Hepatocellular carcinoma (HCC) is a common tumor seen

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2010;8: Antiviral Therapy Reduces Risk of Hepatocellular Carcinoma in Patients With Hepatitis C Virus Related Cirrhosis ASHWANI K. SINGAL,*, AMANPAL SINGH,*, SATHYA JAGANMOHAN,*, PRAVEEN GUTURU, RAJASEKHARA MUMMADI,*, YONG FANG KUO, and GAGAN K. SOOD*, *Department of Gastroenterology and Hepatology, Department of Internal Medicine, and Sealy Center of Aging, University of Texas Medical Branch, Galveston, Texas This article has an accompanying continuing medical education activity on page e21. Learning Objectives At the end of this activity, the learner should explain the risk for developing hepatocellular carcinoma in chronic hepatitis C, and identify the outcome of antiviral therapy that is most important in reducing the risk. See related article, Lok AS et al, on page 493 in Gastroenterology. BACKGROUND & AIMS: The effects of antiviral therapy on prevention of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related cirrhosis are unclear. We performed a systematic review and meta-analysis to assess HCC risk reduction in patients with HCV-related cirrhosis who have received antiviral therapy. METHODS: Twenty studies (4700 patients) were analyzed that compared untreated patients with those given interferon (IFN) alone or ribavirin. Risk ratios (RRs) determined effect size using a random effects model. RESULTS: Pooled data showed reduced HCC risk in the treatment group (RR, 0.43; 95% confidence interval [CI], ), although the data were heterogenous ( ). Meta-regression analysis showed that studies with follow-up durations of more than 5 years contributed to heterogeneity. Analysis of 14 studies (n 3310) reporting sustained virologic response (SVR) rates with antiviral treatment showed reduced HCC risk in patients with an SVR, compared with nonresponders (RR, 0.35; 95% CI, ); the maximum benefits were observed in patients treated with ribavirin-based regimens (RR, 0.25; 95% CI, ). Meta-analysis of 4 studies assessing the role of maintenance IFN in nonresponders did not show HCC risk reduction (RR, 0.58; 95% CI, ). No publication bias was detected by the Egger test analysis (P 0.1). CONCLUSIONS: The risk of HCC is reduced among patients with HCV who achieve an SVR with antiviral therapy. Maintenance therapy with IFN does not reduce HCC risk among patients who do not respond to initial therapy. View this article s video abstract at Hepatocellular carcinoma (HCC) is a common tumor seen worldwide with an increasing incidence in the United States. 1 3 Cirrhosis is the strongest risk factor for HCC with hepatitis C virus (HCV) being the most common etiology. 4 Development of HCC has been shown to predict mortality in cirrhotic patients because it hastens decompensation of the liver disease. 5 Further, the overall outcome of this tumor is dismal, with a median survival of only 8 months. 6 Currently, patients with HCV infection are treated using a combination of pegylated interferon (PEG-IFN) and ribavirin (RBV) with sustained virologic response (SVR) of 30% to 50% in HCV cirrhotic patients Patients unable to achieve SVR remain at risk for developing HCC. It has been shown that IFN reduces the inflammation and fibrosis in HCV cirrhotic patients even in the absence of virologic response. 11 Based on this observation, maintenance treatment with low-dose IFN has been evaluated in randomized controlled trials (RCTs) with conflicting data. 12,13 The effect of antiviral therapy in HCV cirrhotic patients on the development of HCC has been the subject of many studies. A randomized trial of 90 patients showed the benefit of IFN in reducing the risk of HCC in treated patients. 14 Since then, many studies have shown this benefit. Only 4 of these are RCTs14 17 whereas a majority are either non-randomized prospective or retrospective cohort studies Two independently published meta-analyses have shown that IFN prevents development of HCC in HCV cirrhotic patients. 41,42 However, the response was defined based on biochemical parameters and not the SVR. Moreover, all the included studies have used IFN as the sole treatment agent. 41,42 We performed this systematic review and meta-analysis with the objective to assess the efficacy of antiviral treatment in risk reduction of HCC in HCV-related cirrhosis in the following groups: (1) treatment-naive patients with HCV cirrhosis treated with either IFN or IFN and RBV, (2) patients who achieve SVR to initial antiviral therapy, and (3) nonresponders to initial antiviral therapy treated with low-dose maintenance IFN. Methods Identification and Selection of Studies Literature search. Two independent investigators (A.K.S. and G.K.S.) searched the electronic database literature (Medline, Cochrane reviews, and EMBASE, ISI Web of science) Abbreviations used in this paper: CI, confidence interval; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; MU, million units; PEG- IFN, pegylated interferon; RBV, ribavirin; RCT, randomized controlled trial; RR, risk ratio; SVR, sustained virologic response by the AGA Institute /10/$36.00 doi: /j.cgh

2 February 2010 HCC IN HCV-RELATED CIRRHOSIS 193 from 1991 to 2008 for all types of publications including abstracts. The search terms used were cirrhosis, hepatitis C, HCV, HCC, hepatocellular carcinoma, and interferon. Boolean logic was used to combine the words. In addition, a manual search was performed for cross-references from publications reviewed. Study selection. Criteria for study selection. Three independent reviewers (A.K.S., A.S., and G.K.S.) selected the studies to analyze the effect of antiviral therapy on HCC risk reduction in treatment-naive HCV cirrhotic patients using the following criteria: (1) study design: any design including RCT, retrospective, or open prospective; (2) study population: patients with HCV cirrhosis; studies that were reported on chronic hepatitis C patients but had separate data on cirrhotic patients also were included; (3) treatment: IFN alone or an RBV-based regimen for a minimum of 6 months; only studies with treatment-naive patients were included; (4) follow-up evaluation: minimum of 2 years; (5) definition of SVR: negative HCV RNA 6 months after stopping the treatment. Criteria used to assess the maintenance IFN in nonresponder HCV cirrhotic patients were as follows: (1) inclusion of subjects with failure to achieve SVR and (2) minimum of 2 years of treatment with low-dose IFN. Outcome measure. The outcome measure was the occurrence of HCC at the time of last follow-up evaluation. Assessment of study quality. Two independent reviewers (A.K.S. and G.K.S.) assessed the study quality. Any conflict between the reviewers was resolved by consensus. Studies were graded using the following 10 parameters: (1) randomized or not; (2) prospective or retrospective; (3) defined exclusions criteria; (4) similarity between treated and control groups; (5) defined treatment intervention; (6) follow-up period of more than 5 years; (7) diagnosis of HCC using standard criteria as defined by the American Association for Study of Liver Diseases; 43 (8) defined treatment response; (9) analysis of results based on intention-to-treat model; and (10) details of drop outs or deaths. Each parameter was given a numeric score of 1 with a maximum score of 10. Studies with a score of less than 5 were rated as poor quality and those with a score of 5 or more points were classified as good-quality studies. Data collection. Data were collected for studies as follows: (1) comparing antiviral treatment with controls or no treatment, (2) reporting the SVR data, and (3) maintenance IFN in nonresponders to initial antiviral therapy for study characteristics, patient demographics, sample size and patient characteristics, treatment details, duration of follow-up evaluation, and number of patients with HCC at the time of last follow-up evaluation. Data analysis and statistical methods. Data were entered into the software (Revman 5) adding one study at a time. The risk ratio (RR) was used as a measure of association. After adding data from all the studies, summary RRs with 95% confidence intervals (CIs) and Forrest plot graphs were obtained. Study heterogeneity was obtained to assess whether the treatment effect variation across the studies was significant ( 2 P.1) than one expected by chance. To take the effect of heterogeneity into consideration, the DerSimonian and Laird 44 random effects model was used for analysis. If there was significant heterogeneity among studies, metaregression was performed based on the origin of the study (Western vs Asian), design of the study (RCT vs observational), publication type (abstract vs original article), quality of studies (good quality vs poor quality), rate of HCC in controls ( 20% vs 20%), total dose of IFN ( 450 million units [MU] vs 450 MU), baseline features (similar vs different), treatment regimen (RBV-based vs IFN alone), and follow-up period ( 5 yvs 5 y). Comprehensive meta-analysis version 2.2 (Biostat, Englewood, NJ) was used for performing meta-regression. Publication bias was investigated through visual inspection of funnel plots as well as using the Egger test. Sensitivity analysis was performed after excluding studies with the highest and lowest RRs. Results Selection of Studies After initial screening, 83 relevant reports were selected pertaining to the effect of antiviral therapy on HCC development in HCV-related cirrhosis. After applying the inclusion criteria, only 32 studies were available to analyze the effect of antiviral therapy on the HCC risk reduction in HCV cirrhotic Figure 1. Literature search and study selection process.

3 Table 1. Characteristics of Studies on Antiviral Therapy and Risk Reduction of HCC in HCV Cirrhosis Study Design Sample size Males, % GT1 or 4% Mean age, y Regimen Median dose a Type of IFN Median follow-up period, mo b Studies comparing treated and untreated patients Mazella 18 P IFN alone 720 Alfa 2a, 2b, lymphoblastoid 32 5 Fattovich 10 R 329 NA NA 53 IFN alone 200 Alfa 60 4 Bruno 20 P IFN alone 432 Alfa 68 7 Benvegnu 21 P NA 57 IFN alone NA Serfaty 22 P IFN alone 396 Alfa 2a and 2b 40 7 HCC SG 23 R 491 NA NA NA IFN alone 276 Alfa 2a, 2b, lymphoblastoid 36 4 Imai 24 R NA NA IFN alone 480 Alfa 2a 48 4 Sofia 25c R NA 57 IFN alone 585 NA 43 4 Valla 15 RCT IFN alone 432 Alfa 2b 37 7 Yoshida 26d R 337 NA NA 50 IFN alone 480 Alfa and/or 51 5 Mura 16c RCT 57 NA NA NA IFN alone NA 76 6 Okanoue 27d R NA 57 IFN alone Alfa 67 4 Shioda 28c,d R 646 NA NA NA IFN alone Alfa 2a/2b, 54 4 Nishiguchi 45 RCT IFN alone 432 Alfa Gramaenzi 29 P NA 58 IFN alone 741 Alfa 58 4 Ikeda 30 R IFN alone 600 Alfa, 90 5 Testino 31 R IFN alone 432 NA 96 3 Azzarolli 17d RCT RBV based 1052 Alfa 2b 60 8 Shiratori 32d P IFN alone Alfa 2a 80 7 Yu 33d R RBV based Alfa 62 7 Studies comparing SVR and nonresponders Nishiguchi 14 RCT IFN alone 432 Alfa Tanaka 34 P NA 49 IFN alone Lymphoblastoid 42 5 Hung 35 P RBV based 300 Alfa 2b 37 7 Hasegawa 36 R IFN, RBV based e 399 Alfa,, PEG-IFN 1 Bruno 37 R IFN alone Alfa 96 7 Veldt 38 R IFN, RBV based 399 Alfa IFN, PEG-IFN 25 4 Braks 39 R RBV based NA Alfa IFN, PEG-IFN 92 6 Floreani 40 R RBV based mcg PEG-IFN 24 3 Studies on maintenance IFN in nonresponders to initial antiviral therapy Afdhal CO-PILOT 49 RCT IFN alone 52 PEG-IFN 24 8 Fartoux 13f RCT IFN alone 936 Alfa 2a 24 8 Erhardt 50c RCT 88 NA NA NA IFN alone PEG-IFN Di Bisceglie HALT-C 12f RCT IFN alone PEG-IFN 42 9 NOTE. Whenever the 2 groups were not similar, data for males and genotype 1 or 4% are recorded for the treatment group. GT, genotype; HCCSG, hepatocellular carcinoma study group; R, retrospective; P, prospective; NA, not available; COPILOT, Colchicine versus PEGINTRON Long Term; HALT-C, Hepatitis C Antiviral Long-term Treatment Against Cirrhosis. a Median dose in MU for IFN and in micrograms for PEG-IFN. b If the 2 groups were not similar, the longest follow-up duration was recorded. c Studies reported in abstract form. d Studies also reporting SVR data and included in SVR versus NSVR analysis. e Only 10 patients were treated with RBV-based regimen and separate data for these patients were not available. f Studies on maintenance IFN. Control group was treated with colchicine in the study by Afdhal et al. 49 Study quality 194 SINGAL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 8, No. 2

4 February 2010 HCC IN HCV-RELATED CIRRHOSIS 195 Figure 2. Forrest plot for HCC development in patients with HCV cirrhosis: comparison of treated patients with antiviral therapy (IFN or IFN and RBV) and untreated patients. patients (Figure 1). Careful search methodology was used to avoid duplicate data and overlapping of cases. Of these, 20 studies (n 4700) assessed the risk reduction of HCC in patients treated with antiviral therapy (n 2691) compared with untreated (n 2009) patients. Fourteen studies (n 2778) reported data on HCC occurrence based on the SVR (Figure 1). Four studies met the inclusion criteria for studies analyzing the effect of maintenance IFN in HCV cirrhotic nonresponders to initial antiviral therapy. Features of Studies Nine studies were RCTs, 15 were retrospective, and 8 were prospective (Table 1). Four were published as abstracts and 28 were published as original articles. Nineteen studies were published from Western countries, mostly from Europe, and 13 studies were published from Asia, mostly Japan. Duplicate studies from 2 investigators were included because they reported data on treated versus untreated patients in one report 20,45 and the data of HCC based on SVR in the other report. 14,46 Sample size varied from 52 to 920, with mean age varying from 47 to 58 years. The male population varied from 47% 29 to 80%. 21 RBVbased regimens were used in 6 studies, 17,33,35,39,40 whereas IFN alone was used in the other studies. Other treatment variations were type, regimen, and duration of IFN. Total calculated median dose of IFN varied from 276 to 2376 MU. Diagnosis of HCC on follow-up evaluation was made as per the American Association for Study of Liver Diseases guidelines in only 20 studies. The median follow-up duration after the completion of IFN treatment varied from 2 to 15 years. Overall, 20 studies were rated as good quality (score, 5) whereas 12 studies were rated as poor quality based on our quality scoring discussed in the Methods section. Quantitative Analysis Antiviral treatment (interferon or interferon and ribavirin) and risk of hepatocellular carcinoma: treated versus untreated. Pooled data from 20 studies on the risk of HCC among patients receiving antiviral therapy compared with untreated patients showed an RR of 0.43 (95% CI, ; P ) in favor of antiviral therapy but with significant heterogeneity (Figure 2). The sensitivity analyses after excluding the studies with highest and lowest RRs again showed heterogeneity ( ; P.00001). Meta-regression models were fitted to identify variables that could explain lack of homogeneity. All the independent vari- Table 2. Meta-Regression on 17 Studies Published as Articles on Patients With HCV Cirrhosis Comparing Untreated and Patients Treated With Antiviral Therapy Variable Coefficient Standard error P RCT design Western origin Good quality Male population, 60% Follow-up period, 5 y HCC, 20% in control group Median weekly IFN, 450 MU

5 196 SINGAL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 8, No. 2 Figure 3. Forrest plot for HCC development in patients with HCV cirrhosis: comparison of SVR and nonresponders (NSVR) after antiviral therapy (IFN or IFN and RBV). ables mentioned in the Methods section were studied with effect of IFN on HCC as a dependent variable (Table 2). Covariates explaining heterogeneity were type of publication (P.0002) and follow-up duration of more than 5 years (P.0008). After excluding 3 abstract publications, meta-regression analysis showed that studies with a follow-up duration of more than 5 years contributed to heterogeneity (P.03). Antiviral treatment (interferon or interferon plus ribavirin) and risk of hepatocellular carcinoma: sustained virologic response versus nonsustained virologic response. Fourteen studies reported data on HCC development based on SVR. Of these, 9 were retrospective, 35 37,39,40,47,48 3 were prospective, 32,34,35 and 2 were RCTs. 14,17 There was a significant reduction in the occurrence of HCC favoring SVR over nonresponders (RR, 0.35; 95% CI, ; P.00001) (Figure 3). There was no heterogeneity among these studies ( ; P.80). Subgroup analysis of 5 studies on 485 patients using RBV-based regimens (IFN-alfa in 2 studies, PEG-IFN in 2 studies, and both in 1 study) showed the most pronounced efficacy in HCC risk reduction (RR, 0.25; 95% CI, ; P.00001) in favor of SVR compared with nonresponders. The data were homogeneous ( ; P.64). To evaluate the effect of antiviral therapy on the risk of HCC reduction in nonresponders, we compared this group with untreated patients among 7 studies for which data were available. The pooled effect for HCC occurrence was still in favor of antiviral therapy (RR, 0.37; 95% CI, ). However, the data were heterogeneous ( ; P.00001). Maintenance interferon and risk of hepatocellular carcinoma: treated versus untreated. Four RCTs assessing maintenance IFN in 1152 nonresponders to initial antiviral therapy were analyzed separately. 12,13,49,50 Follow-up evaluation among these studies varied from 5 to 12 years, except one study that followed up patients for a mean period of 17 months. 50 Pooled data from these 4 studies comparing maintenance IFN with no treatment (n 825) did not show any risk reduction in occurrence of HCC (RR, 0.58; 95% CI, ), without any heterogeneity in the data ( ; P.28) (Figure 4). Discussion We first compared patients treated with antiviral therapy (IFN alone or RBV-based regimen) and untreated patients. The pooled data showed an overall risk reduction of HCC with antiviral therapy. Similar results were reported in 2 previous meta-analyses. 41,42 We tried to improve the results by including studies reported in the past 8 years since these meta-analysis were published. However, our analysis also was limited by the availability of only 4 RCTs and significant heterogeneity among studies. Meta-regression analysis showed that studies with a follow-up duration of more than 5 years contributed to the heterogeneity. Incidence of HCC increases with disease duration especially when the virus continues to persist. 51 Moreover, even biochemical response with normalization of liver enzyme levels in patients with persistent viremia may not be durable. These factors may explain heterogeneity in the pooled data by studies with longer follow-up evaluation. Differences between treated and untreated patients could be related to differences in the SVR rate among various studies. Achievement of SVR with antiviral treatment is considered the best marker for HCV eradication. 8 Currently, SVR is defined as negative HCV RNA 6 months after discontinuation of antiviral therapy. Previous meta-analysis included studies defining response based on biochemical parameters. We only included studies defining response based on SVR. Pooled data from 14 such studies showed the most obvious benefit of antiviral ther-

6 February 2010 HCC IN HCV-RELATED CIRRHOSIS 197 Figure 4. Forrest plot for HCC development in patients with HCV cirrhosis who did not respond to initial antiviral therapy (IFN or IFN and RBV): comparison of maintenance IFN and controls or no treatment. apy in HCC risk reduction in favor of SVR with homogeneous data. This observation has been reaffirmed in a recently reported prospective study on a large cohort of HCV cirrhotic patients followed up for a long period. 5 Five of the 6 studies looking at the risk of HCC in responders after treatment with RBV-based regimens reported data on occurrence of HCC based on SVR. Subgroup analysis of these 5 studies (n 485) showed the maximum benefit in terms of HCC risk reduction in favor of SVR on treatment with RBV-based regimens (RR, 0.25; 95% CI, ; P.00001). Overall SVR in the pooled data from 14 studies was 27%, which was higher with RBV-based regimens compared with IFN alone (48% vs 24%). These are comparable with SVR of 30% with IFN and 50% with RBV-based regimens in compensated HCV cirrhotic patients. 9,10 What is concerning is that about 5% of patients achieving SVR are still at risk for HCC development on long-term follow-up evaluation. Persistent low-level viremia undetectable by available commercial polymerase chain reaction assay may explain HCC risk in these patients. 52 Therefore, it is crucial that patients should continue with regular surveillance for HCC, even after achieving SVR. The main concern is the risk of HCC in nonresponders to initial antiviral therapy. In this pooled analysis, HCC occurred in about 16% of nonresponders treated with antiviral therapy. There is evidence that IFN leads to histologic improvement even in nonresponders. 11 This prompted assessment of maintenance IFN using a low dose of 90 mcg PEG-IFN for a prolonged period. Pooled homogenous data ( ; P.28) from these 4 studies 12,13,49,50 on 1152 patients did not show any therapeutic benefit. Two of these studies have a large sample size, with 534 patients in the Colchicine Versus PEG-Intron Long Term study, 49 and 428 in the Hepatitis C Antiviral Longterm Treatment Against Cirrhosis study. 12 Lack of benefit with maintenance IFN in nonresponders is in contrast to some benefit observed in our current meta-analysis in nonresponders. This may be related to the fact that IFN delays the development of HCC but does not prevent it in the presence of persistent viremia and cirrhosis. This becomes more evident with longer follow-up duration. One of the 4 studies 50 in which IFN showed benefit had a mean follow-up period of only 17 months, but in the studies with longer follow-up evaluation the beneficial effect of IFN was not seen. Moreover, maintenance IFN uses only a 90-mcg dose, without RBV being part of the regimen. In conclusion, antiviral treatment with IFN alone or in combination with RBV reduces the development of HCC in HCV cirrhotic patients with achievement of SVR. However, these patients should continue to undergo surveillance for HCC detection. Among patients with HCV cirrhosis who do not achieve SVR with antiviral therapy, maintenance IFN therapy does not reduce the risk of HCC. Supplementary data To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at and at doi: / j.cgh References 1. Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Semin Liver Dis 1999;19: el-serag HB. Epidemiology of hepatocellular carcinoma. Clin Liver Dis 2001;5:87 107, vi. 3. Davila JA, Morgan RO, Shaib Y, et al. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a populationbased study. Gastroenterology 2004;127: Tsukuma H, Hiyama T, Tanaka S, et al. 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8 February 2010 HCC IN HCV-RELATED CIRRHOSIS 199 lular carcinoma after interferon therapy. Clin Gastroenterol Hepatol 2005;3:S89 S Veldt BJ, Poterucha JJ, Watt KD, et al. Impact of pegylated interferon and ribavirin treatment on graft survival in liver transplant patients with recurrent hepatitis C infection. Am J Transplant 2008;8: Afdhal NFB, Levine R, Black M, et al. Colchicine versus PEG- INTRON long term (COPILOT) trial: interim analysis of clinical outcomes at year 2. Hepatology 2004;40:239A. 50. Erhardt AH-PU, Boecher W, Wedemeyer H, et al. Long-term treatment with PEG-IFN-alfa 2b reduces hepatocellular incidence and prevents clinical complications in hepatitis C cirrhosis an interim analysis of a multicenter trial. J Hepatol 2007;46:S Fattovich G, Stroffolini T, Zagni I, et al. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127:S35 S Gerotto M, Dal Pero F, Bortoletto G, et al. Hepatitis C minimal residual viremia (MRV) detected by TMA at the end of Peg-IFN plus ribavirin therapy predicts post-treatment relapse. J Hepatol 2006;44: Reprint requests Address requests for reprints to: Gagan K. Sood, MD, Baylor College of Medicine, 1709 Dryden, Suite 1500, Houston, Texas gksood@bcm.edu; fax: (713) Conflicts of interest The authors disclose no conflicts.