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HCV INFECTION AND MANAGEMENT IN ADVANCED LIVER DISEASE Kimberly Brown, M.D. Chief, Division of Gastroenterology and Hepatology Henry Ford Hospital Slide 2 Disclosures - Grants/Research Support: Merck, Vertex, Ikaria, Hyperion, Exelenz, Gilead, BMS, ABBVIE, Janssen - Consultant: Merck, BMS, Gilead, Janssen, ABBVIE - Speakers Bureau: Gilead, ABBVIE, Simply Speaking, HCV Viewpoints - Stock Shareholder: none - Boards: CLDF, CLD Journal - Other Financial or Material Support: none Slide 3 Learning Objectives - Review epidemiologic trends of liver-related morbidity and mortality in chronic HCV infection - Discuss HCV-related management approaches for patients with advanced fibrosis and cirrhosis - Discuss HCV-related management approaches for patients who are candidates for liver transplantation Slide 4 Advanced Liver Disease: Basic Principles Hepatic fibrosis - Not reliably diagnosed by ultrasound or other imaging modalities Liver fibrosis rates - Not predictable or linear Progression from compensated cirrhosis to decompensated liver disease - Occurs in 5% of patients per year Hepatocellular carcinoma - Develops in 1% to 2% of patients with hepatitis-related cirrhosis each year Sherman KE. Top HIV Med. 2011;19:121-125. Slide 5 Chronic HCV Infection: Natural History Liver Decompensation (5%/year) HCC (2%-8%/year) Resolved Exposure (Acute phase) Cirrhosis Chronic 5%-30% Over 20-30 Years 15%-45% 55%-85% Poynard T, et al. Lancet. 1997;349:825-832. Co-morbidities Slide 6 Progression of Fibrosis in Viral Hepatitis on Biopsy (Metavir) No Fibrosis Stage 1 Fibrous expansion of some portal areas Stage 2 Fibrous expansion of most portal areas with occasional portal to portal bridging Stage 3 Stage 4 Cirrhotic Liver Fibrous expansion of portal areas with marked bridging (portal-to-portal and portal-to-central) Cirrhosis Faria SC, et al. Radiographics. 2009;29:1615-1635. Adapted from Everson GT. Slide 7 FibroScan The probe induces an elastic wave through the liver The velocity of the wave is evaluated in a region located from 2.5 to 6.5 cm below the skin surface Diagnostic accuracy: Significant fibrosis: 0.79 Advanced fibrosis: 0.91 Cirrhosis: 0.97 8.89.614.6 FibroScan (kPa) Liver Fibrosis (METAVIR) F0-F1 F2 F3 F4 Ziol M, et al. Hepatology. 2005;41:48-54. Slide 8 Projected Burden of Advanced Fibrosis Over the Next Decade Davis GL, Gastroenterology. 2010;138:513-521. 1990 77.6% F0/1; cirrhosis =5% 2010 41.8% F0/1; cirrhosis =25% 2020 cirrhosis = 37.2% Slide 9 Annual Prevalence Rates Between 1996 and 2006 Among HCV-Infected Veterans Progressive Increase in Incidence of HCV-Related Cirrhosis and HCC in US El-Serag HB. Gastroenterology 2012;142:12641273. Slide 10 100 80 60 40 20 0 Years after diagnosis After 1st complication Adapted from Fattovich G et al. Gastroenterology. 1997;112:466-467. Survival probability (%) Compensated Natural History of HCV Cirrhosis 123456789100 Deaths Liver-related (70%) Other cause (30%) Slide 11 By 2007, Deaths From HCV Surpassed Those From HIV Change in Mortality Rates From 1999 to 2007 Rate per 100,000 People 7 6 5 4 3 2 1 0 199920002001200220032004200520062007 Year HIV Hepatitis C Hepatitis B 15,106 12,734 1,815 Ly KN, et al. Ann Intern Med. 2012;156(4):271-278. Slide 12 Risk Factors for Progressive Fibrosis and Cirrhosis Persistently elevated ALT levels Longer duration of infection Alcohol excess (>50 g/day) Age >40 years at time of infection HIV or HBV coinfection High BMI Male gender Presence of steatosis on biopsy Poynard T, et al. Lancet. 1997;349:825-832. Kim WR, et al. Gastroenterology. 2004;127:749-755. Slide 13 HCV Incremental All-Cause Health Care Costs by Liver Disease Severity (USD 2009) Difference between HCV and non-HCV matched controls. Numbers in parentheses are +SD. Costs normalized to 2009 dollars using Consumer Price Index. McAdam-Marx C, et al. J Manag Care Pharm. 2012;17:531-546. Incremental All-Cause Costs (per-patient-per-year) 5879 (157) 5330 (491) 27,845 (965) 810 (49) 974 (194) 15,464 (710) 1721 (123) 1081 (275) 5818 (292) 641 (37) 93 (130) 4526 (213) 2659 (41) 3102 (157) 1893 (123) No liver disease (n=26,977) Compensated cirrhosis (n=1521) Decompensated cirrhosis (n=4249) Inpatient Total Health Care Costs Outpatient Physician Services Pharmacy Costs Place of Service Slide 14 Ghany MG, et al. Hepatology. 2009;49(4):1335-1374. HCV Can Now Be Cured in Most Patients Unlike HIV and HBV infection, HCV infection is a curable disease What does cure mean? - Sustained Viral Response - Undetectable HCV RNA 12 weeks after completion of antiviral therapy for chronic HCV infection - Long term morbidity and mortality benefits Slide 15 Treatment Goals HCV Infection Viral Eradication Prevent HCC? Delay Disease Progression Delay Time to Decompensation Slide 16 Time (years) Percent All-Cause Mortality International, multicenter, long-term follow-up study from 5 large tertiary care hospitals in Europe and Canada. Patients with chronic HCV infection started an interferon-based treatment regimen between 1990 and 2003 (n=530). van der Meer AJ, et al. JAMA. 2012;308:2584-2593. SVR Was Associated With Reduced Long-Term Risk of All-Cause Mortality in an International, Multicenter Study Slide 17 Years Cumulative Mortality (%) Genotype 1 (n=12,166) Genotype 2 (n=2904) Genotype 3 (n=1794) SVR Reduced Risk of All-Cause Mortality in a Retrospective VA Study Retrospective analysis of veterans who received pegylated interferon plus ribavirin at any VA medical facility (2001-2008). SVR=sustained virological response. Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:509-516. 17 SVR rate: 35%SVR rate: 72%SVR rate: 62% Slide 18 Percent Cumulative Incidence of Any Liver-Related Outcome Among Patients With Bridging Fibrosis or Cirrhosis Analysis of liver outcomes (decompensation, HCC, or death) in the HALT-C trial database. All comparisons P French National Early Access Program: Interim Analysis of the CUPIC Cohort (Genotype 1) Prospective cohort, HCV genotype 1, compensated cirrhosis - Relapse or prior partial responders to PR SVR12 - Telaprevir: 40% (range: 29%-53%) - Boceprevir: 41% (range: 11%-51%) Discontinuations: 47% Serious adverse events: 40% - Early treatment discontinuation: 21.3% - Death: 2.0% - Anemia ( Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + Decompensation Afdhal N, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O68. Sofosbuvir qd + RBV (n=25) Observation (n=25) Open-Label Genotypes 1-4 Treatment-nave and experienced Compensated cirrhosis (Child-Pugh 5-6, A) Decompensated cirrhosis (Child-Pugh 7-9, B) Esophageal or gastric varices Hepatic venous gradient (HVPG): >6 mm Hg) Week 0 24 48 72 Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor) + RBV (1000-1200 mg). HVPG at day 0 and 48 in the sofosbuvir-treated patients. Baseline demographics and disease characteristics: Male: 72%-80%; age: 55-56 years; white: 84%-96%, treatment-naive: 68%-92%. Genotype 1a, 1b, 2, 3, 4: 36%-40%, 24%-36%, 4%-8%, 8%-32%, 4%-8%. IL28B non-CC: 72%-88%. HVPG >12 mm Hg: 76%-80%. CTP score 5-6, 7-9: 36%-44%, 56%-60%. MELD SOLAR-1 (Decompensated Cirrhosis) GT 1 and 4, CPT Class B and C 108 patients randomized 1:1 to 12 or 24 Weeks of Treatment Broad inclusion criteria - Total bilirubin 10 mg/dL, Hemoglobin 10 g/dL - CL cr 40 mL/min, platelets > 30,000 x 10 3 /L, - CPT 12 Stratified by CPT score B or C LDV/SOF + RBV Wk 0 Wk 12Wk 24 SVR12 Wk 36 Flamm, et al, AASLD 2014 Slide 47 Baseline Disease Characteristics GT 1 and 4, CPT Class B and C Flamm, et al, AASLD 2014 Slide 48 SVR12 GT 1 and 4, CPT Class B and C 6 subjects (2 CPT B/24 Wk, 1 CPT C/12 Wk and 3 CPT C/24 Wk) excluded (transplant on study); 3 subjects CPT C/24 Wk have not reached SVR12.. CPT BCPT C SVR12 (%) 26/3019/2218/20 Overall 24/2745/5242/47 LDV/SOF + RBV 12 WeeksLDV/SOF + RBV 24 Weeks Flamm, et al, AASLD 2014 3 relapses 1 death 1 relapse 2 deaths 1 relapse 2 death 1 LTFU 1 relapse 1 death Slide 49 Change in MELD Score Baseline Through Follow-up Week 4 GT 1 and 4, CPT Class B and C 49 n=5 n=2 n=3 (-8) (+10) CPT B CPT C 12 wk (n=30)*24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)* *Missing FU-4: n=2 CPT B 12 wks; n=4 CPT B 24 wks; n=2 CPT C 12 wk; n=7 CPT C 24 wk. Flamm, et al, AASLD 2014 Slide 50 Safety Summary GT 1 and 4, CPT Class B and C Related SAEs: Anemia (2), Hepatic Encephalopathy, Peritoneal Hemorrhage Flamm, et al, AASLD 2014 Slide 51 Risk of HCC Remains After SVR in HCV Patients With Advanced Hepatic Fibrosis Meta-analysis (n=1000) - 10 cohorts, individual patient data - SVR with IFN-based therapy - Bridging fibrosis or cirrhosis 51 events of HCC over 5.1 years of follow-up Patients with HCV-induced cirrhosis who achieve SVR remain at risk for HCC Risk increased with age, severity of liver disease, and presence of diabetes mellitus van der Meer AJ, et al. Hepatology. 2013;58(suppl 1):280A. Abstract 143. Rate (%) Cumulative HCC by Age Group 0 1 2 3 4 5 6 7 8 Years After SVR P=0.006 12.2% 2.6% 9.7% Age Group 60 years Slide 52 Adult-to-Adult Living Donor Liver Transplant Cohort Study (A2ALL) First, randomized, controlled trial of pre-transplant PR (LADR) to prevent recurrent HCV post-transplant Randomized to either pegIFN + RBV (LADR) or control (untreated) Primary endpoint - Post-transplant HCV RNA undetectable at week 12 Everson GT, et al. Hepatology. 2013;57:1752-1762. PR: pegIFN + RBV; LADR: low accelerating dose regimen. Treatment (n=63) Control (n=16) Male (%)7381 Age (years)56 Genotype (%) 1/4 or 6 2/3 47/4 24/25 88/12 0/0 HCV RNA (log 10 IU/mL)5.7 HCC upgrade (%)5494 MELD12.0 CPT score7.06.3 Hemoglobin (g/dL)13.113.5 ANC (/L)794531 Platelets (x10 3 /L)9293 Previous IFN treatment (%)9293 Baseline Characteristics Slide 53 A2ALL Study: Virologic Response With PR Treated Patients (%) Overall (n=44) 59% 25% 22% 2, 3 (n=21) Virologic Response by Genotype 52% HCV RNA Undetectable At liver transplantation Week 12 post-transplant Everson GT, et al. Hepatology. 2013;57:1752-1762. 29% 67% 1, 4, 6 (n=23) HCV Genotype Per protocol analysis. PR: pegIFN + RBV. Treated Patients (%) 16 (n=14) Virologic Response by Treatment Duration 68% HCV RNA Undetectable At liver transplantation Week 12 post-transplant 50% 64% 8 to 16 (n=22) PegIFN + RBV Duration (Weeks) Slide 54 HCV Treatment Before Liver Transplantation in Patients With Decompensated Cirrhosis G1 (%) Child-Pugh (%)Treatment EOTR G1/non-G1 (%) SVR G1/non-G1 (%) HCV RNA Negative Post Transplant (%) Crippin 2002 (pilot study; n=15) 7311.9IFN + RBV33 (overall) NA0 Thomas 2003 (single cohort; n=20) 6710.0IFN60 (overall) NA20 Everson 2005 (single cohort; n=124) 707.4IFN + RBV (LADR) 30/8213/5026 Forns 2003 (single cohort; n=30) 70A (50%); B (43%); C (7%) IFN + RBV30 (overall) NA20 Carrion 2009 (case controlled; n=51) 80A (45%); B (43%); C (4%) PR20/100NA20 Everson 2013 (randomized, controlled; n=79) 567.0PR (LADR) 41/53NA25 Crippin JS, et al. Liver Transpl. 2002;8:350-355; Thomas RM, et al. Liver Transpl. 2003;9:905-915; Everson GT, et al. Hepatology. 2005;42:255-262; Forns X, et al. J Hepatol. 2003;39:389-396; Carrion JA, et al. J Hepatol. 2009;50:719-728; Everson GT, et al. Hepatology. 2013;57:1752-1762. G: genotype; EOTR: end-of-treatment response (HCV RVA undetectable); PR: peg IFN + RBV; LADR: low accelerating dose regimen. Slide 55 Pre-Liver Transplant Sofosbuvir + RBV: Prevention of Recurrent HCV Open-label, phase 2 study conducted at 16 sites (n=61) - Deceased donor liver transplantation candidates with HCV - HCC meeting MILAN criteria - MELD exception for HCC - CPT Pre-Liver Transplant Sofosbuvir + RBV: Virologic Response in HCV Genotypes 1-4 HCV recurrence prevented in 64% of patients HCV RNA 12 Weeks Treatment (n=33) At Transplant Slide 57 Pre-Liver Transplant Sofosbuvir + RBV: Target Not Detected and Safety in Genotypes 1-4 Median days TND - No HCV recurrence (n=28): 95 - HCV recurrence (n=10): 5.5 (P30 days TND HCV recurrence (n=10) No HCV recurrence (n=28) Slide 58 HCV Treatment Considerations for Transplant Recipients Achieving sustained virologic response - Possible in some well-selected patients with HCV and decompensated cirrhosis Post-transplantation recurrence of HCV may be prevented if SVR is achieved pretransplant Potential benefits of HCV therapy need to be balanced against the risk of sepsis, hepatic failure, and death Childs C cirrhotics - Risks usually outweigh benefits Transplantation evaluation - Complete before initiating HCV treatment begins (in case patient should decompensate) Ghany MG, et al. Hepatology. 2009;49:1335-1374. Slide 59 HCV THERAPY AFTER LIVER TRANSPLANTATION Slide 60 Early Antiviral Therapy to Prevent HCV Recurrence After Liver Transplantation G1 (%) Treatment Initiation Post-Transplant (weeks)Treatment SVR (%) Treatment Discontinuation (%) Rejection (%) Mazzafero 2001 (single cohort; n=36) 833IFN + RBV33 (G1/4: 20 G2/3: 100) 00 Sugawara 2004 (single cohort; n=21) 834IFN + RBV39 (G1/4: 33 G2/3: 100) 2526 Chalasani 2005 (phase 3b study; n=54) 743PR Untreated 8 (G1/4: 5 G2/3: 14) 0 31 32 12 21 Shergill 2005 (randomized, controlled; n=54) NR2 to 6pegIFN PR 4.5 18.2 41 NR 22.7 NR Bzowej 2011 (randomized, controlled; n=115) 7910 to 26PR Untreated 22 0 28 NR 5.6 NR Mazzafero V, et al. Transplant Proc. 2001;33:1355-1357; Sugawara Y, et al. Transplantation. 2004;78:1308- 1311; Chalasani N, et al. Hepatology. 2005;41:289-298; Shergill AK, et al. Am J Transplant. 2005;5:118-124; Bzowej N, et al. Liver Transplant. 2011;17:528-538. PR: pegIFN + RBV; G: genotype; NR: not reported. Slide 61 Delayed Antiviral Therapy to Treat HCV Recurrence After Liver Transplantation Advantages of delaying treatment until established HCV recurrence - Reduced risk of acute cellular rejection - Better graft function - Lower doses of immunosuppression Numerous studies with PR - SVR rates: 8% to 45% - Challenges High discontinuation rates Poor tolerability (fatigue, asthenia, pyrexia, cytopenias), especially in severe hepatitis post-transplant Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354. Terrault N. Best Best Pract Res Clin Gastroenterol. 2012;26:531-548. Roche B, et al. Liver Int. 2011;32(suppl 1):120-128. PR: pegIFN + RBV. Slide 62 Delayed Antiviral Therapy to Treat HCV Recurrence After Liver Transplantation G1 (%) Advanced Fibrosis (%) Treatment Initiation Post-Transplant (months)Treatment SVR (%) Treatment Discontinuation (%) Dumortier 2004 (single cohort; n=20) 80NR28PR4520 Oton 2006 (2-center cohort; n=55) 913363PR44 (G1: 40) 24 Angelico 2007 (randomized, controlled; n=42) 83NR44PR pegIFN 33 38 29 24 Carrion 2007 (randomized, controlled; n=81) 903315PR Untreated 48 19 40 0 Picciotto 2007 (single center; n=61) 874625PR 28 15 Hanouneh 2008 (retrospective, medical records; n=53) 791915PR 35 26 Dumortier J, et al. J Hepatol. 2004;40:669-674; Oton E, et al. Am J Transplant. 2006;6:2348-2355; Angelico M, et al. J Hepatol. 2007;46:1009-1017; Carrion JA, et al. Gastroenterology. 2007;132:1746-756; Picciotto FP, et al. J Hepatol. 2007;46:459-465; Hanouneh IA, et al. Liver Transplant. 2008;14:53-58. PR: pegIFN + RBV; G: genotype; NR: not reported. Slide 63 Direct-Acting Antiviral Agents to Treat HCV Recurrence After Liver Transplantation Telaprevir or boceprevir + PR - Promising preliminary SVR rates in genotype 1 - Significant dose reductions required for cyclosporine and tacrolimus - Increased adverse event profile Anemia occurs in most patients RBV dose reduction and hematologic growth support factors/blood transfusions - No data on viral resistance and impact on post-transplant period IFN-free regimens - Simplified dosing - Promising preliminary SVR rates in multiple genotypes - No drug interactions with common immunosuppressant agents (?SMV) - Lower incidence of adverse events, including anemia Lucey MR, et al. Liver Transplant. 2013;19:3-26; Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354; Terrault N. Best Best Pract Res Clin Gastroenterol. 2012;26:531-548; Roche B, et al. Liver Int. 2011;32(suppl 1):120-128. PR: pegIFN + RBV. Slide 64 REFRESH Study: Telaprevir + PR in HCV Genotype 1 Liver Transplant Recipients Interim results with telaprevir + PR show promising efficacy Anemia - Mild or moderate: 41% - Severe: 6.5% - RBV dose reduction: 43% - Erythropoietin/blood transfusions: 30%/6.5% No reports of - Rejections, autoimmune hepatitis, or deaths - Severe or potentially life- threatening cases of rash or pruritus Brown K, et al. Hepatology. 2013;58(suppl 1):209A. Abstract 3. Patients (n=46) HCV RNASlide 65 CRUSH-C: Virologic Response in HCV Genotype 1 eRVR is highly predictive of SVR12 Treatment duration 36 (n=46/11) Achieved eRVR Treatment Duration (weeks) 16% 59% 50% 93% *P CRUSH-C (All Patients): Safety in HCV Genotype 1 High rates of hospitalizations (27%) and >0.5 mg/dL increase in creatinine (41%) Anemia is a significant problem PegIFN + RBV dose reduction: 38%/86% Erythropoietin/blood transfusions: 84%/56% Death (7%) Mainly due to liver-related causes, usually in patients with advanced disease Stravitz R, et al. Hepatology. 2013;58(suppl 1):429A. Abstract 461. Slide 67 Sofosbuvir Compassionate Use Program: Recurrent HCV Following Liver Transplantation Patients with severe recurrent HCV infection following liver transplantation - Likely to haveSlide 68 Sofosbuvir Compassionate Use Program: Initial Treatment Evaluations Overall, liver function tests significantly improved over time Most patients improved clinically or remained stable All serious adverse events (48%) - Leading to treatment discontinuation (13%) Deaths (13%) were mostly a result of disease progression in this very sick population - On treatment (n=8) - Post treatment follow-up (n=5) Patients (%) Treatment Outcomes 62% 21% SVR12 (n=85) Improved*Stable *Improved: improvement in decompensation events (ie, significant decrease in hepatitic encephalopathy episodes, improvement or disappearance of ascites, and improvement in liver-related laboratory values. Forns X, et al. J Hepatol. 2014;60(suppl 1):S26. Abstract O62. Worse Clinical Outcomes (n=104) 21% Slide 69 Sofosbuvir + RBV: Treatment of Recurrent HCV After Liver Transplantation Open-label study - Genotype 1(83%), 3 (15%), 4 (3%) - CTP