Review Does antiviral therapy prevent hepatocellular carcinoma?

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1 Antiviral Therapy 2011; 16: (doi: /IMP1895) Review Does antiviral therapy prevent hepatocellular carcinoma? Hellan Kwon 1, Anna S Lok 1 * 1 Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA *Corresponding author aslok@umich.edu Chronic infection with HBV or HCV can lead to the development of hepatocellular carcinoma (HCC). The major risk factors for HBV-related HCC are persistent presence of hepatitis B e antigen (HBeAg) and/or high serum HBV DNA levels, and cirrhosis. The major risk factor for HCVrelated HCC is cirrhosis. One randomized double blind controlled trial of lamivudine in patients with HBeAg and/or high serum HBV DNA levels showed that antiviral therapy prevented disease progression and reduced the incidence of HCC. A beneficial effect of antiviral therapy on the risk of HCC has also been shown in cohort studies and meta-analyses, particularly among responders. Several randomized controlled trials of interferon in patients with HCV-related cirrhosis showed that treated patients had a lower incidence of HCC. A greater effect was observed in patients who achieved sustained virological response, while the benefit in non-responders is unclear. Antiviral therapies for hepatitis B and hepatitis C can prevent but not completely eliminate HCC. Improvement in identification of infected persons, accessibility of care and affordability of treatment is needed for antiviral therapy to have a major impact on the global incidence of HCC. Introduction Chronic HBV and chronic HCV infection are the most common causes of hepatocellular carcinoma (HCC), accounting for 43% of cases in developed countries and 93% of cases in developing countries [1]. Progression to HBV- and HCV-related HCC can be interrupted at several stages (Figure 1). The most effective method is to prevent the occurrence of HBV and HCV infection through avoidance of exposures or vaccination. HBV vaccine has been shown to be safe and highly effective in preventing HBV infection and in decreasing the incidence of HCC [2]. However, an effective vaccine to prevent HCV infection has yet to be developed. Acute HBV or HCV infection is often subclinical; therefore, intervention to prevent the progression to chronic infection is rarely feasible even if effective therapies are available. Once chronic HBV or HCV infection has been established, suppression or elimination of virus replication by antiviral therapy may decrease liver damage and prevent progression to cirrhosis and HCC. Methodological assessment The most robust evidence to support that antiviral therapy can prevent HCC would be a randomized controlled trial with HCC as the primary end point. Given the indolent course of chronic HBV and chronic HCV infection, this would require enrolment of a large number of patients who would be followed for many years and treatment would need to be withheld from the control group for the duration of the trial. Enrolment and retention of a large number of patients for a long duration of time, particularly those in the control group would not be practical or feasible. Furthermore, new treatments may become available and the standard of care may evolve with time. Studies focused on patients who are at high risk for HCC would reduce the sample size or the duration of follow-up required but increase the ethical dilemma and difficulties of enrolment and retention of study subjects. As a result of these challenges, evidence to support that antiviral therapy can prevent HCC has largely been based on cohort follow up studies or retrospective studies comparing a treatment group to an untreated control group that may not have the same risks of HCC. Additionally, meta-analyses to pool the data from published studies that individually are under-powered have been performed to determine whether antiviral therapy can prevent HCC. Surrogates for HCC Due to the difficulties in conducting studies with HCC as the primary end point, many studies have used virological, biochemical or histological end points as surrogates 2011 International Medical Press (print) (online) 787

2 H Kwon & AS Lok Figure 1. Strategies to prevent HCC in patients with chronic HBV or HCV infection HCV Acute hepatitis Chronic hepatitis Cirrhosis HCC HBV Vaccine Antiviral therapy Reproduced with permission [54]. HCC, hepatocellular carcinoma. for HCC. These end points were chosen because they had been shown to be predictive of the risk of HCC. The most important risk factors for the development of HCC in patients with chronic HBV infection are cirrhosis and high viral levels. Evidence to support the contribution of high HBV DNA levels to HCC development has been shown through prospective cohort studies. In one study, 3,653 participants in a community study in Taiwan were followed for 11.4 years (41,779 person-years follow up). During this period, 164 cases of HCC were observed. Participants with high serum HBV DNA levels had significantly higher incidence of HCC. The hazard ratio (HR) of HCC for those with baseline serum HBV DNA>6 log 10 copies/ ml was 10.7 (95% CI ) compared to those with baseline serum HBV DNA<4 log 10 copies/ml [3]. Analysis of data from this cohort also found that high serum HBV DNA was associated with increased risk of cirrhosis. The cumulative incidence of cirrhosis after a mean follow up of 11 years increased from 4.5% for participants with baseline HBV DNA<300 copies/ml to 36.2% for those with HBV DNA>1 million copies/ml [4]. Another prospective cohort study included 11,893 Taiwanese men followed for a mean of 8.5 years. Compared to subjects who were hepatitis B surface antigen (HBsAg)-negative, the relative risk of HCC was 9.6 for those who were HBsAg-positive and hepatitis B e antigen (HBeAg)-negative and 60.2 for subjects who were HBsAg-positive and HBeAg-positive [5]. A nested case-control study of 44 HCC cases and matched controls who were HBsAg-positive and HBeAg-negative at enrolment found that the adjusted odds ratio (OR) for HCC was 6.0 (95% CI ) for subjects with serum HBV DNA>13 pg/ml (~2 million copies/ ml) compared to those with undetectable HBV DNA (<2.5 pg/ml; ~400,000 copies/ml) at enrolment [5]. An association between high HBV DNA levels and the risk for HCC was also shown in a nested case-control study with 154 HCC cases and 316 controls. Subjects with baseline HBV DNA in the highest quintile ( log 10 copies/ml) had an adjusted OR for HCC of 7.26 (95% CI ; P<0.001) compared to those with the lowest quintile of HBV DNA levels [6]. Reversion from HBeAg-negative back to HBeAg-positive is also associated with an increased risk of HCC. A population-based cohort study of 1,536 native Alaskans with chronic HBV infection found that among those who cleared HBeAg, reversion to HBeAg positivity was associated with an increased risk of HCC with HR of 2.6 (95% CI ) after adjustment for potential confounders [7]. Elevated serum alanine aminotransferase (ALT) levels and cirrhosis have been associated with an increased risk of HBV- and HCV-related HCC, death from liver disease and liver-related complications [8 11]. Prospective follow-up of a cohort of 188 patients with chronic HBV infection found that 14 patients developed HCC during a mean follow-up of 80.6 months. Multivariate analysis showed that the OR for HCC development was 5.9 (95% CI ; P<0.01) for cirrhosis and 1.5 (95% CI ; P=0.05) for elevated baseline ALT [12]. The incidence of HCC in patients with HCV-cirrhosis has been estimated to be 3.7 per 100 person-years (95% CI ) based on studies in Europe and United States and 7.1 per 100 person-years (95% CI ) in studies in Japan. By contrast, in patients with chronic hepatitis C that has not progressed to cirrhosis, the incidence of HCC was zero per 100 personyears in one European study and estimated to be 1.8 per 100 person-years (95% CI ) based on studies in Japan [9]. Evidence to support that antiviral therapy can prevent HBV-HCC Interferon treatment Most of the studies supporting a benefit of interferon (IFN) in preventing HCC pertain to conventional IFN treatment. Pegylated IFN has replaced conventional IFN because of the higher rate of response and the convenience of once-a-week dosing. Although data on longterm outcome of pegylated IFN treatment are limited, the clinical benefits of pegylated IFN are expected to be similar if not better than that of conventional IFN. To date, there is only one randomized controlled trial of IFN therapy with HCC as the primary outcome. In this trial, 101 Taiwanese patients who were HBsAg- and HBeAg-positive were randomized into three groups; IFN alone (n=31), prednisone priming followed by IFN (n=36) and no treatment (n=34) [13]. HCC was detected International Medical Press

3 Does antiviral therapy prevent hepatocellular carcinoma? in one (1.5%) IFN-treated patient and four (12%) untreated controls. The single IFN-treated patient that developed HCC had HBeAg seroconversion during treatment but reverted to HBeAg-positive with elevated ALT during follow up. The four untreated controls that developed HCC all remained HBeAg-positive. Prospective cohort studies have shown that the rate of HCC is lower in patients with HBV-cirrhosis who received IFN treatment and the benefit of IFN in preventing HCC was more pronounced in those with high serum HBV DNA levels. In one study, 233 HBeAg-positive Taiwanese patients who received IFN treatment was compared to 233 matched controls and followed for a median of 6.8 years [14]. The cumulative incidence of HCC for patients with pre-existing cirrhosis was higher in the control group than in the treatment group (58.9% versus 19.7%; P=0.009). Another study compared 313 concurrent Japanese patients with histologically proven HBV-cirrhosis who were either treated with IFN (n=91) or followed without treatment (n=219) [15]. The two groups were comparable except for a higher prevalence of HBeAg in the IFN-treatment group (P=0.002). The cumulative incidence of HCC was 7.0% and 19.6% at 5 years and 17% and 30.8% at 10 years among the IFN-treated and untreated patients, respectively (P=0.012). IFN treatment was an independent factor in lowering the rate of HCC (OR=0.39; P=0.031) and IFN had a greater impact on the incidence of HCC in patients with baseline HBV DNA 10 MEq/ml (~2 million IU/ml) [15]. A third study of Chinese patients did not show a decrease in the incidence of HCC in IFNtreated patients. In this study, 208 IFN-treated patients and 203 untreated controls were followed for a median of 108 months. Five patients in the IFN group and none in the control group developed HCC during the follow up period [16]. The inclusion of mostly young patients with minimal liver damage accounts for the low incidence of HCC in this study making it difficult to determine if IFN treatment had an impact on HCC development. A benefit of IFN treatment in preventing HCC is less obvious in non-asian patients possibly related to the lower incidence of HCC. A multicentre European study followed 90 HBeAg-positive patients with Child s A cirrhosis for a mean of 7 years. HCC was diagnosed in 4 (10%) of the 40 IFN-treated and 6 (12%) of the 50 untreated patients. Among the patients who achieved HBeAg clearance with persistent normalization of ALT, none of the IFN-treated and two of the control patients developed HCC [17]. Several meta-analyses showed that IFN treatment decreased the incidence of HCC in patients with chronic HBV infection, especially in those with cirrhosis. One report included 11 studies with a total of 2,082 patients with and without cirrhosis. HCC occurred in 5.2% (52/1,006) of IFN-treated patients and 11.7% (126/1,076) of untreated controls during a follow up period of 4 7 years [18]. Another meta-analysis included 12 studies of which 10 were cohort studies. A total of 2,742 patients were followed for 4.7 to 8.9 years. When data from each study were analysed separately, only 2 of the 12 studies showed a statistically significant benefit of IFN therapy [19]. Pooling of the data from all 12 studies found a significantly lower rate of HCC in the IFN-treated subjects compared to the controls (4.6% versus 9.0%, relative risk [RR] 0.66, 95% CI ). Subgroup analysis of patients with early cirrhosis also reported a significantly lower rate of HCC in the IFN-treated group (11.6% versus 21.5%, RR 0.53, 95% CI ). The third metaanalysis included seven studies with a total of 1,505 Child s A cirrhotic patients and 122 HCC cases. The pooled estimate of the risk of HCC showed a benefit of IFN treatment (Risk difference -6.4; 95% CI ; P<0.001) [20]. Of note, there was remarkable heterogeneity among the studies. Additional limitations of these meta-analyses are that a mix of randomized and nonrandomized studies is included and the control group was not matched to the treatment group in some of the studies. Furthermore, the treatment regimens and the duration of follow up varied. Both conventional and pegylated IFN have been demonstrated to result in an improvement of surrogate end points: HBV DNA suppression, HBeAg seroconversion, HBsAg loss, ALT normalization and improvement in liver histology [21 23]. Several meta-analyses have confirmed a beneficial effect of conventional IFN treatment on HBeAg and HBsAg seroclearance [24], reduction in the rate of fibrosis progression [25] and development of cirrhosis [18]. Nucleoside/nucleotide analogues Only one randomized controlled trial of nucleoside/ nucleotide analogue (NA) treatment in patients with chronic HBV infection reported HCC as an outcome (Figure 2). In this double blind, randomized controlled trial, 651 patients with advanced fibrosis or cirrhosis who were HBeAg-positive or had serum HBV DNA>0.7 meq/ml (~>140,000 IU/ml) were randomized 2:1 to receive lamivudine or placebo [26]. The primary end point was an increase in Child Turcotte Pugh score by 2 or more points or development of 1 of the following complications: HCC, spontaneous bacterial peritonitis, renal insufficiency, variceal bleeding or death due to liver disease. The study was terminated after a median duration of treatment of 32.4 months (range 1 42) because a significant difference in outcome between the two groups was observed. The combined end point was reached in 7.8% of lamivudine-treated and 17.7% of control patients with a HR for disease progression of 0.45 (95% CI ; P=0.001). HCC occurred in Antiviral Therapy

4 H Kwon & AS Lok Figure 2. Randomized controlled trial of lamivudine therapy in patients with HBV-related advanced fibrosis/cirrhosis showing that antiviral therapy can decrease the incidence of HCC 25 Diagnosis of hepatocellular carcinoma (% of patients) Placebo n=173 n=43 n=122 0 n=198 Lamivudine n=385 n= Months Reproduced with permission from the Massachusetts Medical Society [26]. n values represent number of patients at risk. P-value comparing lamivudine and placebo group is HCC, hepatocellular carcinoma. 3.9% of the lamivudine group and 7.4% of the placebo group (HR 0.49, 95% CI ; P=0.047). A systematic review and a meta-analysis also found a reduction in HCC incidence in patients who received NA therapy. The systematic review included 21 studies with a total of 3,881 patients (49.2% HBeAgpositive) with or without cirrhosis who were treated with NA. In the 3 studies with untreated controls HCC was detected less frequently (22/779 or 2.8%) in the treated patients than in the untreated controls (33/534 or 6.4%; P=0.003) [27]. The meta-analysis included 5 studies with a total of 1,267 patients who received lamivudine with or without adefovir rescue and 1,022 patients who received placebo or no treatment followed for years. There was a fourfold reduction in incidence of HCC in the patients who received NA (2.5%) compared to the control group (11.7%; RR= 0.22, 95% CI ); however, there was significant heterogeneity among the studies. Subgroup analysis of three studies that included patients with compensated cirrhosis showed a significantly lower risk of HCC in the NA-treated group (3.9%) compared to the control group (22.4%; RR=0.17, 95% CI ). The two studies that enrolled patients without cirrhosis also reported fewer HCC in the NAtreated group, 1.8% versus 8.0% in the control group (RR=0.21, 95% CI ) [19]. The systematic review and the meta-analysis had some limitations. The studies analysed included patients with various stages of liver disease and most studies used therapies that are now considered suboptimal lamivudine with or without adefovir rescue. Maintenance of viral suppression is important in improving clinical outcomes. In the randomized controlled trial of lamivudine mentioned above [26], patients with virological breakthrough due to lamivudine resistance had a higher rate of clinical end points than those without lamivudine resistance, 11% versus 5% (P=0.02). In the systematic review of 21 studies [27], HCC was diagnosed in 23/982 (2.3%) patients in virological remission and in 64/852 (7.5%) patients with virological non-response or breakthrough (P<0.001). In two studies with cirrhosis patients only, HCC was also detected less frequently in patients with virological response versus those without virological remission (3/36, 8.3% versus 17/45, 37.8%; P=0.004) [27]. These data suggest that NAs that are more potent and have a higher genetic barrier to resistance such as entecavir or tenofovir may lead to a greater reduction in risk of HCC. A retrospective study of 216 HBeAg-negative Greek patients with cirrhosis found that the incidence of HCC did not differ in patients with or without virological remission (11.3% versus 10.2%; P=0.99) [28]. However, in many patients HCC was diagnosed within 12 months of achieving virological remission and within 24 months of starting antiviral treatment. It is likely that HCC was present in these patients prior to the onset of antiviral therapy. Indeed, when patients with International Medical Press

5 Does antiviral therapy prevent hepatocellular carcinoma? HCC diagnosed within the first 24 months of treatment were excluded from the entire cohort of 818 patients (cirrhotic and non-cirrhotic), there was a trend toward a lower incidence of HCC among those with virological remission (P=0.06). These data suggest that a longer duration of antiviral therapy and a longer duration of virological response may be necessary to decrease the risk of HCC in patients who have already progressed to cirrhosis. Evidence to support that antiviral therapy can prevent HCV-HCC The effect of antiviral treatment on the development of HCC in patients with HCV-cirrhosis has been the subject of many studies. An important goal in the treatment of chronic hepatitis C is to achieve sustained virological response (SVR). Many studies showed that patients who achieved SVR had lower risk of HCC compared to non-responders, while data comparing non-responders to untreated controls are mixed [29,30]. Table 1 summarizes the incidence of HCC in studies comparing treatment versus no treatment, SVR versus no SVR and non-responder versus no treatment. IFN treatment versus no treatment In a small randomized controlled trial of 90 Japanese patients with HCV-cirrhosis, the relative risk of HCC in the IFN-treated patients was (95% CI ; P=0.010) compared to the untreated controls (Figure 3) [31]. Other studies have also found a decrease in incidence of HCC in patients who received IFN treatment versus those who were not treated; however, not all studies matched the controls to the treated patients (Table 1) [29,32 34]. SVR versus no SVR Among the patients who received IFN treatment, those who achieved SVR had a lower incidence of HCC compared to those who did not achieve SVR (Table 1) [29,33,35 37]. An Italian study of 920 patients with HCV cirrhosis who received IFN treatment showed that patients who did not achieve SVR had a 2.59-fold higher rate (95% CI ; P<0.01) of HCC than patients who achieved SVR (Table 1) [38]. The incidence of HCC per 100 person-years of follow up were 0.66 (95% CI ) for patients with SVR and 2.10 (95% CI ) for those who did not achieve SVR. The Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) Trial found that among patients with HCV-related advanced fibrosis or cirrhosis, the adjusted cumulative incidence of HCC 7.5 years from enrolment was 1.1%, 5.5% and 8.8% among those with SVR, breakthrough or relapse, and nonresponders, respectively [35]. These data indicate that the risk of HCC is significantly decreased but not eliminated in patients with advanced fibrosis or cirrhosis who achieved SVR. Whether HCC surveillance would be cost-effective in cirrhotic patients who achieved SVR remains to be determined. Non-response versus no treatment One study found that non-responders to IFN treatment had a lower incidence of HCC compared to untreated controls but this was not confirmed in two other studies (Table 1) [29,33,39]. Meta-analyses Four independently published meta-analyses all showed that IFN decreased the incidence of HCC in patients with HCV-cirrhosis [20,30,40,41]. One of the more recent meta-analysis included 32 studies: 9 randomized controlled trials, 15 retrospective studies and 8 prospective cohort studies. Twenty studies provided data comparing IFN-treated (n=2,691) and untreated patients (n=2,009) with a median follow up after completion of IFN treatment from 2 15 years. The relative risk (RR) of HCC among patients who received IFN therapy was 0.43 (95% CI ; P< ) but there was significant heterogeneity among the studies [40]. A meta-analysis of 14 studies comparing 906 patients with SVR to 2,402 without SVR showed that achieving SVR was associated with a RR of HCC of 0.35 (95% CI ; P< ) and the results were consistent across these studies. Comparison of non-responders to untreated patients from 7 studies for which data were available also showed a benefit of IFN therapy (RR 0.37; 95% CI ); however, there was significant heterogeneity among these studies [40]. Maintenance IFN in non-responders IFN has potential antitumour and antifibrotic effects. There have been three large, randomized controlled trials on maintenance treatment with low-dose pegylated IFN in patients with advanced fibrosis or cirrhosis who were non-responders to full dose pegylated IFN and ribavirin. Overall, no beneficial effect of maintenance IFN on disease progression and HCC development was observed in any of these three studies. A more recent sub-analysis suggests a modest benefit on HCC development in the subgroup of patients with cirrhosis. In the HALT-C trial, 1,050 patients with advanced fibrosis or cirrhosis, who had failed to respond to pegylated IFN and ribavirin were randomized to receive pegylated IFN-α2a at 90 µg/week (n=517) or no therapy (n=533) for 3.5 years. The primary end point was progression of liver disease, as indicated by death, HCC, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points. There was Antiviral Therapy

6 H Kwon & AS Lok Table 1. IFN treatment and HCC incidence in patients with HCV-related advanced fibrosis or cirrhosis Type of study n Mean age, years Male gender, % Treatment Follow-up, years Incidence of HCC P-value Reference IFN versus no treatment RCT 90 (45 treated) IFN-α for weeks Mean 4.9 Treated versus control, Nishiguchi et al. [31] 4% versus 38% a RCT 99 (42 treated) IFN-α2b for 48 weeks Median 3 Treated versus control, NS Valla et al. [32] 11.9% versus 23% PC 345 (271 treated) IFN-α for 6 12 months Median 6.8 Treated versus control, 0.03 Shiratori et al. [33] 31% versus 47% PC 1,619 (1,057 treated, IFN-α ±RBV for weeks Mean 5.2 Treated versus control, Yu et al. [29] unmatched controls) 12.2% versus 35.2% RC 329 (193 treated) 55 NA IFN-α Mean 5 Treated versus control, 0.09 Fattovich et al. [34] 3.6% versus 12% SVR versus no SVR RCT 526 (SVR 140) IFN-α and RBV for 48 weeks Median 7.0 SVR versus no SVR, b Morgan et al. [35] 1.4% versus 8.6% PC 1,619 (1,057 treated, IFN-α ±RBV for weeks Mean 5.2 SVR versus no SVR, Yu et al. [29] unmatched controls) 3.0% versus 36% PC 345 (271 treated) IFN-α for 6 12 months Median 6.8 SVR versus no SVR, b Shiratori et al. [33] 17% versus 35% RC 393 (73 SVR) IFN-α for weeks Median 5.6 SVR versus no SVR, 0.04 b Okanoue et al. [36] 4% versus 13% RC 920 (124 SVR) Standard IFN monotherapy Median 8 SVR versus no SVR, <0.001 Bruno et al. [38] 6 12 months 5.7% versus 15.3% RC 479 (142 SVR) IFN-based regime Median 2.1 SVR versus no SVR, 0.25 Veldt et al. [55] 2.1% versus 9.4% Non-response versus no treatment RCT 131 (50 NR, IFN-α2b+RBV for 52 weeks Mean 5 NR versus no treatment, b Azarroli et al. [39] 30 no treatment) 4% versus 30% PC 345 (207 NR, IFN-α for 6 12 months Median 6.8 NR versus no treatment, 0.21 Shiratori et al. [33] 74 no treatment) 35% versus 47%; HR 0.77 (95% CI , age adjusted analysis) PC 1,619 (1,057 NR, 562 no IFN-α ±RBV for weeks Mean 5.2 NR versus no treatment, 0.18 Yu et al. [29] treatment, controls 36% versus 35% were unmatched) a See Figure 3. b P-values were not provided in the original article and were calculated by the authors in this review. HCC, hepatocellular carcinoma; IFN, interferon; NA, not available; NR, non-response; NS, not significant; PC, prospective cohort; RBV, ribavirin; RC, retrospective cohort; RCT, randomized controlled trial; SVR, sustained virological response International Medical Press

7 Does antiviral therapy prevent hepatocellular carcinoma? Figure 3. Randomized controlled trial of IFN therapy in patients with HCV-related cirrhosis showing a significant decrease in the cumulative incidence of HCC with IFN therapy 50 Cumulative incidence of HCC, % Control IFN-α Follow up, years Reprinted from The Lancet [31] with permission from Elsevier. HCC, hepatocellular carcinoma; IFN, interferon. no significant difference between the treated and untreated groups in the rate of primary outcome (34.1% in the treatment group and 33.8% in the control group; HR 1.01; 95% CI ; P=0.90) at the end of the randomized trial [42]. During extended follow-up, excess mortality due to non-liver related causes emerged in the treated patients with fibrosis and at 7 years the cumulative mortality rate was higher in the treatment compared to the control group (20% versus 15%; P=0.049) [43]. An earlier report focused on HCC found that the 5-year cumulative incidence of HCC was similar in the treated and untreated patients (5.4% versus 5.0%, respectively, P=0.78) [44]. During extended follow up to a median of 6.1 years (maximum 8.7 years), 37/515 (7.2%) treated patients and 51/533 (9.6%) controls were diagnosed with HCC (P=0.24) [45]. The 7-year cumulative incidence of HCC in patients with baseline cirrhosis was 7.8% and 24.2% in the treated and control groups, respectively (HR 0.45; 95% CI ); and 8.3% and 6.8%, respectively in patients with baseline bridging fibrosis (HR 1.44; 95% CI ). Patients with 2 log versus <2 log decrease in HCV RNA during maintenance therapy with pegylated IFN had a lower risk of HCC (HR 0.38; 95% CI ; P=0.18) but this difference was not significant and only 15.4% of patients had a 2 log decrease in HCV RNA during low-dose maintenance pegylated IFN therapy. The Colchicine versus Peg-Intron Long-Term study (COPILOT trial) enrolled 555 patients with HCV and advanced liver disease (Ishak stage 3 6). Patients were randomized to receive colchicine or pegylated IFN-α2b (0.5 µg/kg/weekly) for 4 years. Maintenance with pegylated IFN was associated with a higher rate of HCC compared to the colchicine group (n=26 versus n=12) while complications of portal hypertension were more common in the colchicine group (n=39 versus n=26) [46]. In the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC) trial [47,48], 631 subjects with HCV cirrhosis were randomized to pegylated IFN-α2b (0.5 µg/kg/week) or no treatment. The primary end point was time to first clinical event (liver decompensation, death, liver transplant or HCC). The outcome was similar in the two groups with 36 patients in the control arm and 27 in the treatment arm reaching primary end point (HR 1.45, 95% CI ; P=0.14). HCC occurred in 4% of the treatment (n=12) as well as control groups (n=13). Conclusion While there have been very few randomized controlled trials of antiviral therapy in patients with chronic HBV Antiviral Therapy

8 H Kwon & AS Lok or chronic HCV infection with HCC as the outcome, one landmark double blind randomized controlled trial of NA in patients with advanced hepatitis B and several randomized controlled trials of IFN-based therapies in patients with HCV-cirrhosis provided evidence to support that antiviral therapy is associated with decreased risk of HCC. Additional data are provided by cohort studies, case-control studies and meta-analyses. These studies found that a reduction in risk of HCC was observed in the highest risk group patients who had already progressed to cirrhosis at the start of treatment; however, the risk of HCC is not eliminated indicating that HCC surveillance should be continued. These data suggest that initiating treatment earlier may be more effective. Decision to start treatment early in patients with chronic HBV infection must be carefully considered because long-term and often lifelong treatment is required to maintain virus suppression and clinical benefit, and spontaneous remission including HBeAg seroconversion and HBsAg loss can occur in some patients. HCV treatment has the potential for cure and achieving SVR prior to progression to cirrhosis may eliminate the risk of HCC. The decision to start treatment early had been hampered by the low rate of SVR in genotype 1 infection and the side effects of pegylated IFN and ribavirin treatment. The availability of direct-acting antiviral agents such as telaprevir and boceprevir in combination with pegylated IFN and ribavirin increases the rate of SVR but the added side effects and costs would pose a barrier to early treatment in some patients [49 52]. A recent pilot study suggests that combination of direct-acting antiviral agents alone may result in SVR in selected patients [53]. If confirmed, this would increase the uptake of HCV treatment. Substantial progress has been made in the treatment of chronic HBV and HCV infection in the last 15 years and more potent and better tolerated antiviral agents continue to be developed. Availability of efficacious treatment must be accompanied by improvement in identification of infected persons, accessibility of care and affordability of treatment in order that antiviral therapy can effectively prevent the development of HCC. Disclosure statement HK declares no competing interests. ASL has received research grants from Bristol Myers Squibb, Roche, Schering/Merck, Gilead, GlaxoSmithKline and has served as an advisor for Bristol Myers Squibb, Roche, Schering/ Merck, Gilead, GlaxoSmithKline and Abbott. References 1. Parkin DM. The global health burden of infectionassociated cancers in the year Int J Cancer 2006; 118: Chang MH, You S, Chen C, et al. 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