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Controversies in the management of hepatitis C patients with advanced fibrosis and cirrhosis

2004; Elsevier BV; Volume: 2; Issue: 3 Linguagem: Inglês

10.1016/s1542-3565(04)00002-3

1542-7714

Robert J. Fontana, Gregory T. Everson, Sony Tuteja, Hugo E. Vargas, Mitchell L. Shiffman,

Liver Disease and Transplantation

At least 4 million people in the United States have been infected with hepatitis C virus (HCV), of which 2.7 million have chronic hepatitis C (CHC) infection.1Armstrong G.L. Alter M.J. McQuillan G.M. Margolis H.S. The past incidence of hepatitis C virus infection implications for the future burden of chronic liver disease in the United States.Hepatology. 2000; 31: 777-782Crossref PubMed Google Scholar CHC is defined as the presence of HCV-RNA for more than 6 months after exposure. CHC is more prevalent in adult men than women and also among ethnic minorities compared to whites.1Armstrong G.L. Alter M.J. McQuillan G.M. Margolis H.S. The past incidence of hepatitis C virus infection implications for the future burden of chronic liver disease in the United States.Hepatology. 2000; 31: 777-782Crossref PubMed Google Scholar, 2Alter M.J. Kruszon-Moran D. Nainan O.V. McQuillan G.M. Gao F. Moyer L.A. Kaslow R.A. Margolis H.S. et al.The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.N Engl J Med. 1999; 341: 556-562Crossref PubMed Scopus (1988) Google Scholar Although the annual incidence of acute hepatitis C is decreasing because of universal screening of blood products and safe needle programs, the prevalence of liver disease as a result of CHC is increasing because of more frequent detection and diagnosis of asymptomatic individuals as well as the development of clinical manifestations in other patients with CHC.3Kim W.R. The burden of hepatitis C in the United States.Hepatology. 2002; 36: S30-S34Crossref PubMed Google Scholar Figure 1 describes the spectrum of possible clinical outcomes after acute HCV infection.4Hoofnagle J.H. Hepatitis C the clinical spectrum of disease.Hepatology. 1997; 26: 15S-20SCrossref PubMed Google Scholar The most significant clinical sequelae of CHC stem from the development of progressive liver fibrosis, which can lead to cirrhosis, liver failure, and hepatocellular carcinoma (HCC) in some patients. An estimated 5%–15% of chronically infected individuals might develop cirrhosis during a period of 20 years.5Seeff L.B. Miller R.N. Rabkin C.S. Buskell-Bales Z. Straley-Eason K.D. Smoak B.L. Johnson L.D. Lee S.R. Kaplan E.L. et al.45-year follow-up of hepatitis C virus infection in healthy young adults.Ann Intern Med. 2000; 132: 105-111Crossref PubMed Google Scholar Although this might seem like a slowly progressive disease in a minority of the infected population, the economic impact of CHC in the US and worldwide is substantial. For example, in 1998 the cost of hospitalization as a result of CHC-induced liver disease exceeded $1 billion in the US.3Kim W.R. The burden of hepatitis C in the United States.Hepatology. 2002; 36: S30-S34Crossref PubMed Google Scholar Because CHC is the leading indication for liver transplantation and is associated with a rapidly increasing incidence of HCC, the costs of care related to CHC are expected to increase further during the next 2 decades in the US and abroad.6Charlton M. Hepatitis C infection in liver transplantation.Am J Transplant. 2001; 1: 197-203Crossref PubMed Scopus (56) Google Scholar, 7Davis G.L. Albright J.E. Cook S.F. Rosenberg D.M. Projecting future complications of chronic hepatitis C in the United States.Liver Transpl. 2003; 9: 331-338Crossref PubMed Scopus (328) Google Scholar In this review, the host demographic, immunologic, and environmental factors associated with disease progression in patients with CHC will be discussed. In addition to general medical recommendations, the safety and efficacy of standard and pegylated interferons alone and in combination with ribavirin in patients with advanced fibrosis and cirrhosis will be reviewed. Finally, the use of liver histology and clinical progression as end points for antiviral therapy will be discussed in CHC patients with advanced fibrosis. Various studies have reported differing rates of fibrosis progression after infection with the HCV. Many of these differences can be attributed to the varying study designs and patient populations included. In general, retrospective trials report a high frequency (17%–55%)8Kiyosawa K. Sodeyama T. Tanaka E. Gibo Y. Yoshizawa K. Nakano Y. Furuta S. Akahane Y. Nishioka K. Purcell R.H. Alter H.J. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma analysis by detection of antibody to hepatitis C virus.Hepatology. 1990; 12: 671-675Crossref PubMed Google Scholar, 9Tong M.J. el-Farra N.S. Reikes A.R. Co R.L. Clinical outcomes after transfusion-associated hepatitis C.N Engl J Med. 1995; 332: 1463-1466Crossref PubMed Scopus (956) Google Scholar, 10Yano M. Kumada H. Kage M. Ikeda K. Shimamatsu K. Inoue O. Hashimoto E. Lefkowitch J.H. Ludwig J. Okuda K. The long-term pathological evolution of chronic hepatitis C.Hepatology. 1996; 23: 1334-1340Crossref PubMed Google Scholar, 11Niederau C. Lange S. Heintges T. Erhardt A. Buschkamp M. Hurter D. Nawrocki M. Kruska L. Hensel F. Wolfgang P. Haussinger D. Prognosis of chronic hepatitis C results of a large, prospective cohort study.Hepatology. 1998; 28: 1687-1695Crossref PubMed Google Scholar, 12Gordon S.C. Elloway R.S. Long J.C. Dmuchowski C.F. The pathology of hepatitis C as a function of mode of transmission blood transfusion vs intravenous drug use.Hepatology. 1993; 18: 1338-1343Crossref PubMed Google Scholar of cirrhosis development due to the inclusion of patients referred to tertiary care centers with more advanced liver disease or associated comorbidities. Therefore, retrospective studies might reflect an inherent selection bias of patients with more severe liver disease compared to the general population of patients with CHC. The second limitation of retrospective studies is the difficulty in estimating the duration of HCV infection on the basis of a history of parenteral exposure. Duration of HCV infection estimates might be inaccurate because most patients have no clinical symptoms after HCV acquisition, and many patients with a history of illicit drug use, which is the most commonly identified risk factor, report multiple exposures during a range of years. In contrast, most prospective and combined retrospective-prospective studies of the natural history of HCV infection begin with a single exposure from contaminated blood products wherein the duration of infection can be more accurately estimated. In general, prospective and retrospective-prospective studies have reported the development of cirrhosis in only 2%–16% of chronically infected individuals during a period of 20 years.13Di Bisceglie A.M. Goodman Z.D. Ishak K.G. Hoofnagle J.H. Melpolder J.J. Alter H.J. Long-term clinical and histopathological follow-up of chronic posttransfusion hepatitis.Hepatology. 1991; 14: 969-974Crossref PubMed Google Scholar, 14Kenny-Walsh E. the Irish Hepatology Research GroupClinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.N Engl J Med. 1999; 340: 1228-1233Crossref PubMed Scopus (634) Google Scholar, 15Wiese M. Berr F. Lafrenz M. Porst H. Olsen V. Low frequency of cirrhosis in a hepatitis C (genotype 1b) single-source outbreak in Germany a 20 year multicenter study.Hepatology. 2000; 32: 91-96Crossref PubMed Google Scholar Although prospective studies are the preferred method for studying the natural history of HCV, these trials have a relatively short duration of follow-up and include a predominance of young, healthy female patients. Because the majority of HCV patients in the US are middle-aged men whose disease tends to progress more rapidly, the true rate of cirrhosis development is probably somewhere between the estimates provided from the available studies (i.e., 5%–15% per 20 years) and is dependent on a multitude of co-factors. Development of progressive hepatic fibrosis in CHC is the main determinant of subsequent complications of portal hypertension such as ascites, hepatic encephalopathy, and liver failure. In addition, progressive hepatic fibrosis is linked to the risk of HCC, with CHC patients rarely developing HCC in the absence of cirrhosis.16Fattovich G. Progression of hepatitis B and C to hepatocellular carcinoma in Western countries.Hepatogastroenterology. 1998; 45: 1206-1213PubMed Google Scholar Numerous host factors are believed to influence the rate of fibrosis progression in CHC such as age at infection, disease duration, subject gender, immune status, and ethnicity. Similarly, alcohol consumption and iron overload appear to be important environmental co-factors for CHC fibrosis progression.17Alberti A. Chemello L. Benvegnu L. Natural history of hepatitis C.J Hepatol. 1999; 31: 17-24Abstract Full Text PDF PubMed Google Scholar Interestingly, viral factors such as HCV genotype,18Roffi L. Ricci A. Ogliari C. Scalori A. Minola E. Colloredo G. Donada C. Ceriani R. Rinaldi G. Paris B. Fornaciari G. Morales R. Del Poggio P. Sangiovanni A. Buonocore M. Bellia V. Riboli P. Nava M.C. Panizzuti F. Piperno A. Pozzi M. Pioltrelli P. Mancia G. et al.HCV genotypes in Northern Italy a survey of 1368 histologically proven chronic hepatitis C patients.J Hepatol. 1998; 29: 701-706Abstract Full Text PDF PubMed Scopus (63) Google Scholar, 19Poynard T. Ratziu V. Charlotte F. Goodman Z. McHutchison J. Albrecht J. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis C.J Hepatol. 2001; 34: 730-739Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar quantitative HCV viral load,20Lau J.Y. Davis G.L. Kniffen J. Qian K.P. Urdea M.S. Chan C.S. Mizokami M. Neuwald P.D. Wilber J.C. et al.Significance of serum hepatitis C virus RNA levels in chronic hepatitis C.Lancet. 1993; 341: 1501-1504Abstract PubMed Scopus (588) Google Scholar, 21Fanning L. Kenny E. Sheehan M. Cannon B. Whelton M. O’Connell J. Collins J.K. Shanahan F. Viral load and clinicopathological features of chronic hepatitis C (1b) in a homogeneous patient population.Hepatology. 1999; 29: 904-907Crossref PubMed Google Scholar and quasispecies evolution do not appear to influence the rate of fibrosis progression.22Farci P. Shimoda A. Coiana A. Diaz G. Peddis G. Melpolder J.C. Strazzera A. Chien D.Y. Munoz S.J. Balestrieri A. Purcell R.H. Alter H.J. The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies.Science. 2000; 288: 339-344Crossref PubMed Scopus (547) Google Scholar Dynamic variables predictive of short-term fibrosis progression include histologic activity and serum ALT levels. For example, baseline necroinflammation was associated with fibrosis progression during a mean follow-up of 8.8 years in 70 untreated Japanese patients with CHC.10Yano M. Kumada H. Kage M. Ikeda K. Shimamatsu K. Inoue O. Hashimoto E. Lefkowitch J.H. Ludwig J. Okuda K. The long-term pathological evolution of chronic hepatitis C.Hepatology. 1996; 23: 1334-1340Crossref PubMed Google Scholar More recently, Ghany et al. also demonstrated that initial inflammatory score and serum ALT level were associated with fibrosis progression in 123 untreated US patients with CHC followed for a mean of 3.7 years.23Minola E. Prati D. Suter F. Maggiolo F. Caprioli F. Sonzogni A. Fraquelli M. Paggi S. Conte D. et al.Age at infection affects the long-term outcome of transfusion-associated chronic hepatitis C.Blood. 2002; 99: 4588-4591Crossref PubMed Scopus (68) Google Scholar A relationship between hepatic inflammation and fibrosis progression in CHC is not surprising because proinflammatory cytokines within the liver are known to promote and perpetuate activation of hepatic stellate cells (Figure 2).24Bataller R. North K.E. Brenner D.A. Genetic polymorphisms and the progression of liver fibrosis a critical appraisal.Hepatology. 2003; 37: 493-503Crossref PubMed Scopus (195) Google Scholar Cross-sectional studies have also demonstrated less hepatic fibrosis in CHC patients with normal serum ALT levels compared to patients with abnormal serum ALT levels.25Pradat P. Alberti A. Poynard T. Esteban J.I. Weiland O. Marcellin P. Badalamenti S. Trepo C. Predictive value of ALT levels for histologic findings in chronic hepatitis C a European collaborative study.Hepatology. 2002; 36: 973-977PubMed Google Scholar, 26Persico M. Persico E. Suozzo R. Conte S. De Seta M. Coppola L. Palmentieri B. Sasso F.C. Torella R. Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels.Gastroenterology. 2000; 118: 760-764Abstract Full Text Full Text PDF PubMed Google Scholar Recent longitudinal studies have also suggested that CHC patients with persistently normal or minimally elevated serum ALT levels have less rapid fibrosis progression than patients with abnormal ALT levels.26Persico M. Persico E. Suozzo R. Conte S. De Seta M. Coppola L. Palmentieri B. Sasso F.C. Torella R. Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels.Gastroenterology. 2000; 118: 760-764Abstract Full Text Full Text PDF PubMed Google Scholar, 27Ghany M.G. Kleiner D.E. Alter H. Doo E. Khokar F. Promrat K. Herion D. Park Y. Liang T.J. Hoofnagle J.H. Progression of fibrosis in chronic hepatitis C.Gastroenterology. 2003; 124: 97-104Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar The slower rate of fibrosis progression in these patients might be due to less active liver inflammation and hepatocyte turnover.28Kronenberger B. Ruster B. Lee J.H. Sarrazin C. Roth W.K. Herrmann G. Zeuzem S. Hepatocellular proliferation in patients with chronic hepatitis C and persistently normal or abnormal aminotransferase levels.J Hepatol. 2000; 33: 640-647Abstract Full Text Full Text PDF PubMed Google Scholar However, further follow-up of a larger number of patients with CHC is needed to support these preliminary findings regarding the utility of serum ALT monitoring over time. Poynard et al.29Poynard 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: 825-832Abstract Full Text Full Text PDF PubMed Scopus (1879) Google Scholar described a spectrum of fibrosis progression on the basis of a large patient series in which the annual rate of fibrosis progression was calculated by using a single liver biopsy specimen. Patients were deemed rapid progressors if the time from infection to cirrhosis was less than 20 years, intermediate progressors if the time to cirrhosis was 20–50 years, and slow progressors if the time to cirrhosis was more than 50 years. These estimates of fibrosis progression, however, assume that the rate of fibrosis progression remains constant over time, which is unlikely because multiple studies demonstrate more rapid fibrosis progression in older adults compared to children.10Yano M. Kumada H. Kage M. Ikeda K. Shimamatsu K. Inoue O. Hashimoto E. Lefkowitch J.H. Ludwig J. Okuda K. The long-term pathological evolution of chronic hepatitis C.Hepatology. 1996; 23: 1334-1340Crossref PubMed Google Scholar, 23Minola E. Prati D. Suter F. Maggiolo F. Caprioli F. Sonzogni A. Fraquelli M. Paggi S. Conte D. et al.Age at infection affects the long-term outcome of transfusion-associated chronic hepatitis C.Blood. 2002; 99: 4588-4591Crossref PubMed Scopus (68) Google Scholar, 30Vogt M. Lang T. Frosner G. Klingler C. Sendl A.F. Zeller A. Wiebecke B. Langer B. Meisner M.D. Hess M.D. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening.N Engl J Med. 1999; 341: 866-870Crossref PubMed Scopus (360) Google Scholar In addition, host genetic or environmental factors might also play an important role in determining fibrosis progression.24Bataller R. North K.E. Brenner D.A. Genetic polymorphisms and the progression of liver fibrosis a critical appraisal.Hepatology. 2003; 37: 493-503Crossref PubMed Scopus (195) Google Scholar For example, immunosuppressed transplant recipients and human immunodeficiency virus co-infected CHC patients are estimated to have a 5-fold higher rate of fibrosis progression compared to immunocompetent CHC patients.31Thomas D.L. Hepatitis C and human immunodeficiency virus infection.Hepatology. 2002; 36: S201-S209Crossref PubMed Scopus (0) Google Scholar Similarly, newly infected infants and children appear to have a slower rate of fibrosis progression compared to newly infected adults aged 40 to 60 years.30Vogt M. Lang T. Frosner G. Klingler C. Sendl A.F. Zeller A. Wiebecke B. Langer B. Meisner M.D. Hess M.D. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening.N Engl J Med. 1999; 341: 866-870Crossref PubMed Scopus (360) Google Scholar, 32Seeff L.B. Buskell-Bales Z. Wright E.C. Durako S.J. Alter H.J. Iber F.L. Hollinger F.B. Gitnick G. Knodell R.G. Perrillo R.P. Long-term mortality after transfusion-associated non-A, non-B hepatitis the National Heart, Lung, and Blood Institute Study Group.N Engl J Med. 1992; 327: 1906-1911Crossref PubMed Google Scholar, 33Seeff L.B. Hollinger F.B. Alter H.J. Wright E.C. Cain C.M. Buskell Z.J. Ishak K.G. Iber F.L. Samanta A. Koreta R. Perrillo R.P. Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis a National Heart, Lung, and Blood Institute collaborative study.Hepatology. 2001; 33: 455-463Crossref PubMed Scopus (233) Google Scholar In summary, the rate of fibrosis progression is highly variable among patients with CHC, and additional large, prospective studies are needed to better define the risk factors for disease progression. A baseline liver biopsy is considered the gold standard for determining disease stage and activity in CHC patients because other demographic features and laboratory tests do not reliably predict disease severity.34Dienstag J.L. The role of liver biopsy in chronic hepatitis C.Hepatology. 2002; 36: S152-S160Crossref PubMed Google Scholar In addition, a liver biopsy can exclude other causes of chronic liver disease, although these are rarely encountered in clinical practice.35Saadeh S. Cammell G. Carey W.D. Younossi Z. Barnes D. Easley K. The role of liver biopsy in chronic hepatitis C.Hepatology. 2001; 33: 196-200Crossref PubMed Scopus (176) Google Scholar Patients with bridging fibrosis and cirrhosis are at greatest risk of developing complications and should be followed more carefully and prioritized for antiviral treatment compared to CHC patients with less severe fibrosis.10Yano M. Kumada H. Kage M. Ikeda K. Shimamatsu K. Inoue O. Hashimoto E. Lefkowitch J.H. Ludwig J. Okuda K. The long-term pathological evolution of chronic hepatitis C.Hepatology. 1996; 23: 1334-1340Crossref PubMed Google Scholar, 36Fontana R.J. Lok A.S. Noninvasive monitoring of patients with chronic hepatitis C.Hepatology. 2002; 36: S57-S64Crossref PubMed Google Scholar Hepatic fibrosis occurs as a result of increased collagen fiber deposition in the liver, which is mediated by hepatic stellate cells (Figure 2).37Friedman S.L. Evaluation of fibrosis and hepatitis C.Am J Med. 1999; 107: 27S-30SAbstract Full Text Full Text PDF PubMed Google Scholar In most chronic liver diseases, fibrolysis of the low density extracellular matrix (ECM) is initiated by liver injury and followed by deposition of a high density ECM characterized by increasing amounts of types 1 and 3 collagen. As fibrosis progresses, the ECM becomes denser, and the collagen becomes cross-linked and less amenable to remodeling. Although hepatic fibrosis can impede intrahepatic blood flow and lead to portal hypertension and progressive hepatic dysfunction, recent studies have demonstrated that some CHC patients can have regression or improvement in hepatic fibrosis after antiviral therapy.38Sobesky R. Mathurin P. Charlotte F. Moussalli J. Olivi M. Vidaud M. Ratziu V. Opolon P. Poynard T. Modeling the impact of interferon alfa treatment on liver fibrosis progression in chronic hepatitis C a dynamic view—the Multivirc Group.Gastroenterology. 1999; 116: 378-386Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 39Poniachik J. Bernstein D.E. Reddy K.R. Jeffers L.J. Coelho-Little M.E. Civantos F. Schiff E.R. et al.The role of laparoscopy in the diagnosis of cirrhosis.Gastrointest Endosc. 1996; 43: 568-571Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar, 40Shiratori Y. Imazeki F. Moriyama M. Yano M. Arakawa Y. Yokosuka O. Kuroki T. Nishiguchi S. Sata M. Yamada G. Fujiyama S. Yoshida H. Omata M. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy.Ann Intern Med. 2000; 132: 517-524Crossref PubMed Google Scholar, 41Kage M. Shimamatu K. Nakashima E. Kojiro M. Inoue O. Yano M. Long-term evolution of fibrosis from chronic hepatitis to cirrhosis in patients with hepatitis C morphometric analysis of repeated biopsies.Hepatology. 1997; 25: 1028-1031Crossref PubMed Scopus (86) Google Scholar The improvement in liver histology in sustained virologic responders is presumably due to elimination of the inflammatory stimulus (i.e., the HCV) and subsequent tissue remodeling. However, interferon has antiproliferative, anti-inflammatory, and antifibrotic effects in addition to its direct antiviral effect, which might lead to histologic benefit even in the absence of viral clearance. For example, interferon therapy has been associated with a significant reduction in the number and activity of hepatic stellate cells in patients with CHC.42Guido M. Rugge M. Chemello L. Leandro G. Fattovich G. Giustina G. Cassaro M. Alberti A. Liver stellate cells in chronic viral hepatitis the effect of interferon therapy.J Hepatol. 1996; 24: 301-307Abstract Full Text PDF PubMed Scopus (63) Google Scholar An accurate assessment of hepatic fibrosis is vital in the management of CHC and might be critical in the future as an end point in clinical trials of antiviral agents. Unfortunately, liver biopsy is subject to sampling error and interobserver and intraobserver variability. In particular, liver biopsy specimens less than 2 cm in length might be understaged.38Sobesky R. Mathurin P. Charlotte F. Moussalli J. Olivi M. Vidaud M. Ratziu V. Opolon P. Poynard T. Modeling the impact of interferon alfa treatment on liver fibrosis progression in chronic hepatitis C a dynamic view—the Multivirc Group.Gastroenterology. 1999; 116: 378-386Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 43Westin J. Lagging L.M. Wejstal R. Norkrans G. Dhillon A.P. Interobserver study of liver histopathology using the Ishak score in patients with chronic hepatitis C virus infection.Liver. 1999; 19: 183-187Crossref PubMed Scopus (116) Google Scholar A recent study in which 124 patients with CHC underwent a simultaneous laparoscopic liver biopsy of the right and left lobes demonstrated a sampling error of 34%.44Regev A. Berho M. Jeffers L.J. Milikowski C. Molina E.G. Pyrsopoulos N.T. Feng Z. Reddy K.R. Schiff E.R. et al.Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection.Am J Gastroenterol. 2002; 97: 2614-2618Crossref PubMed Google Scholar In addition, there was a tendency to understage cirrhosis in 14% of patients compared to laparoscopy. Therefore, liver biopsy is a gold standard with limitations. A multitude of histologic scoring systems have been used in studies of patients with CHC (Table 1). However, all of the proposed scoring systems are semiquantitative and rely on subjective interpretation of stained liver biopsy samples. Therefore, it is not surprising that there is substantial intraobserver and interobserver variability in assessing hepatic fibrosis even among expert hepatopathologists.43Westin J. Lagging L.M. Wejstal R. Norkrans G. Dhillon A.P. Interobserver study of liver histopathology using the Ishak score in patients with chronic hepatitis C virus infection.Liver. 1999; 19: 183-187Crossref PubMed Scopus (116) Google Scholar, 45The French METAVIR Cooperative Study GroupIntraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C.Hepatology. 1994; 20: 15-20Crossref PubMed Google Scholar The Knodell histological activity index (HAI), which has a range of 0–22 for the total score, has been most widely used in CHC treatment trials.46Heathcote E.J. Shiffman M.L. Cooksley W.G. Dusheiko G.M. Lee S.S. Balart L. Reindollar R. Reddy R.K. Wright T.L. Lin A. Hoffman J. DePamphilis J. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis.N Engl J Med. 2000; 343: 1673-1680Crossref PubMed Scopus (749) Google Scholar, 47Shiffman M.L. Hofmann C.M. Contos M.J. Luketic V.A. Sanyal A.J. Sterling R.K. Ferreira’-Gonzalez A. Mills A.S. Garret C. A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia.Gastroenterology. 1999; 117: 1164-1172Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, 48Davis G.L. Esteban-Mur R. Rustgi V. Hoefs J. Gordon S.C. Trepo C. Shiffman M.L. Zeuzem S. Craxi A. Ling M.H. Albrecht J. 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: 1493-1499Crossref PubMed Scopus (1184) Google Scholar Unfortunately, the fibrosis component of this scoring system is nonlinear, with possible fibrosis scores of 0, 1, 3, and 4.49Brunt E.M. Grading and staging the histopathological lesions of chronic hepatitis the Knodell histology activity index and beyond.Hepatology. 2000; 31: 241-246Crossref PubMed Google Scholar A recent modification to the Knodell score termed the Ishak score has a range of fibrosis scores of 0–6, which allows a more refined assessment of hepatic fibrosis.50Ishak K. Baptista A. Bianchi L. Callea F. De Groote J. Gudat F. Denk H. Desmet V. Korb G. MacSween R.N.M. Phillips M.J. Portmann B.G. Poulsen H. Scheuer P.J. Schmid M. Thaler H. Histological grading and staging of chronic hepatitis.J Hepatol. 1995; 22: 696-699Abstract Full Text PDF PubMed Scopus (2336) Google Scholar However, studies have demonstrated that the interobserver level of agreement is lower with the Ishak fibrosis scoring system compared to the Knodell or Metavir systems.43Westin J. Lagging L.M. Wejstal R. Norkrans G. Dhillon A.P. Interobserver study of liver histopathology using the Ishak score in patients with chronic hepatitis C virus infection.Liver. 1999; 19: 183-187Crossref PubMed Scopus (116) Google ScholarTable 1Histopathologic Scoring Systems for Hepatic Fibrosis in Hepatitis CKnodellIshakMetavirAbsent000Portal fibrosis (some)111Portal fibrosis (most)121Bridging fibrosis (few)332Bridging fibrosis (many)343Incomplete cirrhosis454Cirrhosis464 Open table in a new tab In clinical practice, a uniform scoring system for staging fibrosis in CHC has not yet been defined. Although scoring systems with greater distinction between levels of fibrosis might be desirable for research studies, they might not be applicable to routine clinical practice. Before fibrosis can be established as a clinical end point for antiviral therapy, a consensus regarding a fibrosis scoring system for CHC must be attained. In addition, discernible changes in hepatic fibrosis must be accepted as clinically meaningful outcomes of antiviral treatment by regulatory authorities and practicing physicians. Last, because liver biopsy might be associated with serious but infrequent complications, patient inconvenience, and substantial cost, both physicians and patients might be reluctant to perform serial liver biopsies to assess disease progression. The limitations of semiquantitative scoring systems for hepatic fibrosis have led to proposals of alternative assessments. Quantitative assessment of hepatic collagen content by using computerized morphometry offers the advantage of an objective, sensitive, and reproducible methodology.51Duchatelle V. Marcellin P. Giostra E. Bregeaud L. Pouteau M. Boyer N. Auperin A. Guerret S. Erlinger S. Henin D. Degott C. Changes in liver fibrosis at the end of alpha interferon therapy and 6 to 18 months later in patients with chronic hepatitis C quantitative assessment by a morphometric method.J Hepatol. 1998; 29: 20-28Abstract Full Text PDF PubMed Scopus (58) Google Scholar However, the cost and complexity of this approach and the persistent problem with sampling error have limited its application to patients with CHC. Quantitative liver function tests (QLFTs) have been proposed as measures of hepatic function and disease severity.36Fontana R.J. Lok A.S. Noninvasive monitoring of patients with chronic hepatitis C.Hepatology. 2002; 36: S57-S64Crossref PubMed Google Scholar Published literature indicates that these tests might be cumbersome and limited in their ability to distinguish patients with mild from severe hepatic fibrosis.52Herold C. Heinz R. Niedobitek G. Schneider T. Hahn E.G. Schuppan D. Quantitative testing of liver function in relation to fibrosis in patients with chronic hepatitis B and C.Liver. 2001; 21: 260-265Crossref PubMed Scopus (40) Google Scholar However, a battery of QLFTs is currently under investigation in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial, and preliminary results suggest that certain tests do correlate with cirrhosis and manifestations of portal hypertension (Everson GT, personal communication, December 2003). Several serum markers are also under investigation for use as estimates of liver fibrosis and changes over time. Poynard et al.53Poynard T. Imbert-Bismut F. Ratziu V. Chevret S. Jardel C. Moussalli J. et al.Biochemical markers of liver fibrosis in patients infected by hepatitis C virus longitudinal validation in a randomized trial.J Viral Hepatol. 2002; 9