Cirrhosis and HCV Jonathan Israel M.D.
Outline Relationship of fibrosis and cirrhosisprevalence and epidemiology. Sequelae of cirrhosis Diagnosis of cirrhosis Effect of cirrhosis on efficacy of treatment Difficulty in treating cirrhotic patients
Rate of fibrosis Average time from infection to cirrohsis 20 years-some can exceed 50 years Progression rate.133 Metavir stage/year Many factors influence fibrosis Degree of inflammation: 10 year risk of cirrhosis 10-13% minimal hepatitis 44-100% moderate hepatitis EtOH: Progression 1.5-3x higher with heavy use Aquired at older age Genotype does not influence fibrosis
Mortality Compensated cirrhosis 3.9% per yr Decompensated cirrhosis Esophageal variceal bleed 22% 50%5 yrs 48% Ascites Death 10-33%/3yrs
Liver transplant
Complications of cirrhosis Ascites 21% mortality in 6 months 10% mortality for SBP Hepatic encephalopathy Grade 2 60% mortality at 1 year Esophageal varices 20% mortality in 6 weeks Hepatocellular carcinoma 50% mortality in 10 months
Liver function tests 25%-46% of patients with chronic HCV have persistently normal ALT 1/3 have moderate to severe inflammation 10% have advanced fibrosis Elevated ALT 90% have moderate to severe inflammation 25% have advanced fibrosis Response to treatment is the same in patients with normal and elevated ALT Bacon Hepatlogy 2002 Alberti Ann Int Med 2002 Shiffman Clinical Gastro Hep 2006 Bini Aliment Pharmacol Ther 2006
Chronic HCV Infection Normal vs Elevated Serum ALT No fibrosis 23% Portal 26% Normal ALT Bridging 6% Cirrhosis 6% Mild 39% Portal 20% Bridging 13% No fibrosis 16% Mild 33% Elevated ALT Cirrhosis 18% Shiffman ML, et al. J Infect Dis. 2000;182:1595-1601.
Conclusions Liver tests do not reliably predict severity or treatment response Fibrosis on liver biopsy predicts progression of liver disease Cirrhotics have worse treatment response Genotype determines treatment response, duration, and medications used
Log HCV RNA (copies/ml) HCV RNA effect on Liver Histology & Fibrosis Serum HCV RNA does not correlate with level of fibrosis 8 6 4 2 Genotype 1 2 3 4 0 No Fibrosis Portal Fibrosis Bridging Fibrosis Cirrhosis Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.
HCV Infection - Liver Biopsy Only test that can accurately assess Severity of inflammation Degree of fibrosis Determines the following Risk for developing cirrhosis in future Need for therapy Need for ongoing therapy when initial treatment has failed
Staging of chronic hepatitis
Staging of chronic hepatitis
Approximate Percentage of Patients With Cirrhosis Chronic HCV: Progression to Cirrhosis Proportion of Patients Developing Cirrhosis According to Initial Level of Fibrosis 100 80 60 40 Bridging Portal None 20 0 0 5 10 15 20 Time (Years) Yano M, et al. Hepatology. 1996;23:1334-1340.
Zeuzem NEJM 2011 Fibrosis predicts response to treatment
Issues in Treating HCV Patients with Cirrhosis Three large international trials demonstrate genotype 1 and 4 patients decreases from 60% no sig firbrosis, 51% bridging fibrosis, 33% cirrhosis. Similar data for genotype 2 and 3 patients were 76% (no sig fibrosis), 61% (advanced fibrosis) and 57% (cirrhosis)
Issues in Treating HCV Patients with Cirrhosis Patient with advance liver disease are generally older and have poor tolerance to therapy Adverse events such as thrombocytopenia, leukopenia and anemia are more frequent from portal hypertension
Issues in Treating HCV Patients with Cirrhosis Older individuals have more frequent comorbidities such as DM, HTN and depression which can negatively impact viral clearance and treatment adherence. May even have have contraindications to treatment. Journal Hepatology 2010 vol.52, pg 624-626.
Issues in Treating HCV Patients with Cirrhosis Multiple retrospective studies have shown that HCV clearance is associated with improved outcomes and less decompensation in cirrhotics. Hepatology 2007;45:579-587. Ann Intern Med 2007;2007;147:677-684. Journal Hepatology2010;52: 652-657.
Issues in Treating HCV Patients with Cirrhosis The decrease in necroinflammatory changes and regression (or stabilization) of fibrosis undoubtedly explain the reduced decompensation in treated patients who achieve SVR.
Patients with SVR (%) Treatment-Naïve ADVANCE Trial: Overall SVR 100 80 79% P<0.0001* 60 40 46% 20 0 n/n= 285/363 166/361 INCIVEK combination treatment Peg-IFN/RBV alone ADVANCE was a randomized, double-blind, placebo-controlled, parallel-group, multicenter Phase III trial of INCIVEK combination treatment in treatment-naïve patients with genotype 1 chronic HCV and compensated liver disease (N=1088) *Data on file. INCIVEK combination treatment=incivek + peg-ifn/rbv for 12 weeks and an additional 12 or 36 weeks of peg-ifn/rbv. Sustained virologic response (SVR)=HCV RNA <25 IU/mL at 24 weeks after the planned end of treatment. Treatment-naïve=patients who have received no prior therapy for HCV, including interferon or pegylated interferon monotherapy. Please see full Prescribing Information for INCIVEK. Please see full Prescribing Information for peginterferon alfa and ribavirin.
Patients with SVR (%) Treatment-Naïve ADVANCE Trial: SVR in 100 80 60 Subgroups * INCIVEK combination treatment Peg-IFN/RBV alone 62% 62% 74% 40 33% 25% 39% 20 0 13/21 7/21 16/26 7/28 26/35 15/38 Cirrhosis Black/African American Hispanic/Latino Higher SVR rates were seen across all subgroups, including more advanced liver fibrosis, ethnicity, race, baseline viral load, body mass index, HCV genotype subtype, age, or sex There were small numbers of patients enrolled in some key subgroups INCIVEK is only approved for patients with compensated liver disease *INCIVEK combination treatment=incivek + peg-ifn/rbv for 12 weeks and an additional 12 or 36 weeks of peg-ifn/rbv. Jacobson IM, et al. N Engl J Med 2011;364:2405-16. Please see full Prescribing Information for INCIVEK. Please see full Prescribing Information for peginterferon alfa and ribavirin.
Patients with SVR (%) Patients with SVR (%) Previously Treated REALIZE Trial: SVR in Subgroups Cirrhotics With Compensated Liver Disease by Prior Response Overall by Race/Ethnicity* n/n= 48/55 2/15 11/32 1/5 7/50 1/10 n/n= 12/19 4/11 37/52 2/20 INCIVEK combination treatment Peg-IFN/RBV alone SVR rates were higher across subgroups by sex, age, ethnicity, body mass index, HCV genotype subtype, baseline HCV RNA level, and extent of liver fibrosis There were small numbers of patients enrolled in some key subgroups INCIVEK is only approved for patients with compensated liver disease *Data on file. INCIVEK combination treatment=incivek + peg-ifn/rbv for 12 weeks and an additional 12 or 36 weeks of peg-ifn/rbv. Please see full Prescribing Information for INCIVEK. Please see full Prescribing Information for peginterferon alfa and ribavirin.
Issues in Treating HCV Patients with Cirrhosis After transplantation, HCV recurs and may rapidly progress to cirrhosis HCV often results in decompensted cirrhosis and is most common indication for liver transplantation. Large prospective studies have examined tolerability and efficacy of pre txpl antiviral therapy in such patients.
Issues in Treating HCV Patients with Cirrhosis Less than half the eligible patients met entry criteria. (US pilot study) 33%loss HCV RNA, 55% decrease viral titers 20 serious adverse events Authors conclude that although pre trxplnt antiviral therapy may reduce HCV titers, adverse events are freq and often severe. Liver Transplantation vol8, no 4 (april), 2002:pp350-355.
Issues in Treating HCV Patients with Cirrhosis European study with non treated group 20% of treated patients had an SVR Majority of patients Childs B, MELD<18 MAJORITY Genotype I 13 patients with SVR survived without transplantation During follow up of 30 months 18 controls and 9 nonresponders died or went to transplant.
Issues in Treating HCV Patients with Cirrhosis All 13 patients with SVR survived without transplant. Successful therapy only achieved in minority of patients Genotype II patients with 41% SVR Genotype I patients with 7% SVR Authors conclude that HCV clearance with antiviral therapy may be life-saving. Journal Hepatology 46(2007)206-212.
Issues in Treating HCV Patients with Cirrhosis US study of low accelerating dose regiment of antiviral Mean MELD score 11.0, CPT was 7.4 SVR 13% geno I, 50% non geno I Authors conclude that in a sizeable proportion of patients with advanced HCV treatment can stabilize course and prevent post transplant recurrence.
Conclusions Goal of therapy for HCVis to avoid cirrhosis Cirrhosis negatively impacts efficacy of treatment of HCV Cirrhotics more difficult to get thru treatment