Expert Review of Gastroenterology & Hepatology

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Managing hepatitis B to prevent liver cancer: recent advances Simone I Strasser To cite this article: Simone I Strasser (2014) Managing hepatitis B to prevent liver cancer: recent advances, Expert Review of Gastroenterology & Hepatology, 8:4, 409-415 To link to this article: http://dx.doi.org/10.1586/17474124.2014.893823

Published online: 03 Mar 2014.

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Managing hepatitis B to prevent liver cancer: recent advances Expert Rev. Gastroenterol. Hepatol. 8(4), 409–415 (2014)

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Simone I Strasser Royal Prince Alfred Hospital – AW Morrow Gastroenterology and Liver Centre, Missenden Rd, Camperdown, New South Wales 2050, Australia [email protected]

Chronic hepatitis B (CHB) infection is a major cause of human mortality worldwide. The majority of people with CHB are infected early in life, and 20–40% of men and 15% of women with chronic infection will develop hepatocellular carcinoma (HCC). Antiviral therapy is recommended for patients with CHB who have cirrhosis or active disease with the aims of reducing disease progression to cirrhosis, liver failure and liver cancer, thereby preventing death. Evidence that treatment with interferon or with early nucleos(t)ide analogue therapy reduces HCC has been somewhat conflicting, however evidence is emerging to support a significant role in HCC prevention of the more effective antivirals, entecavir and tenofovir. Older patients, those with cirrhosis, and those undergoing curative treatments for HCC derive the greatest medium-term benefit in terms of HCC reduction, but HCC can still occur and long-term surveillance is recommended. KEYWORDS: cirrhosis • entecavir • hepatitis B • hepatocellular carcinoma • interferon • tenofovir

Chronic hepatitis B (CHB) infection is a major cause of human mortality worldwide. The Global Burden of Disease Study 2010 [1] identified 786,000 deaths in 2010 attributable to hepatitis B, making it the 15th highest ranked cause of death globally [2]. The majority of people with CHB are infected early in life, and 20–40% of men and 15% of women with chronic infection will develop hepatocellular carcinoma (HCC) [3]. With over 350 million people in the world affected by CHB, international guidelines make strong recommendations for screening, assessment and management with the stated aims of reducing disease progression to cirrhosis, liver failure, liver cancer and preventing death [4–6]. The mainstay of management involves antiviral therapy with either oral nucleos(t)ide analogs (NAs) or pegylated interferon with patients selected for therapy on the basis of where they are in the natural history of infection. Specifically, treatment is targeted at patients in the immune clearance and immune escape (HBeAg-negative hepatitis) phases, when there is significant viremia and elevated alanine aminotransferase (ALT) levels, as well as those with cirrhosis. None of the current therapies eradicates hepatitis B virus (HBV) infection, informahealthcare.com

10.1586/17474124.2014.893823

attributed to the persistence of the replicative intermediate, covalently closed circular DNA, which acts as a reservoir for viral reactivation once therapy is ceased [7]. Therefore, the aims of treatment can only be attained by effective viral suppression, usually requiring long-term therapy. Studies are emerging, showing the impact of prolonged viral suppression on longterm clinical outcomes, and in particular, significant reductions in the incidence of HCC. Pathogenesis of HCC in hepatitis B

A strong link exists between CHB infection and the development of HCC. The pathogenic mechanisms in HBV-associated HCC have recently been reviewed [8]. HCC usually develops in a situation of chronic inflammation and regeneration and is a feature of many chronic liver diseases apart from HBV infection. However, in some regions of the world, particularly Asia and Africa, HBV-associated HCC can emerge in the absence of cirrhosis or significant inflammation [9]. In these circumstances, HBV mutations involving the pre-S region, in particular, may be of particular relevance [10]. Regardless of whether HCC is associated with cirrhosis or not, persistent viral replication appears to be of paramount importance in the

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pathogenesis. Changes in host gene expression and cellular phenotypes related to HBV-encoded proteins promote many of the changes recognized as hallmarks of malignancy including cell proliferation, resistance to growth inhibition, tissue invasion, metastasis and angiogenesis [11]. Expressions of specific HBV proteins appear to have direct impact on HCC development, particularly the HBx antigen, a transactivating protein that stimulates virus gene expression and replication and protects virus-infected cells against immune-mediated destruction [12]. In addition, HBx-induced epigenetic changes are emerging as important factors in HCC pathogenesis [13]. HBx expression correlates with the severity of liver disease [14] and immune mechanisms associated with chronic infection and inflammation appear to be of paramount importance in HCC development. The risk of developing HCC seems to be ongoing in HBsAg-negative patients with low-level viremia (occult hepatitis B) [15] where such mechanisms are likely to be of particular relevance.

management of CHB having been replaced by pegylated interferon. Inconsistencies in the conclusions of these studies are most likely related to the ineffectiveness of interferon in achieving viral suppression in the majority of treated patients. Variability in the patient population included in these studies may also have had an impact on the conclusions as the presence of cirrhosis and older age at study entry have been repeatedly demonstrated to be independent predictors of HCC development [26]. Patients, who do achieve complete viral suppression with interferon, particularly if cirrhotic, may have a reduction in the incidence of HCC [24] although patients with cirrhosis also have the highest risk of therapy-related hepatic decompensation which may offset the benefit of treatment. Those who do not achieve viral suppression with interferon therapy continue to be at risk of HCC and disease progression, and switch to NA therapy is recommended for patients with ongoing inflammation and significant fibrosis. Nucleos(t)ide analogue therapy & development of HCC

Rationale for viral suppression to prevent HCC

Progression of liver disease to cirrhosis and HCC is strongly associated with active HBV replication and high viral loads [16–18]. The REVEAL study, a longitudinal study conducted in a large community-based cohort in Taiwan, demonstrated that HBV DNA levels at baseline were a strong predictor for the subsequent development of both cirrhosis and HCC, independent of HBeAg status and ALT levels. HCC is strongly associated with the presence of underlying cirrhosis, with a 5-year cumulative rate of 10–15% [19]. A number of risk-scoring algorithms have been developed [20–22], which identify that HBV viral load, HBeAg status, ALT levels, age and gender are all important determinants of HCC risk. It has been suggested that such risk scores can be utilized to identify which patients should receive antiviral treatment, particularly in males over 40 years with HBeAg-positive disease who may not meet standard treatment criteria according to international guidelines [5,6,4], yet have a high risk for HCC [23]. Interferon therapy & development of HCC

A number of studies have shown a reduction in the incidence of HCC in patients with CHB treated with interferon although the results have been conflicting [24]. A meta-analysis of 12 studies published from 1997 to 2007, involving 1292 patients treated with interferon and 1450 controls, concluded that the incidence of HCC after treatment was 34% lower in the interferon-treated patients (RR: 0.66; 95% CI: 0.48–0.89) [25]. Only one of the studies was a randomized controlled trial with 10 of 12 being cohort studies. The duration of follow-up ranged from 4.7 to 8.9 years. Sensitivity analysis determined that this result was consistent across the high-quality studies. Patients with compensated cirrhosis derived greater benefit in terms of HCC reduction than noncirrhotic patients. All reports with sufficient duration of follow-up to show an impact on HCC incidence are from studies of patients treated with standard interferon, which is no longer used in the 410

Evidence supporting the impact of antiviral therapy on development of HCC is largely drawn from observational cohort and epidemiological studies utilizing historical or untreated controls, as well as clinical trials without an untreated comparator group. Furthermore, almost exclusively, these studies were not primarily designed to examine the impact of antiviral therapy on the incidence of HCC incidence, and the patients were limited to those who met criteria for antiviral treatment based on international guidelines. In the absence of a large prospective randomized controlled trial designed specifically to examine the impact of antiviral therapy on HCC development, it is therefore difficult to extrapolate conclusions from these studies to a broader range of patients with CHB. There is only one randomized controlled study of lamivudine versus placebo, conducted over a decade ago in patients with cirrhosis, which demonstrated a significant reduction in the incidence of HCC [27]. This study, conducted in the AsiaPacific region, was stopped prematurely at a median of 32.4 months by the data and safety monitoring board as the second interim analysis determined that the efficacy endpoint had been reached. Patients treated with lamivudine had a 51% reduction in the incidence of HCC compared with those receiving placebo (3.9 vs 7.4%, p = 0.047). While patients who developed antiviral drug resistance had deterioration of liver function during this trial, there was no difference in the incidence of HCC in patients with ongoing viral suppression (albeit with a relatively insensitive assay) compared with those with YMDD mutations in the short observational time frame. From that time, it became unethical to conduct a placebocontrolled trial as the efficacy of viral suppression on preventing adverse outcomes in HBV cirrhosis had been demonstrated. Antiviral drug resistance is a major problem with lamivudine, yet because of limited availability of alternative agents, it has remained the standard of care until fairly recently in many countries. Therefore, in most of the long-term studies examining the impact of antiviral therapy on rates of cirrhosis, HCC Expert Rev. Gastroenterol. Hepatol. 8(4), (2014)

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and death, patients were commenced on lamivudine but then switched to more effective regimens over time as resistance emerged. A cohort of 360 treatment-naı¨ve patients in Korea initiated on therapy between 2001 and 2005 was followed for a median of 94 months following initiation of antiviral treatment according to Korean national guidelines [28]. Seventy-one percent of the patients required a change of therapy because of suboptimal response or emergence of resistance. At 5-year follow-up, 5.3% developed cirrhosis and 0.8% developed HCC significantly fewer than observed in an historical control group from 1989 (23 and 3% respectively), although it should be noted that the observational group and the historical control group reported in this study may differ significantly as baseline characteristics were unbalanced. Regardless, the presence of cirrhosis was strongly predictive of the development of HCC, even in the modern era (hazard ratio [HR]: 17.470; 95% CI: 5.081–60.063), suggesting that prevention of cirrhosis with effective antiviral therapy may lead to significant reduction in HCC [28]. While antiviral therapy does seem to reduce the incidence of HCC in patients with CHB, it does not prevent it completely. Patients with cirrhosis prior to initiation of lamivudine continue to have a high incidence of HCC. The HEPNET.Greece cohort study of 818 patients with HBeAg-negative disease treated initially with lamivudine for at least 12 months, reported a cumulative incidence of HCC at 5 years of 9.2% in patients with compensated cirrhosis and 19.3% in patients with decompensated cirrhosis compared with 3.2% in patients without cirrhosis [29]. In contrast to other studies, maintenance of virological remission did not seem to impact the incidence of HCC in this study. This was particularly the case in patients with cirrhosis, whereas patients without cirrhosis did seem to have a reduction in the incidence of HCC. Virological failure with lamivudine was high, with only 28% achieving virological remission and 49% patients changing to combination therapy or another NA after emergence of viral breakthrough. As there was no control group in this study, it was not possible to determine if the observed rates of HCC were lower than may have been if the patients had not been treated at all; however, as was recently observed, the rates seem similar to those reported in natural history studies [30]. Clearly, patients with cirrhosis, particularly older men, have an ongoing risk of HCC despite antiviral therapy and require long-term surveillance for HCC. A systematic review published in 2010 examined the impact of NA treatment on the incidence of HCC in 3881 treated and 534 untreated patients from 21 studies meeting predetermined criteria [31]. One-third of patients in the analysis had cirrhosis at baseline. The majority of included studies examined lamivudine in treatment-naı¨ve patients, but a number of studies were of combination lamivudine–adefovir for patients with lamivudine resistance. During a 46-month period (range: 32–108 months) of follow-up, the incidence of HCC was 2.8% in treated and 6.4% in untreated patients. Once again, patients with cirrhosis continued to have a high incidence of HCC (10.8%) compared with patients without cirrhosis informahealthcare.com

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(0.5%). The rate of HCC was lower in patients who remained in virological remission compared with those with virological nonresponse or breakthrough. In contrast to the randomized controlled trial reported by Liaw et al. [27], where no increased rate of HCC was observed in patients with YMDD mutations, patients with lamivudine resistance appeared at particularly high risk of HCC compared with treatment-naı¨ve patients in this larger systematic review. Because of high rates of antiviral resistance, lamivudine is no longer the standard of care for patients with CHB. More potent antivirals with very low rates of resistance are now used in long-term management. Indeed, both tenofovir and entecavir are associated with undetectable levels of HBV DNA by 1 year in over 90% of patients, and almost all patients have undetectable virus with longer treatment durations [32,33]. While these agents have been available for only a relatively short period of time, evidence is emerging that the profound viral suppression associated with such treatments leads to reduced rates of progression to cirrhosis, liver failure and HCC [34]. Recently, a Japanese group reported the impact of long-term treatment on 472 of 510 consecutive patients who were initiated on entecavir between 2004 and 2010 [35]. Patients were treated according to standard indications. Propensity matching to a retrospective cohort of 1143 untreated patients from 1973 to 1999 was undertaken. At 5 years, entecavir-treated patients had a significantly lower cumulative incidence of HCC (3.7 vs 13.7% in matched controls [p < 0.001]). Interestingly, the impact of entecavir therapy on development of HCC was only seen in patients with cirrhosis (5-year cumulative incidence of HCC 7 vs 39% controls [p < 0.001]). At 5 years, the cumulative incidence of HCC in noncirrhotic patients was 2.5% compared with 3.6% in matched untreated patients (p = 0.44). Furthermore, when a number of published risk scores [36] were examined, the benefit of entecavir treatment was seen to be highest in the patients at greatest risk for HCC. Hosaka et al. also examined the entecavir-treated group with a cohort of 492 lamivudine-treated patients and showed that while lamivudine was associated with a lower incidence of HCC than no antiviral treatment, entecavir was significantly more effective than lamivudine, presumably because of the lack of resistance-associated virological failure. A European cohort study (VIRGIL) has reported on clinical outcomes in patients treated with entecavir [37]. This study included 372 patients (including 89 with cirrhosis) treated with entecavir for at least 3 months and for a median of 20 months. To the time of reporting, three patients had developed HCC and in the absence of a control group and with only a relatively short duration of follow-up, it is not possible to conclude that entecavir reduced the incidence of HCC. A recent meta-analysis examined the role of all marketed NAs on the incidence of HCC in 10,025 patients from 49 studies [38]. This analysis included 5946 patients treated with lamivudine, 1929 with adefovir, 879 with entecavir, 657 with tenofovir and 616 with telbivudine. Four hundred and sixty-five patients developed HCC, giving a pooled 411

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incidence rate of 1.3/100 person-years of follow-up although significant heterogeneity was seen in the pooled data. The authors were unable to demonstrate any difference in the HCC incidence rate according to the particular NA used (1.3–1.5/ 100 person-years). The presence of cirrhosis (conferring a 10-fold increase in HCC incidence) and older age, and lack of complete viral suppression were more important factors in the development of HCC than the particular antiviral agent used. A consistent finding among studies from around the world of the impact of NA therapy on HCC incidence, including a recent study conducted in four large integrated US healthcare services [39], is that antiviral therapy, particularly when associated with complete viral suppression, is associated with over a 50% reduction in the rate of HCC. There is a suggestion that the more effective antiviral agents have a greater impact on HCC incidence, but so far, data are limited and mainly derived from uncontrolled short and medium-term studies and from modeling based on published risk scores [40]. At this time, older patients, and those with cirrhosis, should be considered to remain at risk indefinitely and long-term surveillance should continue to be a priority for these patients. The HCC risk, and therefore the role of ongoing surveillance, in younger patients without cirrhosis on long-term potent antiviral therapy remain unclear. Antiviral therapy to prevent recurrent HCC after curative therapy

Hepatic resection and more recently local ablative therapies are regarded as potentially curative in selected patients with HCC. However, HCC recurrence occurs in approximately 70% of patients by 5 years of follow-up, related to a combination of true recurrence, which generally occurs early, and the later development of new tumors [41]. To date, no adjuvant therapy has been demonstrated to reduce the risk of tumor recurrence after potentially curative therapy although a number of strategies are under investigation. The role of adjuvant immunotherapy with interferon in preventing HCC recurrence after surgical resection or local ablation has been controversial. The rationale for using interferon is based on both its antiviral properties and a possible tumoricidal effect. A recent meta-analysis identified seven randomized controlled trials, involving 620 patients, who received interferon or no treatment in the adjuvant setting [42]. The main finding of this meta-analysis was that interferon was associated with a 35% reduction in mortality at 2 years (p < 0.001). A modest 14% reduction in tumor recurrence at 2 years was observed (p = 0.013). With only 2-year outcomes being examined in this study, it is not possible to draw conclusions as to the impact of interferon on later de novo tumor development. Two recent meta-analyses have analyzed the impact of interferon used after curative therapy on the rate of HCC recurrence in both patients with chronic hepatitis C and CHB [43,44]. Both concluded that the literature supports a reduction in HCC recurrence to 5 years in chronic hepatitis C patients, but there was little evidence of a beneficial effect in those with CHB. 412

High-level hepatitis B viremia after resection for HCC has been reported to be associated with an increased risk of late tumor recurrence [45–48]. Furthermore, the presence of HBV genotype C rather than B and the presence of basal core promoter mutation have been associated with an increased risk for recurrent HCC. Viral suppression with NA therapy may therefore be an effective strategy for reducing HCC recurrence and has been examined in a number of retrospective studies, which do provide evidence of a beneficial effect [49]. A meta-analysis, published in 2011, reviewed nine eligible cohort studies incorporating 551 patients of whom 204 received antiviral therapy after hepatic resection and 347 were untreated [50]. The authors identified a 41% reduction in the risk of recurrent HCC (OR: 0.59; 95% CI: 0.35–0.97; p = 0.04). Liver-related and overall mortality was also significantly reduced in the patients treated with antiviral therapy, supporting a role for antiviral therapy after resection in terms of both reduction in tumor recurrence and prevention of liver failure. A recent cohort study reported the rates of tumor recurrence in 142 patients who received adjuvant lamivudine, adefovir or entecavir after surgical resection in comparison to 188 untreated controls [47]. Multivariate analysis showed that recurrence-free survival was significantly improved in patients receiving antiviral therapy (OR: 0.625; 95% CI: 0.448–0.873; p = 0.006). In contrast, a retrospective study of 141 patients treated with lamivudine after radical hepatectomy compared with 337 controls showed that while liver failure rates and overall survival were significantly improved in patients on antiviral therapy, there was no difference in recurrence-free survival to 5 years of follow-up [51]. Clearly, lamivudine is suboptimal therapy in terms of sustained viral suppression, and ongoing viremia or emergence of resistance may have had an impact on HCC recurrence that more effective therapy may have prevented. Recently, a randomized trial examining the role of antiviral therapy in preventing recurrent HCC after surgical resection has been reported [52]. One hundred and sixty-three patients were randomized to either start lamivudine (or combination lamivudine plus adefovir, or entecavir, if resistant) within 1 week of surgery or receive no antiviral therapy. Multivariate analysis demonstrated a significant benefit of antiviral therapy that was associated with a 52% reduction in HCC recurrence (HR: 0.48; 95% CI: 0.32–0.70) and a 74% reduction in risk of HCC-related death (HR: 0.26; 95% CI: 0.14–0.50). It can be seen that data supporting a role of antiviral therapy in prevention of HCC recurrence after surgical resection have been largely derived from retrospective and observational cohort studies, but the findings have also now been supported by a randomized controlled trial. While a positive benefit has also been supported by meta-analysis (that did not include the randomized trial), there are significant limitations in the data available, and a further confirmatory multicenter randomized trial has been recommended [52]. In the meantime, postoperative outcomes in viremic patients undergoing hepatic resection are likely to be significantly improved by antiviral therapy. Expert Rev. Gastroenterol. Hepatol. 8(4), (2014)

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Antiviral therapy to prevent cirrhosis, a key risk factor for HCC development

The presence of cirrhosis is consistently a major determinant in the development of HCC in CHB conferring at least a 10-fold increased risk over no cirrhosis. As has been discussed, there is some evidence to support a role for antiviral therapy, particularly with potent NAs, in the prevention of HCC. The major benefit is seen in patients with established cirrhosis where the risk of HCC is the greatest, yet these patients continue to be at ongoing risk of HCC. A more effective strategy for HCC prevention would therefore be to treat patients at risk for cirrhosis, before it develops. Interferon therapy has been shown to reduce the progression from advanced fibrosis to cirrhosis [53]. In a meta-analysis of 13 studies including 707 treated patients and 787 controls, Poynard et al. concluded that interferon halved the rate of fibrosis progression compared with no treatment [53]. The evidence for reduction in liver inflammation and fibrosis progression is even more striking with NA therapy, particularly when sustained viral suppression is achieved. Furthermore, regression of cirrhosis has been demonstrated with long-term therapy [34]. This is particularly the case with entecavir and tenofovir [54,55], which are associated with negligible antiviral drug resistance, making them the recommended NAs for firstline therapy in international management guidelines [4–6]. While lacking an untreated control group, the long-term clinical trials with entecavir and tenofovir reported extremely low rates of HCC over 5–6 years of follow-up, supporting the notion that sustained viral suppression, control of inflammation, regression of fibrosis and prevention of fibrosis progression will lead to a significant reduction in HCC development. Real-life studies support this conclusion [34]. In patients with cirrhosis at baseline, however, current recommendations are to continue long-term HCC surveillance, regardless of whether regression has occurred as HCC may still occur [29,31]. Cost–effectiveness of antiviral treatment for CHB

A recent review has examined the available literature of cost– effectiveness analyses of currently recommended antiviral therapies in patients with CHB [56]. The cost–effectiveness analyses studies are mainly limited to previously untreated patients including those with cirrhosis. The authors concluded that there is a wide variation across studies and countries related to the availability and costs of specific antiviral drugs to patients and payers, as well as other unit costs involved in the care of patients with complications of CHB. This is a particularly important issue that requires further investigation, particularly in parts of the world with high rates of CHB and HCC, yet limited access to effective antiviral therapies for many of the affected population. Expert commentary

Currently, recommended treatments, when associated with sustained viral suppression, do seem to significantly reduce the incidence of HCC in patients with CHB, particularly in those informahealthcare.com

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with cirrhosis. However, much of the evidence is derived from relatively small studies, with significant limitations in terms of their design and interpretation. Multiple meta-analyses have been undertaken of the available literature, but these are also limited by significant heterogeneity between studies related to variability in both patient and viral characteristics. In particular, studies vary by the age and ethnicity of the patients, the presence of cofactors (including aflatoxin exposure, diabetes, obesity and viral coinfection), the proportion with cirrhosis and the diagnostic criteria for determining the presence of cirrhosis, the use of surveillance for detection of HCC and the diagnostic criteria for HCC. Heterogeneity in viral characteristics relates to sensitivity and reliability of HBV DNA assays and definitions of virological response to therapy, and relative proportions of HBV DNA genotypes and variants. All of these factors may have significant impact on the conclusions of individual studies as well as meta-analyses derived from these studies. Regardless, antiviral therapy to prevent complications, including HCC, is clearly recommended and beneficial in patients with cirrhosis and those at risk of disease progression. At this time, treatment will be long term for the majority of patients, which poses a significant ongoing financial burden to patients and societies around the globe. Furthermore, longterm surveillance for HCC is recommended even if patients have achieved virological suppression and disease regression. We clearly need to develop tools to determine which patients have acquired such a low risk of subsequent HCC development as a consequence of long-term viral suppression that ongoing HCC surveillance is no longer required. Furthermore, affordable and accessible strategies to permanently eradicate HBV in patients with chronic infection are urgently needed. Five-year view

Currently, available therapies for patients with CHB are safe, well tolerated and highly effective in achieving improved outcomes but need to be administered long term. New therapies directed at mechanisms of cellular entry, viral replication and viral assembly are under development [57] and offer the potential for shorter term therapies and viral eradication. These therapies will evolve over the next 5 years; however, it will clearly need a much greater period of time to demonstrate long-term benefits, particularly in terms of HCC prevention. In the meantime, we need well-designed prospective studies that control for important cofounders to clearly demonstrate the benefit of current therapies, particularly entecavir and tenofovir. It is hoped that this evidence will emerge over the next 5 years. Financial & competing interests disclosure

S Strasser has served on advisory boards and has received honoraria from Roche, Bristol Myers Squibb and Gilead Sciences. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. 413

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Key issues • Chronic hepatitis B (CHB) is a major cause of morbidity and mortality globally. • The majority of CHB infections in the world were acquired at birth or in early childhood and 25–40% of those with CHB will die as a consequence of liver failure or hepatocellular carcinoma (HCC). • Antiviral treatment with either pegylated interferon or oral nucleos(t)ide is indicated in patients with cirrhosis or active hepatitis at risk of disease progression. • Therapy-associated viral suppression is associated with improved clinical outcomes including reduced fibrosis progression, regression of cirrhosis and reduced incidence of HCC. • Antiviral therapy after curative management of HCC reduces late tumor recurrence. • Patients with cirrhosis derive the greatest benefit in terms of improved clinical outcomes, but remain at risk of HCC, despite viral

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suppression and long-term treatment and surveillance are indicated.

References

9.

Chen JD, Yang HI, Iloeje UH, et al. Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death. Gastroenterology 2010; 138(5):1747-54

18.

Chan HL, Tse CH, Mo F, et al. High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma. J Clin Oncol 2008;26(2):177-82

10.

Liu S, Zhang H, Gu C, et al. Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis. J Natl Cancer Inst 2009; 101(15):1066-82

19.

Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127(5 Suppl 1):S35-50

20.

11.

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144(5):646-74

12.

Motavaf M, Safari S, Saffari Jourshari M, Alavian SM. Hepatitis B virus-induced hepatocellular carcinoma: the role of the virus x protein. Acta virol 2013;57(4):389-96

Yang HI, Yuen MF, Chan HL, et al. Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score. Lancet Oncol 2011;12(6):568-74

21.

Yuen MF, Tanaka Y, Fong DY, et al. Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B. J Hepatol 2009;50(1):80-8

22.

Wong VW, Chan SL, Mo F, et al. Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers. J Clin Oncol 2010;28(10):1660-5

23.

Shi Y, Wu YH, Wu W, et al. Association between occult hepatitis B infection and the risk of hepatocellular carcinoma: a meta-analysis. Liver Int 2012;32(2): 231-40

Chen TM, Chang CC, Huang PT, et al. Performance of risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B) score in classifying treatment eligibility under 2012 Asian Pacific Association for the Study of the Liver (APASL) guideline for chronic hepatitis B patients. Aliment Pharmacol Ther 2013;37(2):243-51

24.

16.

Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130(3):678-86

Lai CL, Yuen MF. Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy. Hepatology 2013;57(1): 399-408



17.

Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295(1):65-73

Recent review of the impact of antiviral therapy in preventing hepatitis B virus-related HCC.

25.

Sung JJ, Tsoi KK, Wong VW, et al. Metaanalysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther 2008;28(9): 1067-77

Papers of special note have been highlighted as: • of interest •• of considerable interest 1.

Horton R. GBD 2010: understanding disease, injury, and risk. Lancet 2012; 380(9859):2053-4

2.

Cowie BC, Carville KS, Maclachlan JH. Mortality due to viral hepatitis in the Global Burden of Disease Study 2010: new evidence of an urgent global public health priority demanding action. Antivir Ther 2013;In press



Updated figures on the global burden of disease related to viral hepatitis.

3.

McMahon BJ. Chronic hepatitis B virus infection. Med Clin North Am 2014;98(1): 39-54

4.

European Association For The Study Of The Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol 2012;57(1):167-85

5.

Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int 2012;6:531-61

6.

Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50(3):661-2

7.

Wong DK, Seto WK, Fung J, et al. Reduction of hepatitis B surface antigen and covalently closed circular DNA by nucleos (t)ide analogues of different potency. Clin Gastroenterol Hepatol 2013;11(8):1004-10



Article demonstrating the lack of impact of currently available antiviral agents on cccDNA levels.

8.

Arzumanyan A, Reis HM, Feitelson MA. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer 2013;13(2):123-35

••

Excellent review of pathogenesis of hepatocellular carcinoma (HCC) related to viral hepatitis.

414

13.

14.

15.



Tian Y, Yang W, Song J, et al. Hepatitis B virus X protein-induced aberrant epigenetic modifications contributing to human hepatocellular carcinoma pathogenesis. Mol Cell Biol 2013;33(15):2810-16 Jin YM, Yun C, Park C, et al. Expression of hepatitis B virus X protein is closely correlated with the high periportal inflammatory activity of liver diseases. J Viral Hepat 2001;8(5):322-30

Pivotal paper demonstrating the relationship between hepatitis B virus DNA levels and the risk of HCC.

Expert Rev. Gastroenterol. Hepatol. 8(4), (2014)

Managing hepatitis B to prevent liver cancer

Downloaded by [University of Otago] at 01:26 02 November 2015

26.

Lin SM, Sheen IS, Chien RN, et al. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology 1999;29(3):971-5

27.

Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351(15):1521-31

28.

Park YH, Kim BK, Kim JK, et al. Long-term outcomes of chronic hepatitis B virus infection in the era of antiviral therapy in Korea. J Gastroenterol Hepatol 2013;In press

29.

Papatheodoridis GV, Manolakopoulos S, Touloumi G, et al. Virological suppression does not prevent the development of hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients with cirrhosis receiving oral antiviral(s) starting with lamivudine monotherapy: results of the nationwide HEPNET. Greece cohort study. Gut 2011;60(8):1109-16

30.

Thursz M, Brown A. Can antiviral therapy of chronic hepatitis B prevent the development of hepatocellular carcinoma? Gut 2011;60(8):1025-6

31.

Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol 2010;53(2): 348-56

32.

Chang TT, Lai CL, Kew Yoon S, et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2010;51(2): 422-30

33.

Yuen MF, Seto WK, Fung J, et al. Three years of continuous entecavir therapy in treatment-naive chronic hepatitis B patients: VIRAL suppression, viral resistance, and clinical safety. Am J Gastroenterol 2011; 106(7):1264-71

34.

Marcellin P, Asselah T. Long-term therapy for chronic hepatitis B: hepatitis B virus DNA suppression leading to cirrhosis reversal. J Gastroenterol Hepatol 2013;28(6):912-23

35.

Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 2013;58(1):98-107

••

Important study demonstrating that long-term entecavir can reduce the incidence of HCC.

36.

Yang HI, Sherman M, Su J, et al. Nomograms for risk of hepatocellular carcinoma in patients with chronic hepatitis

informahealthcare.com

B virus infection. J Clin Oncol 2010; 28(14):2437-44 37.

38.

39.

40.

41.

Zoutendijk R, Reijnders JG, Zoulim F, et al. Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis. Gut 2013;62(5):760-5 Singal AK, Salameh H, Kuo YF, Fontana RJ. Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B. Aliment Pharmacol Ther 2013;38(2):98-106 Gordon SC, Lamerato LE, Rupp LB, et al. Antiviral Therapy for Chronic HBV Infection and Development of Hepatocellular Carcinoma in a U.S. Population. Clin Gastroenterol Hepatol 2013;In press Triolo M, Corte CD, Colombo M. Impact of HBV therapy on the incidence of hepatocellular carcinoma. Liver Int 2014; 34(Suppl 1):139-45 European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56(4):908-43

Review

B-related hepatocellular carcinoma after curative therapy: a meta-analysis. Hepatol Res 2013; In press 49.

Wu CY, Chen YJ, Ho HJ, et al. Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection. JAMA 2012;308(18):1906-14

50.

Wong JS, Wong GL, Tsoi KK, et al. Metaanalysis: the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther 2011;33(10):1104-12

51.

Ke Y, Ma L, You XM, et al. Antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after radical hepatectomy. Cancer Biol Med 2013;10(3): 158-64

52.

Yin J, Li N, Han Y, et al. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol 2013;31(29):3647-55



A two-stage longitudinal study incorporating a randomized trial of NA therapy after surgical resection for HCC demonstrating a significant benefit in terms of reducing HCC recurrence and improving postoperative survival.

42.

Breitenstein S, Dimitroulis D, Petrowsky H, et al. Systematic review and meta-analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis. Br J Surg 2009;96(9):975-81

53.

43.

Huang TS, Shyu YC, Chen HY, et al. A systematic review and meta-analysis of adjuvant interferon therapy after curative treatment for patients with viral hepatitis-related hepatocellular carcinoma. J Viral Hepat 2013;20(10):729-43

Poynard T, Massard J, Rudler M, et al. Impact of interferon-alpha treatment on liver fibrosis in patients with chronic hepatitis B: an overview of published trials. Gastroenterol Clin Biol 2009;33(10-11): 916-22

54.

44.

Zhuang L, Zeng X, Yang Z, Meng Z. Effect and safety of interferon for hepatocellular carcinoma: a systematic review and meta-analysis. PLoS One 2013;8(9):e61361

45.

Kim BK, Park JY, Kim do Y, et al. Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection. Liver Int 2008;28(3): 393-401

Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010;52(3): 886-93

55.

Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013;381(9865):468-75

••

Article providing evidence that long-term treatment with effective antivirals can result in regression of cirrhosis.

56.

Toy M. Cost-effectiveness of viral hepatitis B & C treatment. Best Pract Res Clin Gastroenterol 2013;27(6):973-85

57.

Strasser SI. Drugs in development for the treatment of chronic hepatitis B. Curr Hepat Rep 2012;11:111-18

46.

47.

48.

Wu JC, Huang YH, Chau GY, et al. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol 2009;51(5):890-7 Yang T, Lu JH, Zhai J, et al. High viral load is associated with poor overall and recurrence-free survival of hepatitis B virus-related hepatocellular carcinoma after curative resection: a prospective cohort study. Eur J Surg Oncol 2012;38(8):683-91 Qu LS, Liu JX, Kuai XL, et al. Significance of viral status on recurrence of hepatitis

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Managing hepatitis B to prevent liver cancer: recent advances.

Chronic hepatitis B (CHB) infection is a major cause of human mortality worldwide. The majority of people with CHB are infected early in life, and 20-...
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