Approach to HCV Treatment in Patients with HCC Mark W. Russo, MD, MPH, FACG Carolinas HealthCare System Charlotte Worldwide Causes of HCC 60% 50% 40% 30% 20% 10% 0% 54% 31% 15% Hepatitis B Hepatitis C Other EASL-EORTC Clinical Practice Guidelines. Management of HCC. J Hepatol 2012;56:908-943 Page 1 of 13
Seroprevalence of HCV and HBV in Patients with HCC - USA Before the year 2000 After the year 2000 De Martel C, et al. Hepatology 2015;62:1190-1200 Age-adjusted incidence of HCC and intrahepatic bile duct cancer 2008-2012 Ryerson AB et al. Cancer 2016;122:1312-37 Page 2 of 13
U.S. Adjusted Rates of Liver/Biliary Cancer El-Serag HB, Kanwal F. Hepatology 2014;1767-1775 Liver Cancer Mortality in the United States 2003-2012 Death rates declined for all cancers combined Decrease of 1.5% per year Deaths from liver cancers increased at the highest rate of all cancer sites Men 2x incidence compared to women Highest risk for persons born after 1947 Ryerson AB et al. Cancer 2016;122:1312-37 Page 3 of 13
Age-specific incidence of liver and intrahepatic bile duct cancer from 2008-2012 U.S. Ryerson AB et al. Cancer 2016;122:1312-37 HCV and HCC Connection HCV Infection 15x 20x increased risk for HCC vs. uninfected individuals HCC cumulative risk of 1% to 3% over 25 years After cirrhosis: HCC annual risk 1% to 8%, average 3.5% Risk factors for HCC in HCV cirrhosis Male sex Coinfection with HBV or HIV Alcohol use Obesity Diabetes Genotype Page 4 of 13
HCC in HCV and Diabetes Taiwan National Health Insurance Research Database (>99% of the population) Patients with chronic HCV who developed new onset diabetes Adjusted Relative Risks for HCC Study population: 1.9 (CI: 1.1-3.3) Age 40-59: 3.09 (CI: 1.04-9.11) Huang YW, et al. Aliment Pharmacol Ther 2015;42:902-911 Increased Risk of HCC in Genotype 3 Infection Observational cohort study of 128,769 HCV patients from the VA HCV Clinical Registry, which compiled electronic medical records data from 1999 to 2010 Cirrhosis (n=123,988) Decompensated cirrhosis (n=128,055) Liver-related hospitalization (n=128,769) GT1 (reference point; n=102,191) GT2 (n=15,113) GT3 (n=9851) Other (n=1614) HCC (n=128,481) 0 0.5 1 1.5 2 Hazard Ratio McCombs J, et al. JAMA Intern Med. 2014;17:204-212. 10 Page 5 of 13
Incidence of HCC According to Genotype VA HCV Clinical Case Registry 2000-2009. 110,484 HCV patients, 8,337 genotype 3 infection G3 patients were younger Adjusted HR for HCC: 1.8 (compared to G1) Independent of: Age Diabetes BMI Kanwal F, et al. Hepatology 2014;60:98-105 Fibrosis and Risk of HCC in HCV HCC develops in the setting of advanced fibrosis in HCV HALT-C Study (n=1,005) Stage 3 or 4 fibrosis Median Follow up 4.6 years Cumulative 5y incidence of HCC: 5.2% Cirrhosis: 7.0% Bridging fibrosis: 4.1% EASL Clinical guidelines recommend HCC screening for F-3 fibrosis in HCV Lok AS, et al. Gastroenterology 2009;136:138-148 Page 6 of 13
Other Factors Predictive of HCC ADVANCED LIVER DISEASE PLATELET COUNT Lok AS, et al. Gastroenterology 2009;136:138-148 Identifying Patients at Risk Take Home Messages Risk restricted to advanced fibrosis (F3-F4) Risk is highest in Cirrhosis Males Genotype 3 infection Advanced liver disease Screening for HCC in F0-2 is not recommended Page 7 of 13
Who to screen How to Screen Cirrhosis (F4 fibrosis) 1 Bridging fibrosis (F3 fibrosis) 2 Current guidelines: Ultrasound exam every 6 months Alpha-fetoprotein is not recommended Lacks sensitivity and specificity Frequent false positive results Normal levels in up to 40% of documented HCC 1. AASLD & EASL guidelines 2. EASL guidelines If you are using AFP AFP cannot be used as the only screening test Many HCV cirrhosis patients will have elevated AFP The trend is more important than the actual value AFP usually rises as ALT rises A normal AFP should not dissuade you from evaluating a possible abnormality on ultrasound Page 8 of 13
Why Screening Fails Only 40% of HCC patients are diagnosed at an early stage 1,005 patients with F3/4 fibrosis, mean follow-up 6.1 years (HALT-C) 69% (692) had consistent surveillance 83 patients had HCC 28% (n=23) were detected beyond Milan Criteria 3/23 had absence of screening 4/23 absence of follow up 16/23 absence of detection Ultrasound is far from a perfect test! Singal AG et al. Am J Gastroenterol 2013;108:425-432 What to do with Screening Results Bruix J, Sherman M. Hepatology 2011;53:1020-1022 Page 9 of 13
Meta-analysis of observational studies Effects of HCV Therapy on HCC All Stages of Fibrosis Advanced Fibrosis HR of HCC after therapy HR of HCC after Therapy Morgan RL, et al. Ann Intern Med 2013;158:329-337 HCV Cure Does Not Eliminate Risk n=530, advanced fibrosis; 8.4 year follow up post SVR. Europe and Canada n=124, biopsy proven cirrhosis; 8-year follow up post SVR. Italy Van der Meer AJ, et al. JAMA 2012;308(24):2584-2593 Ascione A, et al. Hepatology 2007;45:579-587 Page 10 of 13
Direct acting antiviral therapy and HCC % 30 25 20 15 10 Rate of HCC after SVR with DAAs 344 total patients 59 hx of prior HCC 24 wk follow-up Risk factors for HCC o Child Pugh Class o Prior Hx HCC - Younger Age 5 0 Total prior HCC no hx HCC J Hepatol 2016; Jun 24. Direct acting antiviral therapy and HCC 50 Post-Transplant findings % 40 30 20 10 0 outside Milan MVI DAA No DAA All patients started within MIlan J Hepatol 2016, in press. Page 11 of 13
Sofosbuvir + Ribavirin Pre OLT 61 patients CP-A patients with HCC waiting for OLT Treated with sofosbuvir + ribavirin for up to 48 weeks prior to OLT 49% achieved a cure post-olt 43 patients RNA (-) Pre-OLT SVR post OLT: 70% SVR was inversely related to number of days of undetectable RNA 30 days seems to be the cut-off Sofosbuvir + ribavirin is now considered suboptimal therapy for G1 Curry MP et al. Gastroenterology 2015;148:100-107 HCV Recurrence vs. Time Undetectable HCV-RNA Sofosbuvir + ribavirin for up to 48 weeks prior to OLT Curry MP et al. Gastroenterology 2015;148:100-107 Page 12 of 13
Post Liver Transplantation 100% 80% 60% 40% 20% 0% Sofosbuvir + Ledipasvir + Ribavirin 96% 98% 53/55 55/56 No Cirrhosis 12 wks 24 wks AASLD 2015: Ribavirin probably not necessary in post OLT noncirrhotic patients Charlton M, et al. Gastroenterology 2015;149:649-659 HCC in HCV Take Home Points 1. Hepatitis C markedly increases risk of HCC Risk increased in F3 and F4 fibrosis 2. F3 and F4 HCV patients should undergo appropriate HCC screening 3. Cure of HCV markedly reduces risk of HCC in all patients BUT AFFECT OF DAAs on HCC RISK WARRANTS FURTHER STUDY 4. After cure, F3 and F4 patients remain at risk of HCC 5. Timing of treatment of HCV after HCC diagnosis is evolving Page 13 of 13