After the Cure: Long-Term Management of HCV Liver Disease Norah A. Terrault, MD, MPH

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2 After the Cure: Long-Term Management of HCV Liver Disease Norah A. Terrault, MD, MPH Professor of Medicine Department of Gastroenterology Director, Viral Hepatitis Center University of California San Francisco

3 Many Cured Patients Will Have Cirrhosis % F0/1; cirrhosis = 5% % F0/1; cirrhosis = 25% 2020 cirrhosis = 37.2% Davis GL. Gastroenterology. 2010;138:513

4 Patient with Cirrhosis = Patient at Risk Portal hypertension Variceal hemorrhage Ascites Cirrhosis Liver insufficiency Spontaneous bacterial peritonitis Hepatorenal syndrome Encephalopathy Jaundice Regeneration and repair Hepatocellular carcinoma

5 Natural History of Cirrhosis Increasing portal pressure Chronic liver disease Decompensated cirrhosis Compensated cirrhosis 1%* 3%* No varices Varices 15-20%* *1-year mortality Death Variceal hemorrhage Ascites Encephalopathy Jaundice Groszmann et al. NEJM. 2005;353:2254 D Amico et al. J Hepatol. 2006;44:217

6 Natural History of Compensated HCV Cirrhosis HALT-C: 8-year prospective cohort of cirrhotics (N=428) Liver-related Complications Annualized Incidence (N=428) Events after CPT 7 (N=137) CTP 7 5.0% Variceal bleeding 0.9% 1.2% Ascites 2.9% 12.7% Encephalopathy 1.9% 10.3% HCC or presumed HCC 2.4% 4.5% Liver-related death 2.6% 8.7% Liver-related death or LT 4.2% 14.3% Deinstag J, et al. Hepatology 2011

7 Decompensation Shortens Survival 100 Compensated cirrhosis Median survival >12 years Decompensated cirrhosis 20 Median survival ~2 years Months D Amico et al. J Hepatol. 2006;44:217

8 Impact of HCV Treatment on Natural History in Patients with Advanced Fibrosis Improved outcomes in patients who achieve SVR All-cause mortality Liver-related mortality Liver cancer Liver failure/need for liver transplantation HCV treatment in absence of SVR may result in harm (compared with untreated patients) Infectious complications during treatment Risk of decompensation with treatment discontinuation

9 Risks Associated with Antiviral Therapy in Cirrhotics Dose interruptions and discontinuations more frequent than in noncirrhotics Cytopenias more likely to be dose limiting Increased incidence of bacterial infection Potential worsening of liver function Magnitude of risk related to MELD/CPT status at start of treatment Risk of death Iacobellis A, et al. J Hepatol. 2007;46:206 Carrion J. J Hepatol. 2009;50:719 Everson G. Hepatology. 2005;42:255

10 Viral Clearance Reduces Liver-Related Complications HALT-C cohort (patients with bridging fibrosis/cirrhosis) Median follow-up: 85.8 mos SVR and 78.4 mos non-svr Morgan T. Hepatology. 2010;52:833

11 SVR Reduces All-Cause and Liver-Related Mortality van der Meer A, JAMA 2013

12 HCC Risk Among HCV Patients with Advanced Fibrosis Meta-analysis: N=2649 treated patients Incidence of HCC SVR = 1.05% per year No-SVR = 3.30% per year Morgan R. Ann Intern Med. 2013;158:329

13 HCC Rates Among Patients Achieving SVR Five tertiary referral centers, Ishak F4-6 Factors predicting HCC independent of SVR Older age Male Genotype 3 Diabetes History of severe alcohol use Rate per 100 py 95% CI SVR No SVR van der Meer A, JAMA 2013

14 Risk of Varices Reduced in Cirrhotics Achieving SVR N=127 Childs A cirrhotics with no or small varices pretreatment Mean follow-up between EGDs: 68 (SVR) and 57 (non-svr) mos P= /57 8/53 1/5 2/12 D Ambrosio R. Antivir Ther. 2011;16:677

15 Implications of Long-Term Follow-up Studies of Patients with Advanced Fibrosis Achieving SVR Risks of liver-related complications are reduced but not eliminated Unclear when risk period ends 10 years? Longer? Higher-risk groups are those with portal hypertension or higher CPS or concurrent liver conditions Monitoring for liver complications is necessary post-svr Consider referral to liver specialist

16 Managing Risk of Variceal Hemorrhage Surveillance currently is independent of SVR status Upper endoscopy at diagnosis of cirrhosis Every 3 years if no varices; every 2 years if small Annual after first decompensation Prophylaxis dictated by size of varices and cirrhosis severity Garcia-Tsao L, et al. AASLD Practice Guideline 2007

17 Surveillance of Hepatocellular Carcinoma Liver society guidelines indicate surveillance for HCC indicated in ALL cirrhotics if risk 1.5% per year Based on cost-effectiveness analyses HCV patients with advanced fibrosis and SVR have HCC risk that varies from 0.5% to 1.5% per year Subgroups at highest risk not clearly defined Curative therapies for localized HCC are available, providing further support for surveillance Resection, radiofrequency ablation, liver transplantation Bruix J, et al. Hepatology. 2011;53:1020

18 Liver Transplantation for HCC: Milan Criteria 1 lesion 5 cm 2 to 3, none > 3 cm + Absence of Macroscopic Vascular Invasion Absence of Extrahepatic Spread Mazzaferro et al. NEJM. 1996;334:693

19 Liver Transplantation for HCC: Outcomes Applying Milan Criteria Author N Selection Criteria Recurrence 5-Year Survival Mazzaferro (1996) 48 Single <5 cm 3 nodules <3 cm 8% 74% Bismuth (1999) 45 Single <3 cm 3 nodules <3 cm 11% 74% Llovet (1999) 79 Single <5 cm 4% 75% Jonas (2001) 120 Single <5 cm 3 nodules <3 cm 16% 71% Yao (2001) 64 Single <5 cm 3 nodules <3 cm 11% 73% Schwartz M. Gastroenterology. 2004;127(5supp1):S268

20 Surveillance Practices Absolute risk of HCC Rate of tumor growth Whether to perform surveillance Surveillance interval Abdominal imaging: ultrasound is test of choice AFP only in resourced limited settings Interval every 6-12 months Bruix J, et al. Hepatology. 2011;53:1020

21 Monitoring Liver Disease Severity/Progression Frequency of monitoring increases as MELD and/or Child-Pugh score increases Compensated cirrhosis without portal hypertension = Q6 mos Decompensated cirrhosis: weekly to monthly When to refer for liver transplantation First complications of cirrhosis: ascites, bleeding varices, hepatic encephalopathy Increasing MELD (in absence of clinical decompensation); MELD 15 transplant benefit Newly diagnosed localized HCC

22 Three-Month Mortality Better Predicted by MELD Than by CPT Score MELD Score CTP 13-15

23 Liver Transplantation: Absolute Contraindications Severe, irreversible comorbid medical conditions that adversely impact short-term life expectancy Severe, untreated pulmonary hypertension Extrahepatic malignancy Advanced HCC with vascular/ lymph node invasion Severe, uncontrolled systemic infection Extensive portal-mesenteric venous thrombosis Active substance abuse or unacceptable risks for recidivism Noncompliance

24 Increasing Proportion of US Transplants for HCV-Associated HCC UNOS: (accessed 2007)

25 Posttransplant Patient Survival by Pretransplant Etiology (%) HBV: 2406 HCV : ELTR 01/ / HCV+ recipients have 30% higher mortality c/w non-hcv+ recipients after 5-year follow-up* Alcoholic : PBC : Yrs *Forman, Gastroenterology 2002

26 HCV and Transplantation HCV is the most common indication for LT ~10% develop severe, early recurrence with graft loss within 2-5 years of LT Median time to recurrent cirrhosis = 8-10 years 20-30% develop recurrent cirrhosis within 5 years Highest risk: AA, HIV+, older donors Eradication of HCV prior to or after LT improves survival

27 Liver Transplantation: Hepatitis C Disease Progression General Population Post-OLT Kuo A, et al. Am J Transpl. 2006;6:449

28 Pretransplant SVR Protects the Graft from HCV Recurrence Transplantation Antiviral Therapy for 48 wks Follow-up Follow-up SVR 100% HCV-free post-lt Transplantation Antiviral Therapy for 4-16 wks On-Treatment Response Follow-up ~70% HCV-free post-lt

29 After the Cure : Key Aspects of Managing Patients with Cirrhosis Longer-term follow-up for liver complications is essential Complication rates significantly reduced by achieving SVR but not zero Surveillance studies for HCC and varices Monitoring disease progression MELD score plus albumin, sodium Clinical symptoms of decompensation Refer for transplant evaluation if indicated

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