Andrew J. Muir, MD, MHS Chief, Division of Gastroenterology Duke University School of Medicine Durham, North Carolina Treatment of Hepatitis C in Patients.

Andrew J. Muir, MD, MHS Chief, Division of Gastroenterology Duke University School of Medicine Durham, North Carolina Treatment of Hepatitis C in Patients With Cirrhosis Recorded on 10/24/14

of 33 Disclosure Dr Muir has received grants and research support from AbbVie, Achillion Pharmaceuticals, Inc, Bristol-Myers Squibb, Gilead Sciences, Inc, GlaxoSmithKline, Merck & Co, Inc, Roche, and Vertex Pharmaceuticals, Inc. He has served as a consultant to AbbVie, Achillion Pharmaceuticals, Inc, Bristol-Myers Squibb, Gilead Sciences, Inc, GlaxoSmithKline, Merck & Co, Inc, Salix Pharmaceuticals, and Vertex Pharmaceuticals, Inc. (Updated 9/3/14)

of 33 Outline Definitions and diagnostic approach Treatment – Candidacy – Efficacy – Adverse events Decompensated cirrhosis

of 33 Case 54-year-old man presents with new diagnosis – History: no ascites, encephalopathy, GI bleeding – Examination: mentally clear, no ascites or edema – Laboratory data:  AST 60 U/L, ALT 75 U/L, t bili 1.2 mg/dL  Albumin 3.9 gm/dL, creatinine 1.0 mg/dL  Platelet 110 x 10 9 /L  PT-INR 1.1  HCV RNA 1,100,000 IU/mL  Genotype 1a Clinical questions – Does the patient need treatment? – What is the stage of liver disease?

Definitions and Diagnostic Approach

of 33 DiBisceglie A. Hepatology 2000 Cirrhosis 20 % Faster progression with older age at infection alcohol HIV infection post-transplant Acute HCV Chronic HCV 75-85 % 20-50 years HCV natural history

of 33 Liver fibrosis staging F1: portal fibrosis F2: portal fibrosis with few septa F3: septal fibrosis (bridging) F4: cirrhosis Bedossa P. Hepatology 1996

of 33 Gold standard Invasive  Morbidity (3/1,000)  Mortality (1/10,000) Observer variability Sampling error Costly Rockey DC. Hepatology 2009; Regev A. Am J Gastroenterol 2002 Liver biopsy

of 33 Alternatives to liver biopsy Alternative approaches – Serum markers  Standard laboratory tests: APRI, FIB-4  Commercial assays – Radiographic tests  Elastography Limitations – Ability to distinguish F1 versus F2, etc  Better to differentiate advanced versus early – Serologies impacted by inflammation – Indeterminate outcomes common Lin ZH. Hepatology 2011; Vallet-Pichard. Hepatology 2007; Myers RP. Dig Dis Sci 2003; Friedrich-Rust M. Gastroenterology 2006

of 33 www.hcvguidelines.org Recommendations AASLD/IDSA/IAS–USA Guidance – www.hcvguidelines.org www.hcvguidelines.org An assessment of the degree of hepatic fibrosis, using noninvasive testing or liver biopsy, is recommended. Ongoing assessment of liver disease is recommended for persons in whom therapy is deferred.

Treatment

of 33 www.hcvguidelines.org Who needs treatment? AASLD/IDSA/IAS–USA Guidance – www.hcvguidelines.org www.hcvguidelines.org Treatment is recommended for patients with chronic HCV infection. Treatment is assigned the highest priority for those patients with advanced fibrosis (Metavir F3), those with compensated cirrhosis (Metavir F4), liver transplant recipients, and patients with severe extrahepatic hepatitis C.

of 33 Genotype 2 AASLD/IDSA/IAS–USA Guidance – www.hcvguidelines.org www.hcvguidelines.org Sofosbuvir + ribavirin x 12 weeks Peginterferon-α, ribavirin + sofosbuvir Treatment naiveRecommended PEG/RBV nonrespondersRecommended*Alternative * Patients with cirrhosis may benefit by extension of treatment to 16 weeks. www.hcvguidelines.org

of 33 Genotype 2 sofosbuvir + ribavirin SOF/RBV PEG/RBV SOF/RBV x 12 weeks SOF/RBV x 16 weeks 58 59 44 54 10 11 8 13 25 26 23 6 10 7979 FISSION (treatment naive) FUSION (treatment experienced) Lawitz E. NEJM 2013; Jacobson IM. NEJM 2013

of 33 Genotype 3 AASLD/IDSA/IAS–USA Guidance – www.hcvguidelines.org www.hcvguidelines.org Sofosbuvir + ribavirin x 24 weeks Peginterferon-α, ribavirin + sofosbuvir Treatment naiveRecommendedAlternative PEG/RBV nonrespondersRecommendedAlternative www.hcvguidelines.org

of 33 Genotype 3 sofosbuvir + ribavirin SOF/RBV PEG/RBV SOF/RBV x 12 weeks SOF/RBV x 16 weeks 89 145 99 139 13 38 11 37 14 38 25 40 5/26 14 23 FISSION (treatment naive) FUSION (treatment experienced) Lawitz E. NEJM 2013; Jacobson IM. NEJM 2013

of 33 VALENCE study Amended to treat GT 3 for 24 weeks Treatment naive and experienced 12 and 24 weeks similar safety profile Zeuzem S. NEJM 2014 Genotype 3 sofosbuvir + ribavirin

of 33 Afdhal N. NEJM 2014; Poordad F. NEJM 2014; Sulkowski M. NEJM 2014 SVR rates > 90% in genotype 1 – Are outcomes lower in patients with cirrhosis? Sofosbuvir, ledipasvir +/- ribavirin Sofosbuvir, daclatasvir +/- ribavirin ABT450/ritonavir, ombitasvir, dasabuvir, ribavirin Simeprevir, sofosbuvir +/- ribavirin Genotype 1

of 33 Sofosbuvir phase 3 studies – Genotypes 1-3 – SOF/RBV and PEG/RBV/SOF Foster G. EASL 2014 FactorOdds ratioP-value Treatment experienced2.30.001 Male2.30.01 Weight > 75 kg2.50.01 IL28B non-CC3.4< 0.001 Cirrhosis4.0< 0.001 HCV RNA > 800,000 IU/mL4.7< 0.001 Predictors of relapse

of 33 Sofosbuvir phase 3 studies – Genotypes 1-3 – SOF/RBV and PEG/RBV/SOF Foster G. EASL 2014 9999 70 181 182 247 262 60 88 12 21 Predictors of SVR

of 33 Poordad F. NEJM 2014 Treatment in cirrhosis Population – 380 Child Pugh Class A cirrhosis (compensated) – Treatment naive and previously treated Interferon-free combination – Protease inhibitor ABT-450 with ritonavir (ABT-450/r) – NS5A inhibitor ombitasvir (ABT-267) – Nonnucleoside polymerase inhibitor dasabuvir (ABT-333) – Ribavirin Design – Phase 3, randomized, open label – Duration 12 versus 24 weeks

of 33 Poordad F. NEJM 2014 Treatment in cirrhosis

of 33 Poordad F. NEJM 2014 Variable12-week group (N = 208) 24-week group (N = 172) Any adverse event191 (91.8%)156 (90.7%) AE leading to discontinuation4 (1.9%)4 (2.3%) Serious adverse events13 (6.2%)8 (4.7%) Deaths1 (0.5%)0 Treatment in cirrhosis

of 33 Poordad F. NEJM 2014 Common adverse events12-week group (N = 208) 24-week group (N = 172) Fatigue68 (32.7%)80 (46.5%) Headache58 (27.9%)53 (30.8%) Nausea37 (17.8%)35 (20.3%) Pruritus38 (18.3%)33 (19.2%) Diarrhea30 (14.4%)29 (16.9%) Asthenia29 (13.9%)22 (12.8%) Rash23 (11.1%)25 (14.5%) Irritability15 (7.2%)21 (12.2%) Treatment in cirrhosis

of 33 Poordad F. NEJM 2014 Laboratory results12-week group (N = 208) 24-week group (N = 172) ALT, grade 3 or 46 (2.9%)0 AST, grade 3 or 41 (0.5%)0 Total bilirubin, grade 3 or 428 (13.5%)9 (5.2%) Anemia Hemoglobin < 10 gm/dL103 (49.5%)97 (56.4%) Hemoglobin 8-10 gm/dL12 (5.8%)18 (10.5%) Hemoglobin 6.5-8 gm/dL2 (1.0%)1 (0.6%) Hemoglobin < 6.5 gm/dL1 (0.5%)0 Treatment in cirrhosis

Decompensated Cirrhosis

of 33 Decompensated cirrhosis With decompensated cirrhosis, how much better can the liver get? Will this be like HBV? Disclaimer for new agents Have they been studied in decompensated cirrhosis? Simeprevir – increased exposure with Child Pugh class B so use with caution

of 33 Decompensated cirrhosis Sofosbuvir + ribavirin, interim results Afdhal N. EASL 2014. Patients, N = 50 – HCV genotypes 1-4 – HVPG ≥ 6 mmHg – Child Pugh A 40%, B 60% Treatment – Arm 1: SOF/RBV x 48 weeks – Arm 2: Observation x 24 weeks then SOF/RBV x 48 weeks Discontinuations – Arm 1: 1 AE, 1 nonresponder, 1 withdrew – Arm 2: 2 disease progression, 1 withdrew, 1 LTFU

of 33 Afdhal N. EASL 2014. AscitesHepatic encephalopathy Week SOF/RBV N=25 Obs N=25 SOF/RBV N=25 Obs N=25 Baseline6952 Week 125833 Week 240704 Decompensated cirrhosis Sofosbuvir + ribavirin, interim results

of 33 Gane EJ. EASL 2014. Patients, N = 20 – Genotype 1 – Child Pugh class B – Ascites 4 (20%) – Encephalopathy 6 (30%) Duration: 12 weeks Decompensated cirrhosis Sofosbuvir + ledipasvir

of 33 Early positive signs More data needed in new regimens Long-term outcomes important Survival Complications of portal hypertension With decompensated cirrhosis, how much better can the liver get? Decompensated cirrhosis

of 33 Summary All patients with HCV need an assessment of fibrosis – Patients with advanced fibrosis or cirrhosis should be prioritized for treatment HCV treatment is safe and effective in patients with compensated cirrhosis – Sofosbuvir and ribavirin are effective for genotype 2/3 – Multiple interferon-free regimens have been developed for genotype 1 – Adverse events are generally mild with interferon-free regimens – Interferon-free regimens are well tolerated by patients with decompensated cirrhosis, and the long-term effectiveness is under investigation

Andrew J. Muir, MD, MHS Chief, Division of Gastroenterology Duke University School of Medicine Durham, North Carolina Treatment of Hepatitis C in Patients.

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Andrew J. Muir, MD, MHS Chief, Division of Gastroenterology Duke University School of Medicine Durham, North Carolina Treatment of Hepatitis C in Patients.

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