Chronic Hepatitis C

Since the identification and characterization of the hepatitis C virus (HCV) a little more than a decade ago, significant advances have been made in our understanding of the natural history, diagnosis, and treatment of this chronic viral infection. In this supplemental issue of Seminars in Liver Disease, we review our current understanding of chronic HCV and the significant advances that have been made in the treatment of this virus over the past decade. We were fortunate to have assembled a group of internationally recognized hepatologists to contribute to this supplement. Many of these individuals have directly contributed to the advances that have been made in this field during the past decade.

It is currently estimated that nearly 4 million Americans and nearly 150 million individuals worldwide have been infected with HCV.[1] Although infection may resolve spontaneously in a small percentage of such patients; most remain infected throughout their lifetime and at risk for developing progressive liver injury, fibrosis, cirrhosis, and liver cancer. Indeed, in many areas of the world, chronic HCV infection represents the single most common etiologic factor leading to cirrhosis, liver cancer, and liver failure.[2] However, many patients with chronic HCV progress to cirrhosis very slowly or not at all.[3] Our current understanding of the natural history of chronic HCV and those factors that lead to spontaneous resolution of HCV and fibrosis progression is reviewed by Dr. Nezam Afdahl.

Chronic HCV is particularly prevalent in certain high-risk populations. It is now well-known that about one third of all patients infected with HIV are also coinfected with HCV.[4] Over the past decade our understanding of the natural history of HIV-HCV coinfection and the possible detrimental impact that HIV treatment may have on liver disease progression from HCV has become better understood. Drs. Richard Sterling and Mark Sulkowski review this important and controversial topic. Another population of patients with high prevalence for HCV infection comprises those with chronic renal failure. It now appears that at least 20% of all patients with chronic renal failure on hemodialysis are infected with HCV.[5] However, it is important to realize that serological testing for HCV may be problematic in this population and that most of these patients have normal liver transaminases and mild liver injury and may be at low risk for disease progression. Drs. Fred Poordad, Fabrizio Fabrizi, and Paul Martin review HCV in the setting of chronic renal failure and how this may affect the ability for such patients to undergo successful renal transplantation.

Virological testing and monitoring of HCV RNA is now paramount in the diagnosis and treatment of patients with chronic HCV infection. Determination of HCV genotype defines both the duration and dose of pegylated interferon and ribavirin necessary for successful treatment of this infection.[6] Monitoring the change in serum HCV RNA level during the first 12 weeks of therapy enables the clinician to identify those patients who are responding to therapy and those for whom treatment should be continued.[7] In recent years, a universal standard has been established for reporting HCV RNA in international units.[8] Virological assessment of HCV infection and its treatment are discussed by Dr. Andrea Ferreria-Gonzalez and myself.

Several manuscripts within the supplement will focus on the treatment of chronic HCV and the great strides that have been made to improve therapy for patients with chronic infection. Interferon alfa was first used for treatment of chronic non-A, non-B hepatitis even before HCV was isolated and characterized more than a decade ago. Although met with great enthusiasm at the time, we now know that this treatment had very little efficacy; less than 10% of patients achieved sustained virological clearance of HCV.[9] The use of ribavirin along with interferon significantly improved sustained virological clearance, especially in patients infected with genotypes 2 or 3 of HCV.[6] Our experience with interferon alfa and interferon and ribavirin combination therapy is reviewed by Dr. Thierry Poynard. The most recent advance in the treatment of chronic HCV was the development of long-acting pegylated interferons. These agents were developed by linking a polyethylene glycol chain to the native interferon.[10] This modification resulted in a pharmaceutical with prolonged half-life and an enhanced biological effect.[7] [11] The development of the pegylated interferons and the superior pharmacological profile of these agents compared with standard interferon alfa was reviewed by Dr. K. Rajender Reddy. Drs. Jenny Heathcote and Stefan Zeuzem review the efficacy of pegylated interferons when compared with standard interferon alfa monotherapy. Treatment of chronic HCV with the combination of a pegylated interferon and ribavirin is discussed by Drs. Michael Fried and Stephanos Hadziyannis, and Dr. Peter Ferenci reviews those factors associated with sustained virological response that could be used by clinicians to help identify those patients with chronic HCV who have a high likelihood of achieving a virological response during and after treatment. Several studies during the past several years have explored the use of amantadine, amantadine plus interferon, and triple therapy using interferon, ribavirin, and amantadine for chronic HCV infection in several settings. Dr. Stephano Brillanti reviews the possible role of amantadine as an adjunct in the treatment of chronic HCV.

In addition to virological clearance of HCV, it has now been established that interferon therapy can improve liver histology.[12] The greatest improvements in liver histology occur in those patients who achieve a sustained virological response. However, histological benefit has also been documented to occur in a large proportion of virological nonresponders. Dr. Samuel Lee discusses this important concept and the possible use of maintenance pegylated interferon therapy to prevent fibrosis progression and the complications of cirrhosis.

Despite these many advances in treatment over the past decade, many patients with chronic HCV progress to end-stage liver disease and require liver transplantation. Indeed, cirrhosis with or without hepatocellular carcinoma in association with chronic HCV infection represents the single most common indication for liver transplantation throughout the world.[13] Unfortunately, HCV infection returns after liver replacement, and in some cases, this may once again progress to cirrhosis in just 5 to 10 years after the transplant. Treatment of chronic HCV in the posttransplant setting is problematic, although encouraging results with pegylated interferon and ribavirin therapy have recently been reported. Drs. Michael Charlton and Russell Wiesner address the problem of HCV infection in the liver transplant recipient and its management.

Finally, this supplement concludes with a review of the past and the present and a look into the future treatments for chronic HCV. This insightful piece by Dr. Graham Foster places in perspective the advances we have made in our understanding of chronic HCV over the past decade and where we need to focus our efforts in the future. I wish to thank all the contributors to this supplement for their time and the insight they have put into these manuscripts. I hope you will find this supplement of Seminars in Liver Disease a valuable resource for many years to come.

REFERENCES

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• 2 Fattovich G, Giustina G, Degos F et al.. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384.  Gastroenterology. 1997;  112 463-472
• 3 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;  349 825-832
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• 7 Fried M W, Shiffman M L, Reddy K R et al.. Combination of peginterferon alfa-2a (40 kd) plus ribavirin in patients with chronic hepatitis C virus infection.  N Engl J Med. 2002;  347 975-982
• 8 Saldanha J, Lelie N, Heath A et al.. Establishment of the first international standard for nucleic acid amplification technology assays for HCV RNA.  Vox Sang. 1999;  76 149-158
• 9 Davis G L, Balart L A, Schiff E R et al.. Treatment of chronic hepatitis C with recombinant interferon alpha: a multicenter, randomized, controlled trial.  N Engl J Med. 1989;  321 1501-1506
• 10 Shiffman M L. PEGylated interferons: what role will they play in the treatment of chronic hepatitis C?.  Curr Gastroenterol Rep. 2001;  3 30-37
• 11 Manns M P, McHutchinson J G, Gordon S C et al.. Peginterferon-alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial.  Lancet. 2001;  358 958-965
• 12 Shiffman M L, Hofmann C M, Thompson E B et al.. Relationship between biochemical, virologic and histologic response during interferon treatment of chronic hepatitis C.  Hepatology. 1997;  26 780-785
• 13 Charlton M. Natural history of hepatitis C and outcomes following liver transplantation.  Clin Liver Dis. 2003;  7 585-602