Patrick Marcellin, MD
Hôpital Beaujon, Clichy
Université Paris VII
Key Learning Objectives
At the end of the session the participants will be able to:
· describe the rates of progression associated with the natural history of hepatitis C infection
· understand the risk factors known to effect disease progression
· describe the response rates to therapy by genotype and viral load
Hepatitis C is a relatively common disease. An estimated 3% of the world population is chronically infected with hepatitis C virus (HCV), and HCV accounts for approximately 20% of cases of acute hepatitis and 70% of cases of chronic hepatitis.1 Chronic hepatitis C is a major cause of cirrhosis and hepatocellular carcinoma. The severity of HCV related liver disease is extremely variable but may, in some cases, induce progressive liver fibrosis which evolves to cirrhosis and then to hepatocellular carcinoma, in a time frame ranging from a few years to many decades.
An estimated 25% of patients with chronic HCV infection have normal serum ALT levels despite detectable HCV RNA in serum.2 These patients are usually asymptomatic, and the majority have mild lesions on liver biopsy.3
Among patients with chronic hepatitis C with elevated or fluctuating serum ALT levels, approximately 50% have mild chronic hepatitis. This type of chronic hepatitis C generally progresses very slowly and the long-term risk of developing cirrhosis is low. However, a minority of these patients may eventually develop more progressive liver disease.
About 50% of the patients with chronic hepatitis C have moderate to severe chronic hepatitis. The liver biopsy is the most accurate way to distinguish mild from moderate or severe chronic hepatitis and thus assess the prognosis. These patients have a high risk of developing cirrhosis. Age at infection, gender and alcohol consumption are the main factors influencing the progression of fibrosis.4
Cirrhosis and Hepatocellular Carcinoma
For many years HCV related cirrhosis may be silent. Clinical symptoms of portal hypertension or hepatic failure appear late. In patients with HCV related cirrhosis, mortality related to portal hypertension, hepatic failure or hepatocellular carcinoma is 2% to 5% per year.5 End-stage HCV related cirrhosis is the most prevalent indication for liver transplantation. The incidence of hepatocellular carcinoma is high (3% to 10% per year) and justifies systematic monitoring with ultrasonography and alpha-foetoprotein.6
Two recent large controlled trials demonstrated that combination therapy with interferon and ribavirin was more effective than interferon alone.7,8 These studies showed that combination therapy for 24 or 48 weeks gives overall sustained response rates of 38% and 41%, respectively versus 6% and 16% with interferon alone. Another study, in patients having relapse after treat-ment with interferon alone, showed a 50% rate of sustained response with a six-month course of combination therapy versus 5% with interferon alone.9 These results rendered combination therapy as the standard treatment for chronic hepatitis C.10
The main predictors of sustained response are the genotype and baseline viral load. The overall sustained response rate is increased to 64% in patients with HCV genotype 2 or 3, whatever the baseline viral load is, and is 35% in patients with genotype 1 and low viral load. In patients with genotype 1 and high viral load, the sustained response rate depends on the duration of therapy: 28% and 8% with 12 months and 6 months, respectively.7
Conjugation of alpha interferon with polyethylene glycol (pegylated interferon) increases the half-life (90 hours) and improves the pharmacodynamics of the molecule. Therefore, one single injection, once a week is sufficient and the antiviral effect seems significantly improved as compared with standard interferon. A preliminary study showed 36% sustained response with 180 µg of pegylated interferon for 48 weeks as compared with 5% with standard interferon therapy.11
Current trials are assessing the efficacy of pegylated interferon combined with ribavirin. If the improved efficacy related to pegylated interferon on the one hand and to ribavirin on the other hand are additional, combination therapy of pegylated interferon with ribavirin could provide a sustained response of greater than 50%. This optimistic view will hopefully be confirmed.
1. Marcellin P. Hepatitis C: the clinical spectrum of the disease. J Hepatol 1999;31:9-16.
2. Shakil AO, Conry-Cantilena C, Alter HJ, et al. Volunteer blood donors with antibody to hepatitis C virus: clinical, biochemical, virologic and histologic features. Ann Intern Med 1995:123:330-7.
3. Marcellin P, Levy S, Erlinger S. Therapy of hepatitis C: patients with normal aminotransferase levels. Hepatology 1997;26:133S-7S.
4. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997;349:825-32.
5. Alberti A, Chemello L, Benvegnu L. Natural history of hepatitis C. J Hepatol 1999;1:17-24.
6. Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma. Sem Liver Dis 1995;15:64-9.
7. Poynard T, Marcellin P, Lee SS, et al. Randomised trial of interferon a2b plus ribavirin for 48 weeks or for 24 weeks versus interferon a2b plus placebo for 48 weeks for treatment of c hronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group. Lancet 1998;352:1426-32.
8. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med 1998;339:1485-92.
9. Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med 1998;339:1493-9.
10. EASL International Consensus Conference on Hepatitis C. Consensus Statement. J Hepatol 1999;30:956-61.
11. Shiffman ML, Pockros PJ, Reddy RK, et al. A controlled, randomized, multicenter, descending dose phase II trial of pegylated interferon alfa-2A (PEG) vs standard interferon alfa-2A (IFN) for treatment of chronic hepatitis C. Gastroenterology 1999;116:A1275.