Progression of chronic hepatitis C (CHC) in patients with

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2007;5: Effect of Sustained Viral Response on Hepatic Venous Pressure Gradient in Hepatitis C Related Cirrhosis STUART ROBERTS,* ADAM GORDON,* CATRIONA MCLEAN, JOHN PEDERSEN, SCOTT BOWDEN, KENNETH THOMSON, and PETER ANGUS *Department of Gastroenterology, Department of Anatomical Pathology, and Department of Radiology, Alfred Hospital, Melbourne, Victoria, Australia; Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia; and Department of Gastroenterology and Hepatology, Austin Health, Heidelberg, Victoria, Australia See Ripoll C et al on page 481 for companion article in the August 2007 issue of Gastroenterology. Background & Aims: Interferon-based therapy can improve hepatic histology in chronic hepatitis C (CHC) related cirrhosis but its effect on portal hypertension is unclear. The aims of this study were to investigate the effect of treatment with peginterferon alfa-2a and ribavirin on hepatic venous pressure gradient (HVPG) in CHC with compensated cirrhosis. Methods: Forty-seven patients with compensated biopsy examination proven cirrhosis were recruited from 2 metropolitan teaching hospitals and were treated for 48 weeks with combination peginterferon alfa-2a 180 g by subcutaneous injection weekly and ribavirin mg/day orally. A transjugular liver biopsy examination and HVPG measurement were performed at baseline, and 33 patients had a repeat HVPG measurement after 6 months of treatment-free follow-up evaluation. Results: The overall sustained viral response (SVR) was 21%. Posttreatment there was a significant decrease in HVPG level in sustained responders compared with nonresponders ( vs mm Hg; P.05). Among patients with portal hypertension, a higher proportion of sustained responders achieved a 20% or greater reduction in HVPG level compared with nonresponders (71% vs 20%; P.01). There was a significant association between a 20% or greater reduction in HVPG and both histologic response and SVR. Conclusions: Treatment with combination peginterferon plus ribavirin may produce clinically significant reductions in HVPG in patients with CHC-related cirrhosis who achieve an SVR. Progression of chronic hepatitis C (CHC) in patients with hepatitis C virus (HCV) related cirrhosis frequently leads to significant morbidity and mortality. 1 3 Much of the morbidity including the formation of ascites, gastrointestinal bleeding, and hepatic encephalopathy is related to the effects of portal hypertension. 1,2 Peginterferon-alfa combined with ribavirin is the most effective therapy for CHC with cirrhosis. Up to 50% of patients with cirrhosis/advanced fibrosis treated with peginterferon-alfa plus ribavirin combination therapy achieve a sustained viral response (SVR). 4 Treatment with (peg)interferon has a beneficial effect on liver histology in CHC patients, including those with cirrhosis The degree of improvement after treatment closely relates to virologic response with sustained responders achieving the most histologic benefit Although preliminary results suggest that peginterferon therapy can improve portal hypertension and its complications in HCV-related cirrhosis, the long-term effects on portal pressure are not known. 12,13 Thus, we investigated first the efficacy of combination therapy with peginterferon alfa-2a plus ribavirin at reducing portal pressure as measured by hepatic venous pressure gradient (HVPG), and, second, the relationship between virologic response and reduction in portal pressure in patients with HCVrelated compensated cirrhosis. Materials and Methods Patient Population We recruited 47 patients with CHC and compensated cirrhosis from 2 Melbourne metropolitan tertiary hospitals between April 2001 and March Patients were eligible for inclusion if they met the following criteria: (1) age years; (2) HCV-antibody positive; (3) serum HCV RNA level quantifiable at greater than 2000 copies/ml; (4) increased serum alanine aminotransferase activity on at least 2 occasions during the previous 6 months; (5) cirrhosis consistent with CHC on a liver biopsy specimen obtained within the 35-day screening period before enrollment in the study; (6) compensated liver disease with a Child Pugh score of less than 7; and (7) no clinical suspicion or radiologic evidence of hepatocellular carcinoma within 3 months of study entry and a serum -fetoprotein level of less than 100 g/l. Patients whose liver biopsy specimen at screening showed advanced fibrosis but did not meet all histologic criteria for cirrhosis still were eligible if they had cirrhosis shown on a liver biopsy specimen within the past 2 years and had evidence of chronic liver disease on the basis of results from clinical, laboratory, and imaging studies as previously outlined. 14 Patients were excluded from participating in the study if any one of the following were present: (1) any previous treatment with peginterferon alfa-2a with or without Abbreviations used in this paper: CHC, chronic hepatitis C; HAI, histologic activity index; HCV, hepatitis C virus; HVPG, hepatic venous pressure gradient; PCR, polymerase chain reaction; SVR, sustained virologic response by the AGA Institute /07/$32.00 doi: /j.cgh

2 August 2007 EFFECT OF TREATMENT ON HVPG IN CHC CIRRHOSIS 933 ribavirin; (2) evidence of another cause for chronic liver disease on clinical, laboratory, and/or histologic evaluation; (3) human immunodeficiency virus infection; (4) pre-existing severe depression or other significant psychiatric disease; (5) history or evidence of significant comorbidity including cardiac, pulmonary, and renal diseases, seizure disorders, and severe retinopathy; (6) history or other evidence of past decompensated liver disease including bleeding from esophageal varices, ascites, or hepatic encephalopathy; (7) current alcohol consumption of more than 10 g/day and/or a history of heavy alcohol use in the previous 12 months; (8) significant cytopenia including a hemoglobin level of less than 12 g/dl in women or 13 g/dl in men, a neutrophil count of less than 1500 cells/mm 3, or a platelet count of less than 70,000 cells/mm 3 ; (9) females of child-bearing age who were pregnant or intending to become pregnant during the trial period or who were not prepared to use adequate birth control, or male partners of women who were pregnant; and (10) inability to provide informed consent. Patients who had received previous interferon-based therapy were eligible after at least 6 months of treatment-free follow-up evaluation. The study protocol conformed to the principles outlined in the Declaration of Helsinki and was approved by the ethics committees of both Alfred and Austin Hospitals. All patients gave written informed consent before study entry. Study Design Patients underwent screening during which baseline demographic data were recorded and laboratory and virology tests, liver ultrasound, chest radiograph, electrocardiogram, and transjugular liver biopsy examination and HVPG measurement were performed. At the commencement of the study patients received treatment with peginterferon alfa-2a 180 g weekly by subcutaneous injection and ribavirin 800 mg/day orally for 48 weeks. From July 2002, when the final results of the study by Hadziyannis et al 15 were released regarding the optimal dose of ribavirin according to genotype, subjects with genotypes 1 or 4 received ribavirin mg/day orally according to body weight whereas those with genotypes 2 or 3 were continued on ribavirin 800 mg/day. After treatment, patients were followed up for a further 24 weeks, at which time they underwent a repeat transjugular liver biopsy examination and HVPG measurement. Assessments Clinical and laboratory assessments were performed weekly during the first month, two-weekly during the second month, and monthly thereafter. At each visit, all adverse events and serious adverse events were recorded and patient compliance was monitored. Virologic assessments included quantitative serum HCV RNA (AMPLICOR MONITOR; Roche Diagnostics, Nutley, NJ) and HCV genotype (Inno-Lipa II HCV assay; Innogenetics, Ghent, Belgium) at week 0, and qualitative serum HCV RNA by polymerase chain reaction (PCR) (COBAS AM- PLICOR; Roche Diagnostics) at weeks 0, 12, 48, and 72. No early stopping rule was used and patients were encouraged to complete the 48-week treatment course even if they had failed to achieve an early virologic response. The primary treatment end point was an SVR defined as an undetectable serum HCV RNA level at the end of treatment and at the end of 24 weeks of a treatment-free follow-up period; all patients were included in this assessment. Nonresponders were defined as patients with detectable HCV RNA by PCR throughout treatment (primary nonresponders) and those with detectable HCV RNA by PCR during the treatment-free follow-up period after having undetectable HCV RNA by PCR at week 48 (relapsers). Hepatic Venous Pressure Gradient Measurement Forty-seven patients had a baseline HVPG measurement, and 33 patients had a repeat HVPG measurement after 6 months of a treatment-free follow-up period. Procedures were performed after at least 6 hours of fasting in the hemodynamic laboratory of The Alfred (Hospital) by radiology staff blinded to the patient s treatment details. After application of local anesthesia, a 7F venous introducer was placed in the right internal jugular vein by the Seldinger technique, and a 5F multipurpose catheter (LABS-100 Liver Biopsy Set; Cook, Inc., Bloomington, IN) was advanced under fluoroscopic guidance into the main right hepatic vein, where it remained for the study duration. The wedged hepatic venous pressure and the free hepatic venous pressure then could be determined. Wedging of the catheter was confirmed by a dampened pressure trace and injection of contrast. Repeated measures of the wedged hepatic venous pressure and the free hepatic venous pressure, with the catheter floating in the middle of the hepatic vein, were performed. Pressures were recorded on a CO 2 angiographic injector machine (Angiodynamics Inc, Queens Falls, NY). The HVPG was calculated by subtracting the free hepatic venous pressure from the wedged hepatic venous pressure. Pressure measurements were performed in triplicate in each subject with results given as arithmetic means of the 3 determinations. Patients were monitored continuously on an electrocardiograph during the whole procedure. Liver Biopsy Procedure Liver biopsy procedures were performed at baseline and at week 72 via the transjugular route using a Quick-Core biopsy needle with a 20-mm throw (Cook, Inc.). Liver tissue was assessed by 2 independent hepatopathologists who were unaware of the patients identities and the times at which the specimens had been obtained. Biopsy specimens greater than 10 mm in length were scored for necroinflammation and fibrosis according to the modified Knodell histologic activity index (HAI). 16 With this index, the severity of necroinflammation is graded accordingly: severity of periportal necrosis (score range, 0 10), intralobular necrosis (score range, 0 4), portal inflammation (score range, 0 4), and fibrosis (score range, 0 6). Scores for necroinflammation can range from 0 (normal liver) to 18 (severe hepatitis), and fibrosis was not included in the necroinflammation score. A histologic response was defined as a reduction of greater than 2 points in the HAI score, which has been validated previously as a clinically significant histologic indicator in patients. 17,18 Statistical Analysis Baseline descriptive data were expressed as the mean and SD for continuous variables, or as frequencies and percentages for categoric variables. All patients receiving at least 1 dose of treatment were included in the analysis of virologic response, whereas each HVPG efficacy end point was assessed only for patients with no data missing after the completion of the study. For each subject with a baseline HVPG of greater than 5 mm Hg

3 934 ROBERTS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 8 Table 1. Demographic and Clinical Features of the Study Cohort Feature Value Age, y a 48 7 Males, n (%) 43 (91) Method of HCV acquisition Injection drug use, n (%) 24 (51) Transfusion, n (%) 6 (13) Percutaneous, n (%) 4 (9) Sexual, n (%) 2 (4) Unknown, n (%) 11 (23) HCV genotype / HCV viral load 800,000 IU/mL ,000 IU/mL 10 Previous interferon, n (%) 16 (34) Cirrhosis, n (%) 47 (100) Child Pugh score 7,n(%) 47 (100) Laboratory markers b Hemoglobin level, g/l (N 130) 156 ( ; ) Leukocyte, 10 9 /L (N ) Platelets, 10 9 /L (N ) 6.4 ( ; ) Alanine aminotransferase level, 130 (54 455; ) IU/L (N 40) Aspartate aminotransferase 140 (80 493; ) level, IU/L (N 40) Albumin level, g/l (N 35 50) 39 (27 50; 36 41) Bilirubin level, mol/l (N 21) 14 (5 45; 11 18) International normalized ratio, (N 1.1 (1 1.5; ) 1.4) a Mean SD shown. b Median, range, and interquartile range shown. the difference between pretreatment and posttreatment HVPG levels was determined and classified according to the presence of a 20% or greater reduction from baseline. A reduction in HVPG of this magnitude previously has been determined to be an important predictor of clinical outcome. 19 Changes in HVPG were compared according to the virologic response achieved. Differences between groups for continuous variables were assessed using the Student t test and were validated using Wilcoxon rank-sum tests, whereas categoric variables were assessed using the 2 test for equal proportion or the Fisher exact test when numbers were small. Ordinal logistic regression and Spearman correlation were used to assess the significance of associations between ordinal or continuous predictor variables and change in HAI score and reduction in HVPG. For all comparisons, a 2-sided P value of.05 was considered statistically significant. All analyses were performed using SAS version 8.2. (SAS Institute Inc., Cary, NC). Results Demographic and Clinical Features Of the 57 patients who were screened, 47 were eligible and entered the study. The baseline characteristics of the study group are shown in Table 1. There was a male predominance, with the majority of subjects being older, and acquiring HCV infection via injection drug use. Thirty-one (65%) subjects had genotype 1, reflecting the HCV genotype distribution in Australia, whereas 10 (22%) had high ( 800,000 IU/mL) HCV RNA levels. All subjects had compensated liver disease. The median HAI score was 8. Sixteen subjects had received prior interferon therapy (15 interferon monotherapy, 1 combination interferon plus ribavirin) and none of the subjects was receiving nonselective -blocker therapy. Seventeen patients had a gastroscopy within 12 months of study entry, with 5 patients having highrisk varices and 6 having low-risk varices as previously defined. 20 Virologic Response Thirty-eight of the 47 patients receiving treatment completed the 48-week treatment course. Nine patients were withdrawn prematurely from treatment (see later). Overall, 10 patients (21%) achieved an SVR and there were 15 relapsers and 22 primary nonresponders. SVR rates were higher in treatmentnaive subjects (8 of 31; 26%) compared with prior interferon nonresponders (2 of 16; 12.5%), although the differences were not statistically significant (P.1). An early virologic response, defined as a negative week 12 HCV RNA PCR, was the only independent predictor of SVR (P.007). Hemodynamic Features Baseline HVPG levels were obtained successfully in 46 patients. The mean baseline HVPG level of the study group was mm Hg (range, 1 20 mm Hg). Thirty-seven (80%) patients had portal hypertension (HVPG, 5 mm Hg), with 13 (28%) having clinically significant ( 10 mm Hg) HVPG levels. Thirty-three of the 46 patients who successfully underwent baseline HVPG measurement underwent repeat hepatic vein catheterization at week 72, all of whom had completed treatment. Among the 13 subjects who failed to have repeat hemodynamic studies were the 9 treatment withdrawals, 2 nonresponders, and 2 sustained responders. Among treated patients, there was no overall change in HVPG levels after treatment ( mm Hg vs mm Hg). The effect of treatment on HVPG is shown according to virologic response in Table 2 and Figure 1. After treatment, the mean HVPG decreased 23% in sustained viral responders ( mm Hg to mm Hg; P.3), but 2 sustained responders recorded an increase in HVPG. The change in HVPG in sustained responders was significant Table 2. Effect of Treatment on HVPG According to Virologic Response Parameter Virologic response Sustained viral response Nonresponse a P value HVPG, mm Hg Pretreatment NS Posttreatment NS Change in HVPG, mm Hg % decrease in HVPG b 5/7 (71%) 4/20 (20%).01 a Includes primary nonresponders and relapsers. b Includes only subjects with baseline HVPG of greater than 5 mm Hg.

4 August 2007 EFFECT OF TREATMENT ON HVPG IN CHC CIRRHOSIS 935 Variables Associated With Hepatic Venous Pressure Gradient Reduction Table 3 shows the relationship between baseline variables and a 20% or greater decrease in HVPG in subjects with portal hypertension at study entry. The only baseline variables predictive of a 20% or greater decrease in HVPG after treatment was the serum alanine aminotransferase quotient (R 0.41; P.01) and the serum albumin level (R 0.45; P.02). In addition, several treatment-related variables were associated with a 20% or greater reduction in HVPG posttreatment, including SVR (R 0.48; P.01), histologic response (R 0.48; P.02), posttreatment HAI score (R 0.67; P.001), and week 72 serum albumin level (R 0.43; P.03). However, the histologic response was not correlated with a greater than 20% reduction in HVPG in the nonresponder group (R 0.03; P.9). Histologic Features Satisfactory liver biopsy specimens were obtained in 47 patients at baseline and in 33 patients at completion of the follow-up evaluation. After treatment there was a trend to improvement in necroinflammatory activity in the study group (median HAI score, 8.0 vs 6.5; P.07). Histologic response rates in the SVR and nonresponder groups were 67% and 35%, respectively (P.15). The median modified Knodell fibrosis score remained unchanged posttreatment (6 vs 6). Table 3. Association Between Baseline Variables and Reduction in HVPG Parameter HVPG reduction ( 20%) a P value Figure 1. Effect of treatment on HVPG according to virologic response: (A) sustained virologic responders, (B) relapsers, and (C) primary nonresponders. when compared with nonresponders ( vs mm Hg; P.05) (Table 2). A total of 27 patients with portal hypertension (HVPG, 5 mm Hg) underwent repeat HVPG measurement, 9 (33%) had a 20% or greater reduction in HVPG level; these included 5 sustained responders, 2 primary nonresponders, and 2 relapsers. A higher proportion of sustained responders achieved a 20% or greater decrease in HVPG level after treatment compared with nonresponders (71% vs 20%; P.01) (Table 2, Figure 1). There were 6 patients with portal hypertension who had a 20% or greater increase in HVPG level posttreatment; 5 of these were nonresponders. Age, y 50 6/ /10 Sex Male 8/23.70 Female 1/4 Alanine aminotransferase quotient b 3 6/ /18 Albumin level 40 3/ /10 HCV genotype 1 6/19.33 Non-1 3/8 HCV viral load, IU/mL 800,000 6/ ,000 2/5 HAI score 6 1/ /24 Previous interferon Yes 1/7.16 No 8/20 a 20% decrease in HVPG in subjects with HVPG greater than 5 mm Hg. b Alanine aminotransferase level divided by the upper limit of normal.

5 936 ROBERTS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 8 Safety Nine patients were withdrawn from treatment. In 7 of these patients adverse events were related or probably related to the study medication and included depression-related events (n 3), psoriatic arthropathy (n 1), and significant aminotransferase level increases (n 1). Gastrointestinal hemorrhage associated with thrombocytopenia (platelet counts, 49,000/mm 3 ) resulted in the withdrawal of 1 patient, and 1 patient was discontinued because of the development of hepatoma and renal cell carcinoma (n 1). Two patients withdrew consent. Of note, 23 (49%) patients developed hematologic abnormalities including anemia (n 3), neutropenia (n 12), and thrombocytopenia (n 14). Dose modification was required in 23 subjects, predominantly owing to hematologic abnormalities. Twenty-one subjects required a dose modification of peginterferon alfa-2a because of clinical adverse events (n 1) or laboratory abnormalities (n 20), and 6 subjects required dose modification of ribavirin because of clinical adverse events (n 1) or laboratory abnormalities (n 5). No deaths occurred during the study. Discussion Hepatitis C related compensated cirrhosis left untreated progresses to liver decompensation at an annual rate of 5%, with complications of portal hypertension high among the causes of patient morbidity. 1,2 Our study provides evidence that successful treatment of HCV-related compensated cirrhosis with combination peginterferon plus ribavirin therapy is associated with a sustained reduction in portal venous pressure. The main findings are as follows: (1) cirrhotic patients achieving an SVR to peginterferon plus ribavirin show a significant decrease in HVPG level posttreatment in comparison with nonresponders; (2) a higher proportion of sustained responders achieve a 20% or greater reduction in HVPG level compared with nonresponders; and (3) a 20% or greater reduction in HVPG level is associated with both SVR and a histologic response. In this study we treated a group of patients with compensated hepatitis C related cirrhosis, many of whom had HCV genotype 1 infection and high viral load, and had failed previous interferon therapy. Of note, 80% of the group had portal hypertension with more than a quarter having clinically significant ( 10 mm Hg) HVPG levels. Nevertheless, the overall end-of-treatment and SVR rates in this difficult-to-treat population were 40% and 21%, respectively, with 26% SVR in treatment-naive patients and 12.5% SVR in previous interferon nonresponders. Although there was no overall reduction in HVPG after treatment in the study group, the reduction in HVPG in sustained responders was significant when compared with nonresponders. Moreover, more than 70% of sustained responders with portal hypertension achieved a clinically significant ( 20%) reduction in HVPG level after treatment compared with just 20% in nonresponders and 17% in primary nonresponders. Two patients who achieved an SVR recorded increases in HVPG, pretreatment and posttreatment biopsy specimens were available in 1 of these patients, and that patient recorded a reduction in hepatic necroinflammation. Little is known regarding the effects of antiviral therapy on HVPG in HCV-related liver disease. 13,21,22 Garcia-Tsao et al, 21 in abstract form, reported the results of a pilot, randomized, placebo-controlled trial that evaluated the effect of interferon therapy on HVPG in 15 patients with CHC and portal hypertension. Of note, the percentage change in HVPG was significantly greater in the interferon-treated group compared with the placebo group. Subsequently, Valla et al 22 measured HVPG levels in 5 patients with HCV-related cirrhosis before and after 48 weeks of interferon therapy. The mean HVPG levels decreased 20% from baseline in interferon-treated patients and increased by 11% in controls, with a trend toward HVPG reduction in the treated group. More recently, Rincon et al 13 presented the results, in abstract form, of a nonrandomized comparative study of the effect of peginterferon plus ribavirin on HVPG in patients with CHC and fibrosis stages 3 or 4, showing a mean HVPG reduction of 27%, and with an increase seen in the parallel control group. In contrast to our study, posttherapy HVPG measurements were performed immediately after treatment, with no attempt made to correlate changes in HVPG with SVR. Similarly, preliminary results from the COPILOT study indicated that maintenance peginterferon may reduce portal pressure and complications of portal hypertension. In our study, in which HVPG was measured 6 months after therapy, only sustained responders achieved a significant reduction in HVPG level, with no sustainable decrease in HVPG from baseline observed in nonresponders; this reduction therefore likely reflects the impact of a virologic response rather than an independent effect of interferon. The development of portal hypertension in HCV-related cirrhosis results from an increase in intrahepatic vascular resistance, with a fixed component related to disturbance of the normal hepatic architecture, and a variable component related to active hepatic necroinflammation and fibrogenesis (including the contractile activity of hepatic myofibroblasts). 23,24 Interferon therapy improves liver histology with reductions in hepatic necroinflammatory activity, and fibrosis and histologic benefits closely relate to virologic response. 5,11 Similarly, although the numbers in our study were small, we found that histologic response was correlated with SVR. In addition, we found that a clinically relevant reduction in HVPG was associated with both a histologic response and a sustained response. Although these data suggest that a reduction in hepatic inflammation reduces HVPG, it is important to note that this effect was not observed uniformly across the cohort because there was no correlation seen between histologic response and a reduction in HVPG in the nonresponder group. Of note, no overall reduction in histologic stage after treatment was observed. However, more subtle reductions in hepatic fibrogenesis may well have contributed to the decrease in HVPG, and further studies using semiquantitative techniques to measure liver fibrosis and stellate cell activation are needed to explore this concept. The results of our study and that of others provide further evidence to support the concept that treatment with peginterferon-based therapy should be given serious consideration in all patients with CHC and compensated cirrhosis, including those who previously have failed standard interferon. Potential benefits of treatment include histologic improvement, including the possible reversal of cirrhosis; a reduction in portal pressure and hepatic complications, including hepatocellular carcinoma; 2,25 and probably improvement in patient survival. 25 Nevertheless, this difficult-to-treat population presents specific challenges because sustained response rates to combination peginterferon plus ribavirin

6 August 2007 EFFECT OF TREATMENT ON HVPG IN CHC CIRRHOSIS 937 therapy are substantially lower than those in noncirrhotic patients, with our data suggesting that SVR rates may be lower still in subjects with cirrhosis complicated by portal hypertension. 4 This is likely in part owing to the difficulty these patients have in tolerating full-dose therapy because of laboratory abnormalities and/or side effects. In conclusion, our study suggests that treatment with the combination of peginterferon plus ribavirin may produce clinically significant reductions in HVPG, and hepatic necroinflammation in patients with HCV-related cirrhosis who achieve an SVR. This beneficial effect of therapy provides a further rationale for treatment in patients with advanced liver disease caused by hepatitis C. References 1. Benvegnu L, Gios M, Boccato S, et al. Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut 2004;53: Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 1997;112: Fattovich G, Giustina G, Degos F, et al. Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C. European Concerted Action on Viral Hepatitis (EUROHEP). J Hepatol 1997;27: Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347: Poynard T, McHutchison 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: Camma C, Di Bona D, Schepis F, et al. Effect of peginterferon alfa-2a on liver histology in chronic hepatitis C: a meta-analysis of individual patient data. Hepatology 2004;39: Shiratori Y, Imazeki F, Moriyama M, et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med 2000;132: Bruno S, Battezzati PM, Bellati G, et al. Long-term beneficial effects in sustained responders to interferon-alfa therapy for chronic hepatitis C. J Hepatol 2001;34: Heathcote EJ, Shiffman ML, Cooksley GE, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000;343: Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000;343: Toccaceli F, Laghi V, Capurso L, et al. Long-term liver histology improvement in patients with chronic hepatitis C and sustained response to interferon. J Viral Hepat 2003;10: Afdhal N, Freilich B, Levine R, et al. Colchicine Versus Peg-Intron Long Term (COPILOT) trial: interim analysis of clinical outcomes at year 2. Hepatology 2004;40(Suppl 1):239A. 13. Rincon D, Banaras R, Ripoll C, et al. Antiviral therapy decreases hepatic venous pressure gradient in patients with chronic hepatitis C and fibrosis stage 3 or 4. Hepatology 2004;40(Suppl 1):248A. 14. Bellentani S, Tribelli C, Saccoccio G, et al. Prevalence of chronic liver disease in the general population of northern Italy: the Dionysos study. Hepatology 1994;20: Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferonalpha2a and ribavirin combination therapy in chronic hepatitis C: a randomised study of treatment duration and ribavirin dose. Ann Intern Med 2004;140: Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22: Goodman ZD, Ishak KG. Histopathology of hepatitis C virus infection. Semin Liver Dis 1995;15: Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341: Feu F, Garcia-Pagan JC, Bosch J, et al. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Lancet 1995; 346: Jensen DM. Endoscopic screening for varices in cirrhosis: findings, implications, and outcomes. Gastroenterology 2002;122: Garcia-Tsao G, Rodriguez-Perez F, Blei AT, et al. Treatment with interferon reduces portal pressure in patients with chronic hepatitis C. A randomised, placebo-controlled trial. Gastroenterology 1996;10:A Valla DC, Chevallier M, Marcellin P, et al. Treatment of hepatitis C virus-related cirrhosis: a randomised controlled trial of interferon alfa-2b versus no treatment. Hepatology 1999;29: Picchiotti R, Mingazzini PL, Scucchi L, et al. Correlations between sinusoidal pressure and liver morphology in cirrhosis. J Hepatol 1994;20: van Leeuwen DJ, Sherlock S, Scheuer PJ, et al. Wedged hepatic venous pressure recording and venography for assessment of pre-cirrhotic and cirrhotic liver disease. Scand J Gastroenterol 1989;24: Shiratori Y, Ito Y, Yokosuka O, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med 2005;142: Address requests for reprints to: Dr Stuart Roberts, Department of Gastroenterology, The Alfred, Commercial Road, Melbourne, Australia s.roberts@alfred.org.au; fax: (61) A supply of study medication was provided by Roche Products, and a grant was provided to conduct trial monitoring and efficacy and safety data analysis (S.R.).