Treatment of Chronic Hepatitis C

Chronic infection with the hepatitis C virus is extremely prevalent, averaging 1% to 2% of the world population. Fortunately, recognition of potential risk factors, changes in patterns of using injected drugs, and improved safety of the blood supply have led to a dramatic decline in the incidence of new hepatitis C virus infections in recent years. However, since most acutely infected patients become and remain chronically infected, the overall prevalence of chronic infection has not fallen.

Chronic liver disease due to hepatitis C virus typically progresses slowly and usually does not result in major morbidity for many years. However, it is apparent that the large pool of patients with longstanding chronic hepatitis C is beginning to manifest the consequences of chronic infection and cirrhosis. In both the United Kingdom and the United States the incidence of hepatocellular carcinoma is increasing, deaths due to cirrhosis from chronic hepatitis C are on the rise, and hepatitis C is the leading indication for liver transplantation. In recent years, pharmacological treatment has had good results in patients with hepatitis C virus infection, with the virus being permanently eradicated in a large number of patients with a combination of interferon and ribavirin. This is a remarkable achievement in a chronic viral infection where spontaneous clearance is rare.

Early treatment and eradication of hepatitis C virus infection is desirable to prevent spread of infection and to reduce the risk of progression of disease. There has been rapid and phenomenal progress in the treatment of chronic hepatitis C over the past 10 years. Interferons were the first agents studied in the mid-1980s for treatment of what was then called chronic non-A, non-B hepatitis. Interferons are glycoproteins produced in vivo by leucocytes in response to viral infection. Interferons can be commercially manufactured by cell culture or recombinant technology and have been commercially available for the treatment of chronic hepatitis for more than a decade. Short courses (six months) of interferon alfa commonly led to transient normalization of serum aminotransferases, loss of detectable virus in blood, and reduction of inflammation in liver biopsies. Unfortunately, relapse occurred in most of these cases when treatment was stopped. No other treatment options were available for patients with chronic hepatitis Cthus, despite these modest responses, a six month course of treatment with recombinant interferon alfa was approved by regulatory agencies in Europe and the United States in the early 1990s. It was later shown that prolonging the duration of treatment with interferon to at least 12 months doubled the sustained response rate, and this longer regimen was subsequently approved as the standard of care.1 However, sustained responses remained relatively uncommon in patients who were treated with interferon alfa alone. Sustained virological loss was seen in 6-15% of patients after a six month course and this rose to 13-25% after 12 months of treatment.1 Recent studies that have carefully assessed virological end points of treatment with different regimens have clearly shown that sustained viral responses to interferon alfa monotherapy are at the lower end of these ranges. 2 3

It was almost a decade before the next major advance in treatment of chronic hepatitis C emerged, namely, the combination of interferon alfa with the oral nucleoside analogue ribavirin. Although ribavirin alone does not seem to be active against the hepatitis C virus, the combination resulted in much improved and sustained biochemical, virological, and histological response rates. 2 3 The mechanism(s) that accounts for the increased efficacy of ribavirin and interferon as combination therapy for hepatitis C virus infection remains poorly understood. The combination of interferon and ribavirin was approved for treating chronic hepatitis C in 1999. Overall, hepatitis C virus is permanently eradicated in about 40% of patients treated with combination therapy in doses appropriate to viral genotype. 2 3 Obviously, as pointed out in the review by Kjaergard and colleagues in this issue (p 1151),4 many patients who do not respond optimally to the less effective interferon alfa monotherapy will respond to this more effective combination therapy.5

Recent studies have shown that long acting pegylated interferons have better viral responses than standard interferon alfa preparations. Pegylation involves attaching a large inactive molecule, polyethylene glycol, to a protein in order to reduce clearance. This longer half life allows large doses of the drug to be given infrequentlyonce weekly. The process pays a price in that there is variable loss of activity of the native protein, depending on the size and site of attachment of the polyethylene glycol molecule. Pegylated interferon alone is about twice as effective as monotherapy with interferon, but it is not as effective as the combination of standard interferon and ribavirin. 6 7 However, the combination of pegylated interferon and oral ribavirin considerably improves antiviral activity and results in sustained eradication of hepatitis C virus in 54-56% of treated patients. 8 9 Once again, responses are genotype dependent and are sustained in 42-46% in patients infected with genotype 1 and 76-82% in genotype 2 or 3. 8 9

Sustained virological response rates are now achievable in more than half of patients with chronic hepatitis C who are candidates for treatment. 8 9 Viral clearance is associated with a reduction of hepatic inflammation and fibrosis on liver biopsy, 10 11 and it is reasonable to assume that viral clearance will translate into a reduction in morbidity and mortality. This has been projected by mathematical modelling and cost benefit analyses. 12 13 A dedicated and vigorous research effort continues in the hope of identifying new agents that will further improve the response and ease of administration of treatment.

Gary L Davis, professor.

Section of Hepatobiliary Diseases, JHM Health Center, Department of Medicine, University of Florida College of Medicine, Gainesville, FL

32610-0214, USA

1. Poynard T, Leroy V, Cohard M, Thevenot T, Mathurin P, Opolon P, et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 1996; 24: 778-789

2. McHutchison JG, Gordon S, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b montherapy versus interferon alfa-2b plus ribavirin as initial treatment for chronic hepatitis C: results of a US multicenter randomized controlled study. N Engl J Med 1998; 339: 1485-1492

3. Poynard T, Marcellin P, Lee S, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998; 352: 1426-1432

4. Kjaergard LL, Krogsgaard K, Gluud C. Interferon alfa with or without ribavirin for interferon naive patients, relapsers, and non-responders with chronic hepatitis C: systematic review of randomised trials. BMJ 2001; 3231151-1155

5. Davis GL. Current therapy for chronic hepatitis C. Gastroenterology 2000; 118: S1-12

6. Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai MY, Gane E, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000; 343: 1666-1672

7. Lindsay KL, Trepo C, Heintges T, Shiffman ML, Gordon SC, Hoefs JC, et al. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology 2001; 34: 395-403

8. Manns MP, McHutchison JG, Gordon S, Rustgi V, Shiffman ML, Lee WM, et al. PEG interferon alfa-2b plus ribavirin compared to interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C: 24 week treatment analysis of a multicenter, multinational phase III randomized controlled trial Hepatology 2000; 32: 297A.

9. Fried MW, Shiffman ML, Reddy RK, Smith C, Marino G, Goncales F, et al. Pegylated interferon alfa-2a in combination with ribavirin: efficacy and safety results from a phase III, randomized, actively controlled, multicenter study Gastroenterology 2001; 120: A55.

10. Marcellin P, Boyer N, Degott C, Martinot-Peignoux M, Duchatelle V, Giostra E, et al. Long-term histologic and viral changes in patients with chronic hepatitis C who responded to alpha interferon. Liver 1994; 14: 302-307

11. Poynard T, McHutchison J, Davis GL, Esteban_Mur R, Goodman Z, Bedossa P, et al. Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C. Hepatology 2000; 32: 1131-1137

12. Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting the future healthcare burden from hepatitis C in the United States Hepatology 1998; 28: A390

13. Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health 2000; 90: 1562-1569

PAPERS

Interferon alfa with or without ribavirin for chronic hepatitis C: systematic review of randomised trials Lise L Kjaergard, Kim Krogsgaard, and Christian Gluud BMJ 2001 323: 1151-1155