Most chronic hepatitis C sufferers will develop cirrhosis in later life

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Most chronic hepatitis C sufferers will develop cirrhosis in later life

Study suggests cirrhosis and liver disease nearly inevitable for people with hep C

Bethesda, Maryland (Sept. 1, 2005) – Nearly 80 percent of chronic hepatitis C sufferers who have the disease for several decades will develop cirrhosis or end-stage liver disease later in life, according to a study published today in the American Gastroenterological Association (AGA) journal Clinical Gastroenterology and Hepatology. Researchers found that it is highly likely that people who are infected with hepatitis C (HCV) for more than 60 years will develop cirrhosis--the highest rate of hepatitis C-associated cirrhosis reported to date.

Hepatitis C is a virus that affects the liver and is spread primarily by contact with blood and blood products in transfusions and among drug users who share needles. Other common routes of transmission are infants born to HCV-infected mothers, tattoos and body piercings and risky sexual behavior. Of those who are infected, more than 80 percent will be chronic carriers of the disease. HCV can cause long-term scarring of the liver and usually presents with mild and non-specific symptoms, if any. They include fatigue, nausea, poor appetite and muscle and joint pain. It is estimated that more than 4 million Americans are now infected with HCV (more than 170 million people worldwide) and nearly 10,000 Americans die from the disease each year.

"Hepatitis C begins generally as a silent acute infection, with a fraction of the patients developing cirrhosis, end-stage liver disease or liver cancer," according to an editorial appearing in this month's journal. "Although this is a generally accepted scenario in persons infected with HCV, there remains uncertainty about the true frequency of evolution of liver disease and its rate of progression."

According to results of the study from researchers at the Queen Mary's School of Medicine and Dentistry in London, the prevalence of cirrhosis in patients with chronic HCV increases with the duration of the disease. Nearly 80 percent of Asian patients who were infected at birth and lived with the disease for 60 years or more developed cirrhosis--a finding that researchers say can be applied to the general population because of the similarity in the way the disease progresses in all ethnic groups.

"This study suggests that prolonged infection with hepatitis C leads to cirrhosis in the majority of those who are infected," said Graham R. Foster, PhD, FRCP, study author and professor of hepatology at Queen Mary's School of Medicine and Dentistry in London. "While previous studies have found differences in disease progression in various ethnic groups, our findings confirm that fibrosis progression is the same across these groups and leads to development of cirrhosis and liver disease at the same rate in everyone."

Researchers conducted retrospective analyses of 382 patients diagnosed with hepatitis C at three hospitals in northeast London between 1992 and 2003. Study participants were divided into two groups: Asian patients presumably infected in childhood and Caucasian patients. While the prevalence of cirrhosis in Caucasian patients was similar to the findings of previous studies, the statistics in Asians were markedly higher than previously found. The higher prevalence was partially attributed to the longer duration of HCV in the Asian patient population, those patients having suffered with the disease nearly 30 years more than the Caucasian subjects.

This study was funded by local investigators and an unrestricted research grant from Roche Pharmaceuticals.

For more information on hepatitis C, visit www.gastro.org.

About the AGA
The American Gastroenterological Association (AGA) is dedicated to the mission of advancing the science and practice of gastroenterology. Founded in 1897, the AGA is the oldest medical-specialty society in the United States. The AGA's 14,500 members include physicians and scientists who research, diagnose and treat disorders of the gastrointestinal tract and liver. On a monthly basis, the AGA publishes two highly respected journals, Gastroenterology and Clinical Gastroenterology and Hepatology. The AGA's annual meeting is Digestive Disease Week®, which is held each May and is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

About Clinical Gastroenterology and Hepatology
The mission of Clinical Gastroenterology and Hepatology is to provide readers with a broad spectrum of themes in clinical gastroenterology and hepatology. This monthly peer-reviewed journal includes original articles as well as scholarly reviews, with the goal that all articles published will be immediately relevant to the practice of gastroenterology and hepatology. For more information, visit www.cghjournal.org.

http://www.eurekalert.org/pub_releases/2005-09/aga-mch083105.php

A new player in the battle against hepatitis prevents inflammation and the death of liver cells

Ghent, Belgium -- Scientists from the Flanders Interuniversity Institute for Biotechnology (VIB) have again achieved a breakthrough in research on hepatitis. The researchers, connected to Ghent University, have discovered the function of one of the most important proteins involved in hepatitis. Using a mouse model, they have shown that the protein prevents inflammation of the liver as well as the death of liver cells. This discovery can form the basis for the development of a new therapy in the battle against hepatitis in humans.

Hepatitis, a liver disorder

Hepatitis is a collective term for a number of inflammations of the liver whose symptoms strongly resemble each other. These inflammations can have a wide variety of causes, such as alcohol abuse or infection by a hepatitis virus. Hepatitis B and C, for example, are caused by a virus through contact with the blood or other bodily fluids of infected persons. In some cases, the person remains a carrier of the virus, and chronic hepatitis and even cancer of the liver can develop.

In Belgium, at least 700,000 people have had hepatitis B, and 5%-10% of these persons are still chronic carriers of the virus. Each year, there are about 6000 new infections. The number of people with hepatitis C comes to 80,000-100,000 - and 60%-80% of these persons develop chronic hepatitis. There is a vaccination against hepatitis B, but none against hepatitis C.

A new role for the protein ABIN-1

TNF (Tumor Necrosis Factor) is produced by our body, normally in small quantities. In inflammations of the liver, excessive TNF production activates the mechanisms that lead to inflammation and the death of liver cells and liver tissue. In addition, excessive TNF in liver cells stimulates the protein NF-ƒÛB, which is also responsible for the inflammation of the liver. This makes NF-ƒÛB an attractive target for a therapy that would neutralize the inflammation. However, an ideal therapy also needs to prevent the death of the liver cells.

The new player that this research brings a step closer to the realization of such a therapy is the protein ABIN-1. From previous research by the VIB research group - led by Rudi Beyaert - it turns out that ABIN-1 inhibits the action of NF-ƒÛB. Now, Andy Wullaert and several colleagues from this team have shown that an extra dose of ABIN-1 provides a double protection to liver cells in mice. With an elevated production of ABIN-1, this protein will neutralize the inflammation caused by NF-ƒÛB and also prevent the complete death of liver cells after induction by TNF.

ABIN-1 in the treatment of liver disorders

This research discloses the double protective action of ABIN-1 in liver disorders. NF-ƒÛB, also responsible for inflammations, is inhibited by an elevated presence of ABIN-1. In addition, ABIN-1 also counteracts the death of liver cells. Further research can lead to new therapies in the battle against hepatitis, through which - by increasing the presence of ABIN-1 in the liver - one can inhibit the inflammation and prevent dell death.

http://www.eurekalert.org/pub_releases/2005-09/vfii-anp090105.php

Calcineurin Inhibitors and Hepatitis C: Current Views and Future Perspectives 

Dympna H. Kelly, MD   

Introduction

An estimated 4.9 million people in the United States are infected with hepatitis C virus (HCV). Left untreated, chronic HCV infection progresses to cirrhosis in 14% to 45% of patients within 20 years.^[1] HCV is the leading cause of cirrhosis, the most common etiology for hepatocellular carcinoma, and accounts for 50% of liver transplants in most US transplant centers. Five-year graft and patient survival rates in HCV-positive and HCV-negative recipients are 57% and 70% as well as 68% and 77%, respectively.^[2]

HCV Recurrence After Liver Transplantation

Recurrence of HCV infection following liver transplantation (LTX) is universal. The natural history is more aggressive in LTX recipients than in nontransplant patients, with 25% to 30% of HCV-positive recipients developing cirrhosis in 3-7 years^[3] compared with less than 5% of nontransplant HCV-positive individuals.^[4] Histologic features of chronic HCV infection are evident in 70% to 90% of HCV-positive recipients 1 year after transplantation and 90% to 95% after 5 years post transplantation. Accelerated rates of fibrosis are reported in other immunocompromised patients, such as those with AIDS and other types of solid organ transplants. These conditions are associated with a depressed HCV-specific cellular immune response and enhanced HCV replication.

Three patterns of recurrent HCV infection are recognized. The most common is the development of chronic hepatitis with a progression to cirrhosis in 25% of patients in 5-10 years. Cholestatic hepatitis is significantly less common (1% to 10%), but rapidly (within a few months) progresses to graft failure in 50% of patients. In a substantial number of patients, disease progression does not occur and liver injury remains mild despite a high viral load. A number of factors are known to adversely affect outcome in liver transplant recipients with recurrent HCV infection, including a high viral load pretransplantation, recipient age, nonwhite race, viral genotype 1b vs other genotypes, donor age > 55 years, and warm ischemia time > 45 minutes. The role of immunosuppressive agents, in particular, the calcineurin inhibitors (CNIs), in the pattern of recurrence is unclear. This session was aimed at clarifying what is known about the role of immunosuppressive agents in the severity of HCV recurrence.

Kinetics of HCV Recurrence in Liver Transplant Recipients

Didier Samuel, MD, PhD,^[5] of Villejuif, France, summarized key results from studies of HCV kinetics during and immediately following LTX.^[6,7] From these studies, it is known that the viral load decreases sharply during the anhepatic phase and immediately following graft reperfusion (probably due to hepatic viral clearance), and that HCV RNA rapidly increases in the first several days after LTX. Of note, in one study, a reduced viral load correlated only with the absence of corticosteroids (steroids) from the immunosuppressive regimen.^[6] Thus, immunosuppression with steroids appears to influence the severity of disease progression in the HCV-reinfected liver graft.

Viral clearance in nontransplant patients with acute hepatitis is associated with a multispecific CD4+ and CD8+ response, which is more vigorous in those who clear the virus compared with those who do not.^[8] Similar findings were seen in animals with intrahepatic anti-HCV CD4+ and CD8+ responses and interferon gamma production in animals who cleared HCV, but not in those with HCV persistence. On the other hand, chronic HCV infection is associated with an attenuated CD4+ response. The specific CD8+ response also appears to be less vigorous with persistent infection. Although persistent HCV infection is associated with a reduced specific immune response and a nonspecific intrahepatic T-helper lymphocyte type 1 (Th1) cell-like inflammatory response, the sequence of events in the progression of liver damage is unclear.

HCV Recurrence and Liver Allograft Damage

Reinfection of the liver graft occurs immediately following reperfusion of the liver graft, but histologic evidence of graft injury is not detected for approximately 3 weeks, and precedes biochemical evidence of injury, which is detected between 1 and 3 months. Reinfection may be followed by acute hepatitis, cholestatic HCV infection, or chronic HCV disease. Acute hepatitis is associated with the peak of HCV replication, a CD8+ and CD57+ hepatic cellular infiltrate, significant hepatic apoptosis, and proliferation and detection of a specific CD4+ response. Cholestatic infection occurs in < 10% of cases and is characterized by progressive jaundice and rapidly developing liver failure. This syndrome is associated with very high viral loads, no detectable CD4+ response, and an intrahepatic cytokine response more like a Th2 than the more usual Th1 response, with high levels of interleukin (IL)-10 and IL-4. Histologic features are those of a severe cytopathic viral-induced injury. Persistent infection may progress to chronic hepatitis.

The usual intrahepatic cytokine response to HCV is similar to that in the chronically infected nontransplant patient with a Th1 interferon gamma response, but occurs at a viral set point at least 1 log higher than in the nontransplant setting. It is proposed that the high viral load overcomes the inhibitory effect of immunosuppression on the immune system, inducing the immune system to act at a higher level than in nonimmunosuppressed patients with an enhanced inflammatory response, apoptosis, and fibrosis.

Progression of HCV-related liver disease is accelerated in the immunosuppressed patient with a significantly higher rate of fibrosis progression.^[8] Following LTX, the fibrosis stage increases linearly over time, and the rate of posttransplant fibrosis progression is higher than pre-LTX. The median time to cirrhosis following LTX ranges from 9 to 12 years compared with 20-30 years in the non-LTX population. Variables associated with accelerated fibrosis progression included race other than white, a number of steroid boluses, viral load at the time of LTX, and year of LTX with a faster rate of progression in recent years.

CNIs and HCV

Makoto Nakamuta, MD, PhD,^[9] of Kyushu, Japan, focused on the in vitro scientific data supporting an antifibrogenic effect that is associated with cyclosporine (CsA). Hepatic stellate cells (HSCs) play an important role in the development of liver fibrosis, which is characterized by excess deposition of extracellular matrix and altered matrix composition with an increase in collagens 1, 111, and IV. In situations of spontaneous reversal of fibrosis, there is reduced expression of the tissue inhibitor of matrix metalloproteinase (TIMP) and increased collagenase activity with degradation of collagen matrix. Development of cirrhosis is characterized by a diminution of liver collagenase activity suggesting that the diseased liver has a reduced capacity to remodel the fibrous matrix. The key enzyme for the degradation of interstitial collagens 1 and 111 is interstitial collagenase (matrix metalloproteinase [MMP]-1).

HSCs are capable of producing a variety of matrix-degrading metalloproteinases. Following liver injury, HSCs transdifferentiate to an activated myofibroblastic phenotype with expression of alpha-smooth muscle actin (alpha-SMA). These activated cells proliferate and produce extracellular matrix proteins, such as collagens. Dr. Nakamuta discussed details of work from his institution outlining the effect of CsA and tacrolimus (TAC) on cultured HSCs, specifically examining their morphologic characteristics and proliferative indices. Administration of CsA resulted in no change in morphology, decreased expression of alpha-SMA, a decrease in type 1 collagen production, and when administered in high concentrations, an inhibition of cellular proliferation as determined by BrdU incorporation. CsA reduced collagen gene transcription, increased MMP-1, and reduced TIMP-1. TAC did not exhibit any antifibrogenic effects.

Expression of genes involved in the process of cell growth is mainly regulated through MAP kinase (MAPK) signaling pathways, and the phosphorylation states of MAPK, extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 were measured. Both ERK and JNK pathways are involved in regulating collagen gene expression.^[10] CsA administration resulted in a reduction in JNK and p38, but TAC did not produce these effects. Administration of TAC to cell cultures did not produce antifibrogenic effects.

Long-term Follow-up of HCV-Positive Liver Transplant Recipients

Federico Villamil, MD,^[11] of Buenos Aires, Argentina, discussed long-term follow-up of HCV-positive patients in the LIS2T trial. This was the first multicenter, randomized, open-label study to compare the efficacy and safety of CsA-microemulsion (CsA-ME) with C₂ monitoring vs TAC in de novo liver transplant recipients.^[12] Patients were stratified according to HCV status and randomized to receive CsA-ME or TAC with steroids, with or without azathioprine. The proportion of HCV-positive patients was similar in both arms. Groups did not differ with regard to the validated predictors of HCV recurrence. Long-term follow-up data are available in 82% of patients, but the reader is cautioned that virologic data are limited.

The time to HCV histologic recurrence was shorter in and the rates of graft loss and death were higher in the TAC-treated, HCV-positive group compared with the HCV-negative group. Patients who did not receive antiviral therapy demonstrated higher alanine aminotransferase values, but there was no statistical difference between groups; viral load did not differ between groups in the first, second, or third year; the rate of spontaneous clearance of HCV RNA was higher in the CsA-ME group; histologic evidence of hepatitis was significantly higher in the TAC group, and the stage of fibrosis at the time of the last biopsy was more advanced in the TAC group. Whether these findings are entirely HCV-related is unclear because the difference in histologic differentiation between acute rejection and HCV is difficult. Thus, relevance of these findings is speculative and needs to be confirmed in trials designed with these end points. Long-term patient survival, graft survival, and re-LTX rates for HCV-positive patients were not significantly different between groups except when examined for HCV-related causes. Again, although there is a suggestion that HCV-positive patients treated with TAC have poorer outcomes, these results are not definitive.

Herold Metselaar, MD, PhD,^[13] of Rotterdam, The Netherlands, discussed trends in HCV recurrence from his center. The factors there associated with the severity of HCV recurrence post-LTX were the same as described above. The role of immunosuppression, however, remains controversial. The established immunosuppression-related risk factors include high-dose bolus steroids, rapid steroid withdrawal, and treatment with muromonab CD3 (Orthoclone OKT3) -- all of which are associated with more severe disease.

Bartenschlager^[14] and Lohmann and colleagues^[15] examined the effects of immunosuppressive agents on the HCV replicon system, a human hepatoma cell line infected with genetically modified HCV RNA, and found that HCV replication was not inhibited by sirolimus, steroids, or TAC. A dose-dependent inhibition occurred with CsA and mycophenolate mofetil, and a synergistic effect was observed when these agents were combined. The results from clinical trials, however, are equivocal. Berenguer and colleagues^[8] demonstrated reduced survival in HCV-positive patients in recent years, and at least 1 related factor was the overall load of immunosuppression used. Dr. Metselaar^[13] reported his center's experience of a higher incidence of fibrosis in 38 patients treated with TAC, whereas other studies have shown no difference in outcomes between CsA-treated vs TAC-treated HCV-positive liver transplant recipients^[16,17]; thus, the choice of CNIs does not appear to affect the severity of recurrent HCV infection.

Antiviral Treatment

Gary Levy, MD,^[18] of Toronto, Ontario, Canada, discussed some aspects of response to antiviral treatment and described his own experience comparing CsA with TAC in 128 HCV-positive LTX recipients. Yearly liver biopsies and HCV genotypes were performed. Eighty patients received TAC and 48 patients received CsA. No difference was observed in patient or graft survival rates, severity of rejection, or HCV genotype. The TAC group had higher fibrosis scores and a more rapid progression to fibrosis. There was also a trend toward higher viral titers in the TAC group. A total of 61 transplant recipients were treated for HCV with pegylated interferon and ribavirin combination therapy. Sixty-five percent of these patients achieved a sustained response, and a higher proportion of CsA-treated patients cleared the virus.

Conclusion

The magnitude of the problem of recurrent HCV infection in LTX recipients was defined, and what is known about the immune response to HCV and the mechanism of graft injury was described. Although kinetic studies identify the ideal time to administer antiviral treatment for HCV infection recurrence, few LTX recipients are able to tolerate current antiviral treatment in the perioperative period. Although there is in vitro evidence to support the use of CsA in HCV-positive recipients, the clinical implications of the anti-HCV effect of CsA vs TAC require further evaluation in a large-scale, multicenter study to determine optimal immunosuppression for these patients.

References

1. Brown RS, Gaglio PJ. Scope of worldwide hepatitis C problem. Liver Transpl. 2003;9(suppl3):S10-S13.
2. Forman L, Lewis J. Association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology. 2002;12:889-896.
3. Berenguer M, Prieto M, san Juan F, et al. Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients. Hepatology. 2002;36:202-210. Abstract
4. Gane E. The natural history and outcome of liver transplantation in hepatitis C virus-infected recipients. Liver Transpl. 2003;9(suppl3):S28-S34.
5. Samuel D. Calcineurin inhibitors and hepatitis C: hypotheses and trends. Program and abstracts of the 11th Annual Congress of the International Liver Transplantation Society; July 20-23, 2005; Los Angeles, California.
6. Garcia-Retortillo M, Forns X, Feliu A, et al. Hepatitis C virus kinetics during and immediately after liver transplantation. Hepatology. 2002;35:680-687. Abstract
7. McCaughan GW, Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation. J Hepatol. 2004;40:368-374. Abstract
8. Berenguer M, Ferrell L, Watson J, et al. HCV-related fibrosis progression following liver transplantation: increase in recent years. J Hepatol. 2000;32:673-684. Abstract
9. Nakamuta M. Calcineurin inhibitors and hepatitis C: hypotheses and trends. Program and abstracts of the 11th Annual Congress of the International Liver Transplantation Society; July 20-23, 2005; Los Angeles, California.
10. Fukushima M, Nakamuta M, Kohijima M, et al. Fasudil hydrochloride hydrate, a Rho-kinase inhibitor suppresses collagen production and enhances collagenase activity in hepatic stellate cells. Liver Int. 2005;25:829-838. Abstract
11. Villamil F. Calcineurin inhibitors and hepatitis C: hypotheses and trends. Program and abstracts of the 11th Annual Congress of the International Liver Transplantation Society; July 20-23, 2005; Los Angeles, California.
12. Levy G, Villamil F, Samuel D, et al. Results of LIS2T, a multicenter, randomized study comparing cyclosporine microemulsion with C2 monitoring in de novo liver transplantation. Transplantation. 2004;77:1632-1638. Abstract
13. Metselaar H. Calcineurin inhibitors and hepatitis C: hypotheses and trends. Program and abstracts of the 11th Annual Congress of the International Liver Transplantation Society; July 20-23, 2005; Los Angeles, California.
14. Bartenschlager R. The hepatitis C virus replicon system: from basic research to clinical application. J Hepatol. 2005;43:210-216. Abstract
15. Lohmann V, Korner F, Koch J-O, Herian U, Theilmann L, Bartenschlager R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science. 1999;285:110-113. Abstract
16. Martin P, Busuttil RW, Goldstein RM, et al. Impact of tacrolimus versus cyclosporine in hepatitis C virus-infected liver transplant recipients on recurrent hepatitis: a prospective, randomized trial. Liver Transpl. 2004;10:1258-1262. Abstract
17. Wiesner RH. A long term comparison of tacrolimus (FK506) versus cyclosporine in liver transplantation. A report of the United States FK506 study group. Transplantation. 1998;66:493-499. Abstract
18. Levy G. Calcineurin inhibitors and hepatitis C: hypotheses and trends. Program and abstracts of the 11th Annual Congress of the International Liver Transplantation Society; July 20-23, 2005; Los Angeles, California.

http://www.medscape.com/viewarticle/511002?src=mp

Coffee Drinking May Keep Liver Cancer at Bay
by John C. Martin	Article Date: 08-31-05

Can treating HCV prevent progression to cirrhosis? Henry Bodenheimer, NYSGE, 29 August 2005 Hepatic fibrosis is a progressive insult responsible for morbidity and mortality in chronic hepatitis C infection. Thierry Poynard in his 1999 paper in Hepatology analyzed a large data set of liver biopsies in patients with hepatitis C and suggested that liver fibrosis progression was not uniform in individuals infected with hepatitis C. Some individuals appear to progress slowly while others rapidly progressed to cirrhosis. This dichotomy is perhaps most widely recognized in patients who have under gone liver transplantation. Patients with recurrent hepatitis C following transplant may develop cirrhosis in as short an interval as 4 to 5 years while progression to cirrhosis in a non-transplant setting typically takes 2, 3 or more decades. Multiple factors have been identified as contributing to progression of fibrosis in hepatitis C. Three of the factors identified deserve highlighting:   Alcohol consumption is a modifiable cofactor which has been associated with more rapid progression of liver fibrosis. Although regular consumption of alcohol at levels more than 50gms of alcohol per day has been linked with rapid progression of disease, no safe level of alcohol consumption has been identified. It is wise therefore that patients with chronic hepatitis C infection avoid alcohol consumption.     A second factor associated with disease progression is fatty liver. Non-alcoholic fatty liver disease is increasingly recognized as a co-factor in disease progression in patients with various underlying liver conditions. This disorder is difficult to treat and pathogenesis may, in part, be related to insulin resistance associated with hyperlipidemia, diabetes and obesity. Hepatitis C infection itself, however, may contribute to lipid deposition within the infected liver. It is advisable that modifiable factors such as body weight, hyperlipidemia and insulin resistance be addressed and treated in patients with chronic hepatitis C infection.     A third factor which is not able to be modified but is associated with disease progression is the acquisition of HCV at an age greater than 40 years. Older patients appear to have more rapid progression of fibrosis than younger patients. Such information may be important in assessing prognosis and need for antiviral treatment.   A major question is whether liver fibrosis is reversible. Patients with established fibrous septa have shown gradual resolution of fibrosis with years of effective control of viral replication. The question remains, whether decrease in hepatic fibrosis in patients undergoing treatment for hepatitis C is a direct result of anti-fibrotic effect of alpha interferon, or is the beneficial effect a consequence of viral control. A recent report by Poynard in Gastroenterology 2002, addressed this question. Greater than 80% of liver biopsies evaluated in patients with sustained virologic response showed improved fibrosis while less than 10% showed a worsening. In contrast, less than 34% of individuals who showed non-response to interferon showed improvement in fibrosis while more than 20% showed a worsening. Such data suggest that the primary mechanism by which fibrosis is diminished in patients treated with alpha interferon is through control of viral replication . In summation, chronic hepatitis C infection is an epidemic infection leading to chronic liver injury with hepatocyte necrosis subsequent inflammation and stimulation of hepatic fibrosis. This chronic process gradually leads to cirrhosis. Fortunately, with control of viral replication modulation of the intercellular matrix is possible and alpha interferon treatment regimens generating sustained virologic response are associated with improvement in hepatic fibrosis and even resolution of cirrhosis. In the future, assessment of hepatic fibrosis may be possible with non invasive assays and direct anti-fibrotic therapy maybe available to be coupled with inhibitors of viral replication to maximize the resolution of hepatic injury. Join the debate! Click here to post your comments about this Soapbox Speech.   This "Soapbox" was published as part of the syllabus for the New York Society for Gastrointestinal Endoscopy 27th Annual Postgraduate Course - Endoscopic Decision Making 2003, held in New York, NY. 15 and 16 December 2003. See the NYSGE website.   References Castilla A, Prieto J, Fausto N. Transforming growth factors beta 1 and alpha in chronic liver disease. Effects of interferon alfa therapy. N Engl J Med1991; 324: 933-40.     Yano M, Kumada H, Kage M, et al. The long-term pathological evolution of chronic hepatitis C. Hepatology 1996: 23: 1334-40.     Poynard T, Dedossa 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.     Shiffman ML, Hofmann CM, Contos MJ, et al. A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia. Gastroenterology 1999; 117: 1164-72.   Wanless IR, Nakashima E, Sherman M. Regression of human cirrhosis. Morphologic features and genesis of incomplete septal cirrhosis. Arch Pathol Lab Med 2000; 124(11): 1599-607.     Alric L, Duffaut M, Selves J, et al. Maintenance therapy with gradual reduction of interferon dose over one year improves histological response in patients with chronic hepatitis C with biochemical response: results of a randomized trial. J Hepatol 2001; 35: 272-8.     Poynard T, McHutchinson J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002; 122: 1303-13.     Ghany MG, Kleiner DE, Alter H, et al. Progression of fibrosis in chronic hepatitis C. Gastroenterology 2003; 124: 97-104.     Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003; 124: 105-17.