypes 1-6 in Adults with Decompensated Cirrhosis
Abbreviations: SOF-VEL = sofosbuvir-velpatasvir; RBV = ribavirin
Source: Curry MP, O'Leary JG, Bzowej N, et al. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med. 2015;373:2618-28.
Abbreviations: MELD = Model for End-Stage Liver Disease (MELD)
Figure 11. ASTRAL4: Change in MELD Score in Adults with Baseline MELD Score Less than 15
Abbreviations: MELD = Model for End-Stage Liver Disease (MELD)
Source: Curry MP, O'Leary JG, Bzowej N, et al. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med. 2015;373:2618-28.
Abbreviations: MELD = Model for End-Stage Liver Disease (MELD)
Figure 12. ASTRAL4: Change in MELD Score in Adults with Baseline MELD Score of 15 or Greater
Abbreviations: MELD = Model for End-Stage Liver Disease (MELD)
Source: Curry MP, O'Leary JG, Bzowej N, et al. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med. 2015;373:2618-28.
Adults with chronic HCV infection and hepatocellular carcinoma received sofosbuvir plus ribavirin for up to 48 weeks prior to liver transplantation. Sofosbuvir plus ribavirin prevented hepatitis C recurrence in most of the treated patients, with the best success rates observed in those who had undetectable HCV RNA levels for at least 30 days prior to liver transplant.
Figure 13. Treatment of HCV with Sofosbuvir and Ribavirin Prior to Liver Transplantation
Adults with chronic HCV infection and hepatocellular carcinoma received sofosbuvir plus ribavirin for up to 48 weeks prior to liver transplantation. Sofosbuvir plus ribavirin prevented hepatitis C recurrence in most of the treated patients, with the best success rates observed in those who had undetectable HCV RNA levels for at least 30 days prior to liver transplant.
Source: Curry MP, Forns X, Chung RT, et al. Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study. Gastroenterology. 2015:148:100-107.
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