Hepatitis C: Diagnosis and Natural History Risk Factors Tushar Patel, MBChB Prevalence Clotting Factor Treatment Prior to 1987 Blood Long-Term Transfusion Worldwide 170 million ( 3%) Hemodialysis or Organ Transplant Prior to 1992 Risk Factors Multiple for Hepatitis C Injection United States Sexual Partners Drug Use Anti-HCV positive 3.9 million(1.8%) HCV RNA positive 2.7 million(1.4%) Mass Injections Birth from and Traditional Infected Mother Practices Alter MJ et al., New Engl J Med 1999; 341:556 Lavanchy D & McMahon B, In: Liang TJ & Hoofnagle JH (eds.) Hepatitis C. New York: Academic Press, 2000:185 1 Current Likelihood of Transmission Diagnostic Tests • Transfusion ~ 1 in 1,000,000 • Heterosexual partner ~1 in 1,000 per yr • Hepatitis C antibody tests • Needlestick injury • Qualitative HCV RNA tests ¾ HCV-positive source ~ 5% ¾ HCV status unknown ~ 1% • Quantitative HCV RNA tests • Maternal-Infant • Genotyping ¾ Mother HIV-negative ~ 5% ¾ Mother HIV-positive 15 - 20% • Liver biopsy Terrault NA, Hepatology 2002 ;36(Suppl 1):S99 Roberts EA, Yeung L. Hepatology 2002 ;36(Suppl 1):S106 Acute Hepatitis C Infection 1000 HCV RNA positive 800 Anti-HCV ALT 600 Diagnosis and Evaluation (IU/L) 400 Symptoms 200 Normal 0 ALT 02468101224123456 7 Weeks Months Time After Exposure Hoofnagle JH, Hepatology 1997; 26:15S 2 Antibody tests for HCV Genotypes hepatitis C • Six major genotypes found throughout • Indicates past or present infection the world • Inexpensive, sensitive and specific • Major determinant of response to • Poor positive predictive value in low antiviral therapy prevalence populations • In Europe and U.S., 60-70% of patients • Low sensitivity in immunosuppressed have genotype 1 infection patients Qualitative tests for Virological Tests Do Not Predict HCV RNA Natural History of Disease • Confirms diagnosis of HCV infection • No correlation between genotype and • Useful in the early diagnosis of acute progression of disease hepatitis C • No correlation between HCV RNA level and • Demonstrates the presence of active progression of disease infection • “Gold standard” for documenting response to treatment 3 Liver Biopsy • Degree of fibrosis is most important predictor of prognosis • Useful in determining need for anti-viral therapy Natural History • Advanced cirrhosis associated with reduced response to treatment Outcome Following Hepatitis C Infection Stages of Fibrosis In Chronic Hepatitis Acute hepatitis C Portal Periportal 55 - 85% Chronic infection 70% 12 Chronic hepatitis 1 - 4%/yr 20% HCC 3 4 Cirrhosis Decompensation 4 - 5%/yr Time (yr) Septal Cirrhosis 10 20 30 4 Stage of Disease Correlates Hepatocellular Carcinoma With Duration of Infection Incidence in HCV-Positive Cirrhosis 60 Chronic hepatitis % 40 Liver cirrhosis Cumulative incidence 20 Hepatocellular carcinoma Median 00 0205010 30 40 60 012345678910 Years of follow-up Years since transfusion Kiyosawa K, et al., Hepatology 1990; 12:671 Adapted from Ikeda K et al, Hepatology 1993;18:47 Outlook for Those With Factors Associated Compensated Cirrhosis Study A Study B Study C With Fibrosis Number 384 112 103 Follow-up (yr) 5.0 4.5 3.3 • Duration of infection Decompensation (%/yr) 3.9 4.4 5.0 • Alcohol > 50 gm per day HCC (%/yr) 1.4 2.3 3.3 5-Year Survival (%) 91 83 84 • Age > 40 years at infection Post decompensation (%) 50 51 -- • Male gender A: Fattovich G et al. Gastroenterology 1997;112:463 B: Hu K & Tong MJ. Hepatology 1999;29:1311 C: Serfaty L et al. Hepatology 1998;27:1435 Poynard T, et al., Lancet 1997; 349:825 5 Progression to Cirrhosis Can Be Estimated Fibrosis Rate Varies Among From Initial Stage of Liver Biopsy Fibrosis HCV-Infected Individuals 100 4 Men who drink > 50 gm Initial Stage 3+ 80 alcohol daily Initial Stage 2-2.9 3 % 60 Progression Initial Stage 0-1.9 to Cirrhosis40 Stage of 2 (stage 4) Fibrosis 20 1 Women who don’t drink 0 0 2 4 6 8 101214161820 Time (yr) 0 0 5 10 15 20 25 30 35 Duration of Infection (year) Yano M, et. al., Hepatology 1996; 23:1334 Fibrosis Risk Varies Among HIV Co-Infection May Accelerate Individuals Progression to Cirrhosis Patient A Patient B 50 40 Age at infection 25 42 30 Alcohol use Seldom 3-4 drinks/day % HIV Positive With 20 N = 80 Sex Female Male Cirrhosis 10 HIV Negative Fibrosis stage/yr 0.10 0.25 N = 80 0 Years to cirrhosis 40 16 0 5 10 15 20 Duration of HCV Infection (years) Poynard T, et al., Lancet 1997; 349:825 Adapted from Di Martino V et al. Hepatology 2001;34:1193 6 Should we treat Future Prevalence Hepatitis C? of HCV 4 3 • HCV is the only chronic virus infection that can Individuals infected be eradicated (cured) by antiviral therapy. at any time 2 • Cure of infection (SVR) essentially eliminates of Prevalence risk of decompensation in patients with HCV Infections (%) 1 Individuals infected cirrhosis and dramatically reduces risk of HCC. For >20 years 0 1960 1970 1980 1990 2000 2010 2020 2030 Davis, et al. Liver Transplantation 2003. Armstrong GL et al. Hepatology 2000; 31:777-782 Liver-Related Mortality in HCV Related Complications Expected to Chronic Infection Increase Greatly in the Coming Years Results of a Markov Model Based on HCV Natural History Studies* Middle-Aged Young Transfusion Recipients Air Force Recruits 6 HCC 81% 4 Cirrhosis 82% % HCV-Negative Mortality Controls Decompensation 106% From Liver HCV Positive Disease 2 Liver-Related 181% Deaths n=377 n=222 n=8551 n=17 0 0 20 40 60 80 100 120 140 160 180 200 25 Years 45 Years Duration of Follow-Up Estimated % Increase From 2000 to 2020 Seeff LB et al, Ann Intern Med 2000; 132:105 *Assumes no HCV treatment. Seeff LB et al, Hepatology 2001;33:455 Davis GL, et al. Liver Transpl. 2003;9:331-338. 7 Mental Health Evaluation • Psychopathology (e.g., substance abuse, depression, anxiety) is prominent in individuals with chronic HCV • Pegylated IFN, with or without ribavirin, is Pre-treatment evaluation associated with depression rates of 20%-34% • IFN-α and ribavirin can worsen and/or induce depression and other underlying psychiatric conditions Æ Patients should be screened and have any pre- existing psychiatric conditions treated before initiating HCV treatment 1. Asnis GM, De La Garza R II. J Clin Gastroenterol. 2006;40:322-335. 2. Rifai MA, et al. Curr Treat Options Gastroenterol. 2006;9:508-519. Current Practice Predictors of Response to Antiviral Therapy in Chronic Hepatitis C HCV viral load Hepatitis A/ B immunizations Anti-HAV AFP HBsAg +/- US, EGD TSH • Genotype 1 and 4 are less responsive ALT Liver Biopsy than other genotypes CBC Patient referral High viral load is less responsive Mental Health Evaluation • Counseling and review Consent to treat – Natural history of HCV Specialist review as appropriate – Treatment options (ID, optho, card etc) – Adverse effects of Rx • Advanced fibrosis is less responsive – Expected benefits of Rx – Duration of treatment Treatment with regular follow-up visits 8 Hepatitis C Virologic Responses Current and Future 8 7 PegIFN/RBV 6 Treatment IU/mL) 5 10 EVR 2 log decline Maher Azzouz,MD 4 10 Associate Professor of Medicine 3 Director of Endoscopy 2 Slow virologic response Limit of detection Division of Gastroenterolgy Hepatolgy and Nutrition RNA HCV (log 1 RVR cEVR The Comprehensive Transplant Center SVR The Ohio State University 0 0 48 12 18 24 30 36 42 48 54 60 66 72 78 Weeks Goals of HCV Therapy Suboptimal Virologic Responses • Primary goal: eradicate the virus 8 7 PegIFN/RBV • Secondary goals Relapse 6 Null response 9 Slow disease progression IU/mL) 10 5 Partial response Breakthrough 2 log decline 9 Minimize risk of HCC 4 10 9 Improve liver histology 3 2 9 Enhance quality of life Limit of detection HCV RNA HCV (log 1 9 Prevent transmission of virus 0 9 Reduce extrahepatic manifestations 0 48 12 18 24 30 36 42 48 54 60 66 72 78 Weeks Lindsay KL. Hepatology. 2002;36(suppl 1):S114-S120. 9 HCV Therapy IDEAL Trial SVR/Standard Interferon (IFN) Which PegIFN is better Genotype 1 US Patients 100 50 80 40 41 40 38 60 30 43 SVR % 20 40 SVR (%) 10 19 20 6 0 PEG-INTRON 1.0 mcg/kg PEG-INTRON 1.5 mcg/kg Pegasys 180mcg 0 IFN IFN IFN/RBV 24 Weeks 48 Weeks 48 Weeks There were no statistical differences between groups McHutchison J, et al. N Engl J Med. 1998;339:1485-1492. Poynard T, et al. Lancet. 1998;352: 1426-1432. Sulkowski, M., et al. Presented at EASL 2008, Milan, Italy HCV Therapy Peg-IFN + RBV SVR With PegIFN/Ribavirin Response Rates • > 50% of GT 1 Patients Do Not Respond 60 52-53 Naive • PegIFN alfa-2b 1.5 µg/kg/week + • PegIFN alfa-2a 180 µg/week + 50 Retreatment RBV 800 mg/day for 48 weeks[1] weight-based RBV (1000 or 1200 38-41 27-40 mg/day) for 48 weeks[2] 100 40 82 17-29 80 76 30 SVR (%) 19-26 60 56 20 54 46 42 10 2-4 SVR (%) 40 0 20 All Genotypes Genotype 1 HIV/HCV HIV/HCV African American Peg on Peg US Patient Genotype 1 Genotype 1 Non-Responders n = 511 n = 348 n = 163 n = 453 n = 298 n = 140 0 Overall GT 1 GT 2/3 Overall GT 1 GT 2/3 Manns MP, et al. Lancet. 2001;358:958-965. Torriani FJ, et al. N Engl J Med. 2004;351:438-450. Poynard T et al. J Hepatol. 2005:42(Suppl 2):40-41.:Shiffman M.L., et al. Gastroenterology 2004; 126:1015- Jeffers LJ, et al. Hepatology. 2004;39:1702-1708.