Antiviral Therapy 11: Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 2

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1 Antiviral Therapy 11: A sustained virological response to interferon or interferon/ribavirin reduces hepatocellular carcinoma and improves survival in chronic hepatitis C: a nationwide, multicentre study in Taiwan Ming-Lung Yu 1,2, Shi-Ming Lin 3, Wan-Long Chuang 1,4, Chia-Yen Dai 2,4,5, Jing-Houng Wang 6, Sheng-Nan Lu 6, I-Shyan Sheen 3, Wen-Yu Chang 1,2, Chuan-Mo Lee 6 * and Yun-Fan Liaw 3 1 Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 2 Hepatobiliary Division, Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Liver Research Unit, Chang Gung University and Chang Gung Memorial Hospital, Taipei, Taiwan 4 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Department of Occupational Medicine, Kaohsiung Municipal Hsiaokang Hospital, Kaohsiung, Taiwan 6 Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan *Corresponding author: Tel: ; Fax: ; chmolee@ms15.hinet.net Data from the present study were presented in part at the 56th Annual Meeting of the American Association for the Study of Liver Diseases, November 2005, San Francisco, CA, USA. Abstract 962. Background: The long-term benefit for chronic hepatitis C (CHC) patients treated with interferon (IFN)/ribavirin (RBV) combination therapy remains unclear. We aimed to evaluate the long-term effects of IFN monotherapy and IFN/RBV combination therapy on reducing hepatocellular carcinoma (HCC) and mortality in patients with chronic hepatitis C virus (HCV) infection, adjusting for risk factors. Methods: A total of 1,619 patients with biopsy-proven CHC, including 1,057 receiving IFN-based therapy (760 on IFN/RBV combination therapy) and 562 untreated controls from three medical centres and one regional core hospital in Taiwan were enrolled in this retrospectiveprospective cohort study. Results: The incidence of HCC and survival during a followup period of (mean 5.18) and 1 16 (mean 5.15) years in treated and untreated patients, respectively, was analysed using Cox proportional hazards regression. The cumulative incidence of HCC was 35.2% and 12.2% for untreated and treated groups, respectively (P=0.0013). The cumulative survival rate was 93.1% and 96.2% for untreated and treated groups, respectively (P=0.3928). Significantly lower incidences of HCC and mortality were observed in sustained virological responders (both for IFN monotherapy and IFN/RBV combination) but not in nonresponders when compared with untreated patients. HCV genotype 1 patients had significantly higher incidences of HCC than genotype non-1 patients. In multivariate analysis, pre-existing cirrhosis, non-response, HCV genotype-1 and age were associated with HCC; pre-existing cirrhosis and non-response correlated to mortality. Conclusion: A sustained virological response secondary to IFN monotherapy or IFN/RBV combination therapy could reduce the risk for HCC and improve survival of CHC patients. Introduction Hepatitis C virus (HCV) infection frequently causes chronic liver disease leading to cirrhosis and hepatocellular carcinoma (HCC) and has become the main indication for liver transplantation [1 3]. Interferon (IFN) monotherapy has been used in the treatment of chronic hepatitis C (CHC) for viral clearance. Other beneficial effects, including prevention of HCC development and better survival, have been reported in several studies [4 11] but not in another study with a population of cirrhotic patients [12]. The inconsistencies in the latter study may have arisen from relatively small sample sizes, insufficient follow-up periods, low sustained virological response (SVR) rates to IFN monotherapy, and use of a universally predominant HCV genotype 1b population, which is more resistant to IFN. Therapy with a combination of IFN and ribavirin (RBV) has much improved treatment efficacy and is the recommended treatment for CHC patients [13,14] International Medical Press

2 M-L Yu et al. However, data on the long-term benefit for subjects treated with IFN/RBV are still not available [15]. To address this issue, a nationwide multicentre program supported by the Taiwan Department of Health was started in This large-scale, retrospective-prospective cohort study evaluated the long-term effects of IFN monotherapy and IFN/RBV combination therapy on reducing the development of HCC and liver-related death in Taiwan. In our study, approximately half the subjects were HCV genotype non-1, as observed in previous HCV molecular epidemiology studies in Taiwan [16]. Considering the reported role of HCV genotype in the treatment response and disease progression of CHC [1,16 18], HCV genotype data were also included in the analysis. Materials and methods Patients The study was approved on 1 August 2001 by three medical centres and one regional core hospital in Taiwan. All patients were seropositive for HCV antibodies (anti-hcv) and HCV RNA and had biopsyproven chronic hepatitis with or without cirrhosis. Patients with concurrent hepatitis B (seropositive for hepatitis B surface antigen) or HIV, autoimmune hepatitis, alcohol abuse ( 80 g ethanol per day), or evidence of HCC were excluded. In addition, patients with evidence of HCC presenting within 6 months after pretreatment liver biopsy or after initiation of IFNbased therapy were excluded. Observation began exactly 1 year after liver biopsy. For treated patients, only those who had histological data available during the enrollment period, had received IFN at least 3 MU three times weekly for at least 20 weeks with and without RBV combination therapy, and had regular follow-ups for at least 6 months after end-of-treatment were included in the present study. IFN-based therapy was initiated within 6 months after liver biopsy. The enrollment period of the treatment group ranged from 1991 to A total of 1,065 consecutive patients who fulfilled all of the criteria during the enrollment period were selected as the treated group. A group of eight patients who developed HCC within 6 months after initiation of IFN-based therapy were excluded. The remaining 1,057 patients received 3 6 MU of IFN-α three times weekly for weeks with (n=760, 71.9%; weeks, n=724; 48 weeks, n=36) or without (n=297, 28.1%; weeks, n=229; 48 weeks, n=68) 800 1,200 mg/day of RBV (Figure 1). For untreated patients, only those who had histological data available during the enrollment period and had received regular follow-up for at least 1 year after liver biopsy were included in the present study. The enrollment period of the control group ranged from 1985 to A total of 565 consecutive patients who fulfilled the inclusion criteria were selected without the knowledge of their final outcome as untreated controls. Three patients who developed HCC within 6 months after pretreatment liver biopsy were excluded. We advised all patients, whether they were receiving antiviral therapy or not, not to drink alcohol except for infrequent social occasions. Patients who drank more than 80 g/day of alcohol during the followup period were excluded. The present study was conducted before reimbursement of HCV treatment by the Bureau of National Health Insurance in Taiwan. Treatment or no treatment was a patient choice. Follow-up and assessment All patients were followed every 3 to 6 months or more frequently as required for at least 1 year. The follow-up was retrospective before 1 August 2001, and prospective thereafter. The period of follow-up of each treated patient was counted at the time of last visit or the starting date of subsequent retreatment with IFN-based therapy before the time of analysis, 1 June The period of follow-up of each untreated patient was counted at the time of last visit before the time of analysis. No untreated patients received subsequent IFN-based therapy before their last visit. The outcomes of patients were determined based on the occurrence of hepatic complications or not at the last visit before the time of analysis in both cohorts. Search for death registry was not performed for patients lost to followup. Follow-up studies included conventional biochemical tests and HCC screening using serum α-fetoprotein and ultrasonography [19]. The treated and untreated patients were followed with the same number of visits and intervals between visits. Detection of serum HCV RNA was performed using either a nested reverse transcription (RT)-PCR assay with 5 -non-coding region-specific primers in the early and middle 1990s [20] or a standardized automated qualitative RT-PCR assay thereafter (Cobas Amplicor Hepatitis C Virus Test, version 2.0; Roche, Branchburg, NJ, USA). HCV genotypes were determined by RT-PCR/line probe assay (Inno-LIPA; Innogenetics NV, Ghent, Belgium) or by amplification of the core region using genotype-specific primers [21]. The biochemical tests were performed using a standard autoanalyser. The α-fetoprotein was assayed using a commercially available radioimmunoassay kit and an anti-hcv second-generation enzyme immunoassay kit (Abbott Laboratories, North Chicago, IL, USA). A sustained virological responder was defined as a patient showing clearance of HCV RNA by the end of treatment and 6 months after the end of treatment. The others, including relapsed responders and null respon International Medical Press

3 An SVR by IFN/ribavirin reduces HCC and mortality for HCV Figure 1. Flow diagram of the trial IFN-based treated group n=1,065 Untreated group n=565 Exclusion: HCC within 6 months after initiation of IFN-based therapy, n=8 Exclusion: HCC within 6 months after liver biopsy, n=3 Patients enrolled, n=1,057 Patients enrolled n=562 IFN monotherapy (n=297) Intervention: IFN-α 3 6 MU three times weekly for weeks with a follow-up period of at least 1 year. IFN/RBV combination therapy (n=760) Intervention: IFN-α 3 6 MU thrice weekly plus RBV for 800 1,200 mg daily for weeks with a follow-up period of at least 1 year. SVR (n=169) Non-SVR (n=128) SVR (n=546) Non-SVR (n=214) Mean follow-up, 8.09 years Mean follow-up, 4.04 years Mean follow-up, 5.18 years Mean follow-up, 5.15 years IFN monotherapy HCC, n=19 SVR: 4 Non-SVR: 15 Mortality, n=6 SVR: 2 Non-SVR: 4 IFN/ribavirin combination therapy HCC, n=32 SVR: 8 Non-SVR: 24 Mortality, n=10 SVR: 8 Non-SVR: 2 IFN-based treated group, n=1,057 HCC, n=51 (SVR: 12; Non-SVR: 39) Mortality, n=16 (SVR: 10; Non-SVR: 6) Untreated group, n=562 HCC, n=54 Mortality, n=12 HCC, hepatocellular carcinoma; IFN, interferon; RBV, ribavirin; SVR, sustained virological responders. Antiviral Therapy 11:8 987

4 M-L Yu et al. ders, were classified as non-sustained responders. HCC was diagnosed either histologically or by revealing a tumour using coeliac angiography, ultrasound and/or other diagnostic imaging method(s), given an α-fetoprotein level above 400 ng/ml [19]. Statistical analysis The outcomes of patients were determined according to the status of last visit before the time of analysis. Data are presented as means ± standard deviation. Student s t-test, chi-square test and Fisher s exact test were used to compare the values of the variables associated with the groups. Multiple comparisons were made when three or more groups or subgroups were involved. Cumulative incidence curves were determined using the Kaplan Meier method, and the differences between groups were assessed with the log-rank test. We used the Cox proportional hazards regression analysis to examine the factors associated with the incidence of HCC and mortality. The risk ratio attributable to regimens of IFNbased therapy was calculated using dummy variables (IFN monotherapy versus untreated; IFN/RBV combination therapy versus untreated). The risk ratio attributable to responses to IFN-based therapy was also calculated using dummy variables (SVR versus untreated; non-svr versus untreated). Because SVR and IFN-based regimens were mutually dependent when compared with the untreated controls, the risk ratio for HCC and mortality was calculated separately for these factors. The analyses were performed using the SPSS 12.0 statistical package (SPSS, Inc., Chicago, IL, USA). A P-value below 0.05 was considered to be statistically significant. Role of the funding source None of the funding sources had any involvement in study design, collection, analysis, interpretation of data, writing of the report, or in the decision to submit the paper for publication. Results Patient characteristics The baseline characteristics of patients at enrollment are summarized in Table 1. The groups had comparable pretreatment levels of alanine aminotransferase and distribution of sex and HCV genotype. The untreated group was younger than the treated group. The treated group, mainly in the IFN/RBV combination group, had a higher rate of pre-existing cirrhosis than the untreated group. The mean follow-up period was comparable in the untreated and treated groups (5.15 and 5.18 years, respectively). The mean follow-up period for patients with IFN monotherapy and for those with IFN/RBV combination therapy was 8.09 and 4.02 years, respectively. The IFN/RBV combination therapy had a higher rate of HCV type 1 infection. Response to IFN-based therapy Among the treated group, 715 patients (67.6%) were sustained responders. They included 169 of 297 (56.9%) patients who received IFN monotherapy and 546 of 760 (71.8%) who received IFN/RBV combination therapy, including 23 of 63 patients who received a second course of antiviral therapy. A total of 451 (78.6%) HCV genotype non-1 and 264 (54.7%) HCV genotype 1 patients were sustained responders. Stepwise Table 1. Demographic and clinical characteristics and follow-up periods IFN-based treated patients Characteristic Untreated patients All IFN monotherapy IFN/RBV Patients, n Age, year, mean ±SD* 43.6 ± ± ± ±11.5 Sex, n (%) Male 347 (61.7) 639 (60.5) 172 (57.9) 467 (61.4) Female 215 (38.3) 418 (39.5) 125 (42.1) 293 (38.6) ALT level, IU/l, mean ±SD ± ± ± ±122.3 Pre-existing cirrhosis, n (%) No 494 (87.9) 892 (84.4) 264 (88.9) 628 (82.6) Yes 68 (12.1) 165 (15.6) 33 (11.1) 132 (17.4) HCV genotype, n (%) Type (45.4) 483 (45.7) 119 (40.1) 364 (47.9) Type non (54.6) 574 (54.3) 178 (59.9) 396 (52.1) Follow-up period, year, mean ±SD 5.15 ± ± ± ±2.20 *Untreated versus interferon (IFN)-based treated, IFN monotherapy and ribavirin (RBV) combination therapy, all P< Untreated versus IFN-based treated, P=0.063 (versus IFN monotherapy, P=0.739; IFN/RBV combination therapy, P=0.008). Consists of genotypes 2a, 2b mixed and unclassified genotypes infection. IFN monotherapy versus IFN/RBV combination therapy, P= Untreated versus IFN-based treated, P=0.89 (versus IFN monotherapy, P<0.001; IFN/RBV combination therapy, P<0.001). IFN monotherapy versus IFN/RBV combination therapy, P< ALT, alanine aminotransferase; HCV, hepatitis C virus; SD, standard deviation International Medical Press

5 An SVR by IFN/ribavirin reduces HCC and mortality for HCV multivariate logistical regression analysis showed that HCV genotype 1 (versus non-1), IFN/RBV combination therapy (versus IFN monotherapy), pre-existing cirrhosis (versus non-cirrhosis) and age were significant factors associated with SVR with odds ratios (95% confidence interval) of ( ), ( ), ( ) and ( ), respectively. Development of HCC HCC was detected in 54 untreated patients (41 by cytohistopathology and 13 by image combined with α- fetoprotein levels) and in 51 patients (41 by cytohistopathology and 10 by image combined with α-fetoprotein levels) who received IFN-based treatment, including 39 non-responders and 12 sustained responders. The annual incidences of HCC among patient groups are listed in Table 2. The cumulative incidence of HCC was significantly lower in patients who received IFN-based treatment (12.2%) than in untreated patients (35.2%, P=0.0013, Figure 2A). Further analysis by SVR showed that the cumulative incidence of HCC was significantly lower in sustained responders (3.0%) than in non-responders (36.0%, Table 2. Annual incidence of HCC IFN-based treated patients, % (n, N) Annual Untreated incidence patients, IFN monotherapy IFN/RBV combination therapy of HCC % (n, N) All Non-SVR SVR Non-SVR SVR Non-SVR SVR Pre-existing LC ( ) 1.42 (35, 494) 0.32 (15, 892) 0.85 (12, 262) 0.09 (3, 630) 0.92 (7, 108) 0.07 (1, 156) 0.78 (5, 154) 0.11 (2, 474) Pre-existing LC (+) 5.62 (19, 68) 5.27 (36, 165) 7.82 (27, 80) 2.67 (9, 85) 6.54 (8, 20) 3.59 (3, 13) 8.52 (19, 60) 2.36 (6, 72) All 1.92 (54, 562) 0.95 (51, 1057) 2.22 (39, 342) 0.33 (12, 715) 1.69 (15, 128) 0.27 (4, 169) 2.76 (24, 214) 0.37 (8, 546) Incidence calculated using the person-years method. HCC, hepatocellular carcinoma; IFN, interferon; LC, liver cirrhosis; RBV, ribavirin; SVR, sustained virological responders. Figure 2. Cumulative incidence of hepatocellular carcinoma among chronic hepatitis C patients A B Cumulative incidence 0.4 Untreated patients, n= P= IFN-based treated patients, n=1, Follow-up, years Cumulative incidence Non-responders, n=342 P=0.18 Untreated patients, n=562 P< P< Sustained responders, n= Follow-up, years Untreated patients With HCC At risk IFN-based treated patients With HCC At risk Non-sustained responders With HCC At risk Sustained responders With HCC At risk (A) Incidence was 12.2% in patients who received interferon (IFN)-based treatment (solid line with ticks) and 35.2% in untreated patients (solid line with squares); P= (B) Incidence was 3.0% in sustained responders (solid line with ticks), 36.0% in non-responders (dashed line with ticks) and 35.2% in untreated patients (solid line with squares). Sustained responders versus non-responders, P<0.0001; sustained responders versus untreated patients, P<0.0001; non-responders versus untreated patients, P=0.18. All P-values were obtained using the log-rank test. Antiviral Therapy 11:8 989

6 M-L Yu et al. P=0.0007) and untreated patients (P<0.0001, Figure 2B). The cumulative incidence of HCC did not differ between non-responders and untreated patients. Multivariate analysis showed that absence of preexisting cirrhosis, achievement of an SVR, HCV genotype non-1 and younger age were independent negative factors for HCC development (Table 3). There was no difference in HCC development between IFN monotherapy and IFN/RBV combination therapy. Patient survival A total of 28 patients died during the follow-up period: 12 patients (2.1%) from the untreated group and 16 (1.5%) from the IFN-based treatment group, including 12 non-responders (3.5%) and four (0.6%) sustained responders (Table 4). Ten of the untreated patients died of liver-related diseases: six of HCC, three of liver failure and one of varix rupture. Of the two remaining untreated patients, one died of chronic obstructive pulmonary disease and one of an unknown cause. Fourteen of the patients who received IFN-based treatment died of liver-related diseases: 12 of HCC and two of liver failure. Of the two remaining treated patients, one died of cholangiocarcinoma and one of cerebral haemorrhage. The rate of death from liver-related disease was significantly lower in sustained responders (n=3, 0.4%) than in non-responders (n=11, 3.2%, P=0.022) and in untreated patients (n=10, 1.8%, Table 3. Risk factors for HCC and death Risk factor Risk ratio (95% confidence interval) P-value HCC Baseline liver histology Non-cirrhosis 1 Cirrhosis ( ) < Response to IFN-based therapy Untreated control 1 SVR ( ) < Non-SVR ( ) HCV genotype Genotype non-1 1 Genotype ( ) Age Increasing per every 1 year ( ) Death Baseline liver histology Non-cirrhosis 1 Cirrhosis ( ) < Response to IFN-based therapy Untreated control 1 SVR ( ) Non-SVR ( ) Risk ratios for development of hepatocellular carcinoma (HCC) and death were calculated using Cox proportional hazards regression analysis. Factors included age, sex, serum alanine aminotransferase, hepatitis C virus (HCV) type, interferon (IFN)-based treatment (IFN monotherapy or IFN/ribavirin combination therapy), and response to IFN-based therapy [sustained virological response (SVR) and non-svr]. Table 4. Causes of death Interferon-based treated patients Cause of death Untreated patients, n=562 All, n=1,057 Non-SVR, n=342 SVR, n=715 Patients who died, annual incidence of death, n (%) 12 (0.41) 16 (0.29) 12 (0.65) 4 (0.11) Liver-related deaths Overall, n (%) 10 (83.3) 14 (87.5) 11 (91.7) 3 (75.0) Hepatocellular carcinoma, n Liver failure, n Gastrointestinal bleeding, n Liver-unrelated deaths Overall, n (%) 2 (16.7) 2 (12.5) 1 (8.3) 1 (25.0) Cholangiocarcinoma, n Chronic obstructive pulmonary disease, n Cerebral haemorrhage, n Unknown, n Annual incidence of death was calculated using the person-years method. SVR, sustained virological responders International Medical Press

7 An SVR by IFN/ribavirin reduces HCC and mortality for HCV Figure 3. Cumulative survival among chronic hepatitis C patients A B 100 IFN-based treated patients, n=1, Sustained responders, n=715 Cumulative survival P= Untreated patients, n=562 Cumulative survival P= P= Untreated patients, n=562 P= Non-responders, n= Follow-up, years Follow-up, years Untreated patients Death At risk IFN-based treated patients Death At risk Non-sustained responders Death At risk Sustained responders Death At risk (A) Survival was 96.2% in patients who received interferon (IFN)-based treatment (solid line with ticks) and 93.1% in untreated patients (solid line with squares); P= (B) Survival was 99.0% in sustained responders (solid line with ticks), 91.1% in non-responders (dashed line with ticks) and 93.1% in untreated patients (solid line with squares). Sustained responders versus non-responders, P=0.0008; sustained responders versus untreated patients, P=0.0127; non-responders versus untreated patients, P= All P-values were obtained using the log-rank test. P<0.0001) but did not differ between non-responders and untreated patients (P=0.177). The annual incidences of deaths among patient groups are listed in Table 4. The cumulative survival rate did not differ between patients who received IFN-based treatment (96.2%) and untreated patients (93.1%, P=0.3928, Figure 3A). Further analysis by SVR showed that the cumulative survival rate was significantly higher in sustained responders (96.2%) than in non-responders (91.1%, P=0.0008) and untreated patients (93.1%, P=0.0127, Figure 3B). The cumulative survival did not differ between nonresponders and untreated patients. Multivariate analysis showed that pre-existing cirrhosis and failure to achieve an SVR were independent factors for patient death (Table 3). There was no difference in patient survival between IFN monotherapy and IFN/RBV combination therapy. Effect of IFN monotherapy and IFN/RBV combination therapy In Cox proportional hazards regression analysis, when IFN-based treatment and response to IFN-based therapy were taken into account, neither the IFN monotherapy nor the IFN/RBV combination therapy were associated with the development of HCC and patient death (Table 3). Only patients who achieved an SVR were associated with reduced risk of hepatic complications. Effect of HCV genotype HCV genotype 1 patients had significantly higher cumulative incidence of HCC (29.4%) than genotype non-1 patients (21.2%, P=0.0089, Figure 4). There was no difference of cumulative survival between HCV genotype 1 and non-1. Discussion The results of the present study show that an SVR secondary to IFN monotherapy or IFN/RBV combination therapy could reduce HCC development and increase the chance of survival. Several earlier studies also showed long-term beneficial effects in reducing HCC development and prolonging survival [4,5,7 10,22]. All of these earlier studies used IFN monotherapy. Recently, standard IFN or pegylated (peg)-ifn in combination with RBV have been recommended for treatment of CHC patients [23], but data on the long-term benefit of subjects treated with combination therapy are unavailable. Ideally, a randomized controlled trial in a large population would be the best way to elucidate the benefits. However, it would be unethical to withhold antiviral therapy from CHC patients. Studies of combination therapy have not used untreated control groups. Thus, definitive proof of the Antiviral Therapy 11:8 991

8 M-L Yu et al. Figure 4. Cumulative incidence of hepatocellular carcinoma among chronic hepatitis C patients, stratified by HCV genotype Cumulative inidence HCV genotype 1, n= Follow-up, years P= HCV genotype non-1, n= % in hepatitis C virus (HCV) genotype 1 patients (solid line) and 21.2% in HCV genotype non-1 patients (dashed line); P= All P-values were obtained using the log-rank test. effectiveness of combination therapy in preventing disease progression is unlikely to come from prospective controlled trials. Our results have confirmed the observation that HCV eradication has benefits on liver disease progression. Previous reports observed that both sustained responders and non-responders to IFN-based therapy had a reduced overall risk of HCC and prolonged survival in CHC patients [5,6,8,9]. However, our results showed that the reduction of HCC development and improvement of survival were observed only in patients achieving an SVR. Recent studies have disclosed that the benefits of preventing disease progression in CHC patients who did not respond to IFN did not exist in a longer observation period [7,10]; complications of liver disease due to persistent HCV infection continue to occur in non-responders. Subsequent improvements in therapy have resulted in improvements in the SVR rate by using IFN or peg-ifn combined with RBV [13,14,24,25]. However, more than one-third of patients are resistant to the recommended antiviral regimens [1,13,14,26]. The role of long-term maintenance HCV therapy should be explored in the IFN-resistant group [27 29]. Meta-analyses of standard IFN monotherapy trials in patients with HCV-related cirrhosis suggest that IFN has a small but significant effect on reducing HCC risk [12]. Another study indicated that the reduction in HCC is greatest if an SVR is achieved before cirrhosis develops [10]. This is because the SVR rate in patients receiving IFN monotherapy is quite low (6 13%), especially in patients with cirrhosis and HCV genotype 1 (the predominant genotype in most studies) [13]. Recent studies have shown that the improvement of SVR rate in cirrhotic patients and genotype 1 patients receiving IFN (or peg-ifn) with RBV combination therapy [13,14,25] may markedly increase the benefit in HCC prevention. Nevertheless, the annual incidence of HCC development in cirrhotic patients who achieved an SVR remained as high as 2.67% per person-year in our study. Therefore, we strongly recommend that patients with CHC be treated before the onset of cirrhosis. Our results show that both IFN monotherapy and IFN/RBV combination therapy could significantly reduce the complications of liver disease. However, the significance disappeared after response to antiviral treatment was taken into account (Table 3). The benefits were obtained mainly from successful antiviral treatment but were not related to the antiviral regimens. These findings support the concept that eradication of HCV, and not the antiviral regimen is the key in preventing disease progression. However, the magnitude of this preventative effect could increase through the significant improvement of the SVR rate by using a more effective regimen, such as IFN/RBV or peg- IFN/RBV combination therapy [13,14,26]. We did not find a difference in disease progression between IFN monotherapy and IFN/RBV combination therapy possibly because of: (i) insufficient follow-up time in the IFN/RBV combination group, and/or (ii) a proportion of non-responders in the IFN monotherapy group were not enrolled in the present study because they did not fulfill the inclusion criteria or they had no follow-up data 6 months after end-of-treatment. Although studies of cohorts in Japan did not find a relationship between risk for HCC and HCV genotype [7,9], our results are in agreement with previous cross-sectional studies, in that HCV genotype 1 is positively correlated to the development of HCC after controlling for other confounding factors [16,17]. HCV core and nonstructural region 5A proteins have been shown to interact with p53 and inhibit p53-mediated apoptosis, which may play a role in hepatocarcinogenesis of HCV infection [30]. Variations in these regions may contribute to the genotype-related difference in hepatocarcinogenesis. The current study included a large number of IFNbased treated patients and a well-matched distribution of gender, baseline ALT levels and HCV genotype between treated and untreated patients. However, there remain limitations in our study. First, this was not a randomized trial, which may bias the interpretation of the results. In our study, the treated group was older and had a higher proportion of cirrhotic patients than the untreated group did. Nevertheless, age and cirrhosis are two major risk factors for liver disease progression, regardless of antiviral treatment [1,8 10,15]. Thus, the effect of antiviral treatment in reducing complications International Medical Press

9 An SVR by IFN/ribavirin reduces HCC and mortality for HCV of liver disease would not be overestimated in the current study. Second, this is not a truly prospective study. Instead, patients who fulfilled the inclusion criteria of each group were enrolled consecutively, without the knowledge of their final outcome. A range of prospective follow-up periods were continued once patients were included. The follow-up rate did not differ between the two groups; thus, we believe that these biases were small. Third, the follow-up period of patients with IFN/RBV combination therapy ( years) was shorter than that of IFN monotherapy ( years). Comparison is possible only for the first 11 years of the post-treatment period. Whether the long-term outcome after 11 years in patients with IFN/RBV combination therapy is similar to that of IFN monotherapy needs further observation. In conclusion, the present study showed that an SVR secondary to IFN monotherapy or IFN/RBV combination therapy improves prognosis in terms of reduction of HCC development and prolongation of survival in patients with CHC. The benefits are obtained mainly through the achievement of successful viral eradication, whether with or without RBV combination therapy. The greater efficacy in treatment of CHC observed with the use of peg-ifn/rbv combination therapy [13,14,24] may increase the preventive effect on liver disease progression for CHC patients. Finally, there might be HCV genotype-specific differences in hepatocarcinogenesis. Acknowledgements The study was supported by grants from Department of Health, Taiwan (BHP90-HP-1004, BHP90-HP-1005, BPH90-HP-1007, H and DOH 92-HP-2508) and the Taiwan Liver Research Foundation. The authors thank Dr SC Chen, ZY Lin, MY Hsieh, LY Wang and CH Hung for their excellent assistance. References 1. Lauer GM, Walker BD. Hepatitis C virus infection. 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