Chronic Hepatitis B: A Treatment Update

Transcription

1 122 Chronic Hepatitis B: A Treatment Update Vincent Wong, MD 1,2 Henry Chan, MD 1,2 1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong 2 Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Address for correspondence Henry L.Y. Chan, MD, Department of Medicine and Therapeutics, 9/F, Prince of Wales Hospital, Ngan Shing Street, Shatin, Hong Kong ( hlychan@cuhk.edu.hk). Semin Liver Dis 2013;33: Abstract Keywords peginterferon entecavir tenofovir cirrhosis hepatocellular carcinoma In the past two decades, there have been major developments in the treatment of chronic hepatitis B. Peginterferon can be given conveniently with weekly dosing, and its effect on hepatitis B e antigen seroconversion is highly durable. However, it carries numerous side effects and the treatment is successful in only 30 to 40% of patients. Ontreatment hepatitis B surface antigen level is an indirect marker of the level and transcriptional activity of covalently closed circular DNA in the liver and may identify nonresponders to peginterferon. New oral nucleos(t)ide analogs such as entecavir and tenofovir can effectively suppress hepatitis B virus with minimal risk of drug resistance. Many patients, however, develop virologic relapse after cessation of oral antiviral therapy despite prolonged viral suppression and would require long-term treatment. During oral antiviral drug treatment, hepatitis B virus DNA monitoring is essential to assess treatment effect and drug adherence and detect drug resistance. In treatmentnaïve patients, none of the drug combinations have been shown to be superior to monotherapy. Studies combining peginterferon and potent oral agents (entecavir and tenofovir) are underway. Tenofovir is effective in patients with lamivudine resistance and previous exposure to multiple agents. Its long-term efficacy as monotherapy in this setting warrants more studies. In the past two decades, we have witnessed revolutionary changes in the treatment of chronic hepatitis B. The introduction of peginterferon allows a finite course of treatment with convenient dosing. While hepatologists busied themselves managing drug resistance when lamivudine was first used, we now have potent oral nucleos(t)ide analogs (NAs) with high genetic barrier to resistance. This review is not meant to provide a comprehensive summary of the literature on different antiviral therapies, which has been covered in the regional guideline articles. Our focuses are on the practical aspects and controversies in the treatment of chronic hepatitis B. The role of virological tests in guiding treatment is also discussed. Goal of Treatment Various antiviral therapies can lead to normalization of serum alanine aminotransferase (ALT), hepatitis B virus (HBV) DNA suppression, hepatitis B e antigen (HBeAg) seroconversion, hepatitis B surface antigen (HBsAg) seroclearance, and histological improvement. At the end of the day, however, these are all just surrogate markers. The most important goal of treatment is prevention of hepatic mortality and morbidity like hepatocellular carcinoma (HCC) and cirrhotic complications. The strongest evidence on the role of antiviral therapy in preventing clinical complications came from the Cirrhosis Asian Lamivudine Multicentre (CALM) Study. 1 In this placebo-controlled randomized trial, lamivudine treatment for around 3 years reduced the risk of a composite end point of progression in the Child-Pugh score of 2 points or more, cirrhotic complications, HCC, and liver-related deaths from 17.7% to 7.8%. Subsequent meta-analyses including the CALM Study and other observational studies showed that lamivudine treatment, compared with placebo or no treatment, is associated with lower risk of HCC. 2 Successful treatment with Issue Theme Current Perspectives on Chronic Hepatitis B; Guest Editors, Stephen Locarnini, MD, PhD, FRC(Path), and Alexander Thompson, MD, PhD, FRACP Copyright 2013 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) DOI /s ISSN

2 Chronic Hepatitis B: A Treatment Update Wong, Chan 123 conventional interferon is also associated with reduced risk of HCC and cirrhotic complications. 3 Besides, patients with ALT normalization or histological improvement after antiviral therapy have lower incidence of hepatic events than nonresponders, again supporting the role of antiviral therapy in preventing adverse outcomes. 4 For historic reasons, there are scarce data on the effect of new antiviral agents on hard clinical outcomes. When patients treated with peginterferon were followed for 5 to 8 years, liver fibrosis improved gradually and new cases of advanced fibrosis or cirrhosis only occurred rarely in nonresponders. 5 In an uncontrolled cohort study of 372 patients treated with entecavir, HCC, liver decompensation, and death were less frequent in those with on-treatment HBV DNA below 80 IU/mL, but the beneficial effect was only apparent in patients with cirrhosis. 6 Peginterferon Versus Nucleos(T)ide Analogs Worldwide, seven drugs have been registered for the treatment of chronic hepatitis B. These include two interferons (conventional interferon and peginterferon alfa-2a) and five oral NAs (lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxilfumarate). Rather than stating which mode of treatment is the best, the relative merits and limitations of individual agents should be examined. The main advantage of conventional interferon and peginterferon is their finite course of treatment and high durability. Among patients who have achieved HBeAg seroconversion after conventional interferon or peginterferon treatment, 80% continue to have sustained HBeAg seroconversion 5 to 10 years later. 5,7 However, interferon requires subcutaneous injections and is associated with numerous side effects such as flu-like symptoms, bone marrow suppression, thyroid dysfunction, and mood disorders. Dose reduction and premature treatment cessation are often necessary to manage the side effects. Besides, interferon may aggravate liver decompensation in patients with advanced disease or very high ALT level. In contrast, NAs are given conveniently via oral route and carry few side effects. However, because NAs do not have direct immunomodulatory actions, the treatment effect is less durable. Virological relapse after treatment cessation occurs in 30 to 40% of patients with HBeAg-positive disease achieving HBeAg seroconversion and in around 50% of patients with HBeAg-negative disease even after a prolonged period of HBV DNA suppression As a result, the majority of patients require long-term treatment. This is particularly problematic for weaker agents because of their propensity to induce drug resistance. Because of these differences, the choice of antiviral agents should be a joint decision between the patient and the hepatologist. Interferon is often preferred in young patients who do not want long-term treatment, particularly if family planning is an issue. In contrast, NAs are an attractive option for older patients and those with advanced disease because of better tolerance. It should be highlighted that different therapeutic end points should be adopted when different agents are used. When NAs are used, the immediate goal is complete ontreatment virological response undetectable HBV DNA. In contrast, few patients treated with interferon can have persistently undetectable HBV DNA after treatment decision. This, however, should not be taken as evidence of interferon s inferiority. In epidemiological studies, patients with HBV DNA below 2000 IU/mL have similar incidence of HCC to those with undetectable HBV DNA. 11 Besides, current observation suggests that interferon is probably as effective as NAs in preventing adverse clinical outcomes. 2 This implies that complete viral suppression may not be essential. The main reason for maintaining undetectable HBV DNA in NA-treated patients is to prevent drug resistance. Peginterferon Current Evidence and Recommendations Both conventional interferon and peginterferon are recommended as options for finite duration of treatment in chronic hepatitis B Conventional interferon is dosed at 5 to 10 MU three times weekly for 4 to 6 months in HBeAgpositive patients. The data for extended conventional interferon in HBeAg-positive patients is scanty, though there is some data suggesting that prolonging the treatment duration to 32 weeks may improve response rate. 15 As HBeAg-negative patients are generally having a lower sustained response rate, a 12-month course of interferon is usually recommended. The major benefit of peginterferon over conventional interferon is a more convenient once weekly dosing. A phase II, dose ranging, multicenter study has shown superior efficacy of 6-month peginterferon alfa-2a over conventional interferon in HBeAg-positive patients. 16 However, another study in China comparing 6-month peginterferon alfa-2b versus conventional interferon only showed better response with peginterferon among genotype B HBV-infected patients and patients younger than 25 years old. 17 The recommended standard dose of peginterferon alfa-2a is 180 μg weekly for 48 weeks, which is the regime used in all the pivotal studies for both HBeAg-positive and HBeAgnegative patients. 18,19 It takes half a decade before the evidence to support the use of 48-week over 24-week peginterferon is available. 20 In this study (the Nephrotic Syndrome Study Network [NEPTUNE]), peginterferon alfa- 2a at a standard dose of 180 μg/wk for 48 weeks was associated with higher rate of HBeAg seroconversion and HBV DNA suppression than a lower dose (90 μg/wk) or a shorter duration of therapy (24 wk). The recommended dosing of peginterferon alfa-2b is 1.5 μg/kg weekly or 12 months, though the dosing and duration of peginterferon alfa-2b are variable in different studies. 17,21,22 In the multicenter, European study, peginterferon alfa-2b was started with 1.5 μg/kg weekly for 32 weeks, and the dose was reduced to 1.0 μg/kg weekly for the subsequent 20 weeks. 21 More evidence is required to document the optimal dosing of peginterferon alfa-2b in chronic hepatitis B.

3 124 Chronic Hepatitis B: A Treatment Update Wong, Chan Baseline Predictors of Response Many baseline factors have been investigated to predict response to interferon therapy. In a combined analysis of 542 patients in three pivotal studies using both peginterferon alfa-2a and 2b, HBeAg-positive patients, a combination of HBV genotype, HBV DNA, and ALT levels can predict the chance of response to a standard 12-month peginterferon therapy. 23 Genotype A HBV infection has the best response; patients who have either baseline HBV DNA < 9 log copies/ ml or ALT > 2 time upper limit of normal will have a > 30% chance of sustained HBeAg seroconversion. Genotype B and C HBV infections have similar intermediate response; patients need to have both baseline HBV DNA < 9 log copies/ml and ALT > 2 time upper limit of normal before they have a > 30% chance of sustained HBeAg seroconversion. Genotype D HBV is the most difficult to treat and cannot achieve 30% sustained response regardless of the baseline HBV DNA and ALT levels. Similarly, in HBeAg-negative patients, baseline HBVgenotype, HBV DNA, and ALT levels can predict the response to 48-week peginterferon treatment. 24 Some early evidence suggested that host factor such as polymorphism near the IL28Bgene can predict response to peginterferon therapy, but more data are needed for confirmation. 25 On-Treatment Predictor of Response Baseline predictors can only guide the selection of potential good responders for peginterferon treatment. However, they have little value to guide the duration of therapy once treatment is started. As peginterferon therapy involves subcutaneous injection and has many side effects, it is desirable if nonresponders are identified so that peginterferon can be stopped early. In other words, a stopping rule can reduce the unnecessary extension of peginterferon therapy in the nonresponding patients. Patients who have inadequate HBV DNA suppression during the early phase of treatment usually respond poorly to peginterferon. However, the timing and cutoff values of HBV DNA levels are controversial among different studies In a post hoc analysis of the phase III study of peginterferon alfa-2a for HBeAg-positive chronic hepatitis B, an HBeAg level of > 100 PEIU/mL at week 24 has a 96% negative predictive value (NPV) for HBeAg seroconversion 24 weeks posttreatment. 26 Unfortunately, the results of this study have not been validated by other investigators, and HBeAg quantification is not useful in HBeAg-negative patients. Serum HBsAg level is often used as an indirect marker of the level and transcriptional activity of the covalently closed circular DNA in the liver. 29 Pretreatment serum HBsAg level has some correlation with peginterferon response, but it may not be good enough as a standalone marker for patient selection. Responders to peginterferon usually have a more dramatic reduction in serum HBsAg level during treatment. In general, the greater reduction of serum HBsAg to lower level during treatment, the higher the chance of sustained response posttreatment. Based on the phase III study of peginterferon alfa-2a, HBsAg < 1,500 IU/mL at week 12 and 24 can predict an > 50% chance of sustained HBeAg seroconversion while HBsAg >20,000 IU/mL has a high NPV for nonresponse. 30 For HBeAg-negative patients, the best validated rule for nonresponse is an absence of HBsAg decline together with a < 2 log reduction in HBV DNA at week 12 in genotype D HBV infected patients, but more studies are required before it can be generalized to other HBV genotypes. 31 A > 10% decline of serum HBsAg level at week 12 and 24 can also predict a close to 50% chance of sustained response in HBeAgnegative patients. 32 Response-Guided Therapy On-treatment HBsAg levels can be used as the backbone of response-guided therapy with peginterferon. Among patients who are likely nonresponders, peginterferon can be stopped at week 12 or week 24. If clinically indicated, nonresponders to peginterferon can be switched to oral antiviral drugs. For patients with good or intermediate on-treatment HBsAg response, the strategy of response-guided therapy is not certain at the present moment. Continuation of peginterferon for the rest of the year will be a standard strategy. Based on the experience of lamivudine, adefovir and entecavir combination, adding an oral antiviral drug to peginterferon is unlikely able to improve the off-treatment response In a German cohort, even with prolonged adefovir for 2 more years after the 48-week course of peginterferon and adefovir combination, it could not improve the clearance or further suppress the transcription of covalently closed circular DNA in the liver. 36 On the other hand, there is emerging evidence that extension of peginterferon for over 1 year may improve the sustained response and reduce the posttreatment relapse rate. A pilot study including 13 American HBeAg-negative patients treated with peginterferon for 60 weeks has resulted in a 62% virological response (defined as HBV DNA < 20,000 copies/ml with a > 2 log reduction from baseline) and 38% of undetectable HBV DNA at 6 months posttreatment. 37 Recently, an Italian randomized study among predominantly genotype D HBV infected HBeAg-negative patients has shown a significant higher rate of sustained virological suppression with 96-week versus 48-week peginterferon therapy. At 48- weeks posttreatment, 28.8% patients who received 96-week peginterferon and 11.8% patients who received 48-week treatment could achieve HBV DNA < 2,000 IU/mL. 38 Future randomized, controlled studies on the use of extended peginterferon therapy among patients with good or intermediate on-treatment response are awaited. Nucleos(T)ide Analogs Current Evidence and Recommendations Lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxilfumarate are NAs registered for the treatment of chronic hepatitis B. All NAs are given once daily per oral at a fixed dosage ( Table 1). Because all NAs are excreted mostly or fully by the kidneys, dose adjustment is required in patients with estimated glomerular filtration rate below 50 ml/min/1.73 m 2. Data on the use of NAs in patients with

4 Chronic Hepatitis B: A Treatment Update Wong, Chan 125 Table 1 Oral nucleos(t)ide analogs for the treatment of chronic hepatitis B Drugs Dosage Antiviral activity Drug resistance Specific side effects Pregnancy category Lamivudine 100 mg daily Low 70% in 5 y Negligible C Adefovir dipivoxil 10 mg daily Low 29% in 5 y Nephrotoxicity, C hypophosphatemia Entecavir 0.5 mg daily High 1.2% in 5 y Negligible C Telbivudine 600 mg daily High 30% in 3 y Myopathy B Tenofovir disoproxilfumarate 300 mg daily High 0% in 5 y Nephrotoxicity, hypophosphatemia, bone loss B estimated glomerular filtration rate below 30 ml/min/ 1.73 m 2 or on dialysis are scarce. Owing to differences in genetic barrier, current guidelines recommend entecavir and tenofovir as preferred first-line NAs for the treatment of chronic hepatitis B Entecavir is registered to be used at a dose of 0.5 mg daily for treatmentnaïve patients and 1.0 mg daily for lamivudine-refractory patients. It should be noted that entecavir was given at 1.0 mg daily during extended follow-up of the original registration trial. 39 However, real-life cohort studies suggest that entecavir 0.5 mg daily is not associated with increased risk of drug resistance and treatment failure in treatment-naïve patients. 40,41 Although entecavir at a dose of 1.0 mg daily is superior to continuing lamivudine in lamivudine-refractory patients, up to 50% of such patients develop entecavir resistance in 5 years; therefore, this cannot be recommended. 39 This is due to partial cross-resistance between lamivudine and entecavir. Tenofovir is given at a dose of 300 mg daily. In the followup study of the registration trial, no patient developed tenofovir resistance in 5 years. The rate of tenofovir resistance may have been underestimated because patients with HBV DNA above 400 copies/ml at week 72 were allowed to add emtricitabine as a fixed dose combination tablet (Truvada, Gilead, Foster City, CA). 42 However, post hoc analysis suggests that resistance should be very rare, even if the patients were continued with tenofovir monotherapy. In most countries, tenofovir is more commonly used for the treatment of lamivudine resistance or patients exposed heavily to different NAs. Because of different mutational pathways, it comes as no surprise that tenofovir is a highly effective treatment for lamivudine resistance. What is less certain is its efficacy in patients with adefovir resistance. In vitro studies showed that the rta194t mutation confers partial resistance to tenofovir. 43 Around 60 to 90% of adefovir-experienced patients can achieve undetectable HBV DNA with tenofovir and/or emtricitabine treatment ( Table 2) A retrospective study showed that only 33% of patients with adefovir resistance at baseline had undetectable HBV DNA in 1 year, 47 but the findings were not confirmed by others. 45,46,48 The inconsistent use of addon emtricitabine in different studies makes it difficult to determine the role of combination treatment in this context. NAs are largely safe. No specific side effects are associated with lamivudine and entecavir. Adefovir and tenofovir may damage renal tubular cells and cause nephrotoxicity, though the risk appears small and the effect is mostly reversible. 49 Tenofovir treatment has been reported to cause greater loss in bone mineral density in patients infected with human immunodeficiency virus. 50 The same phenomenon has not been reported in patients with chronic hepatitis B. On-Treatment Monitoring During NA treatment, patients should be monitored for drug adherence, resistance, and side effects. The most important monitoring test for treatment efficacy and drug resistance is HBV DNA. When a drug with low genetic barrier to resistance is used, undetectable HBV DNA must be maintained to prevent the development of drug resistance. 51 For drugs with high genetic barrier to resistance, complete viral suppression appears less important. 6,40 In any case, drug adherence should be enquired in case of incomplete virological response. Patients on telbivudine treatment should be monitored for muscle symptoms. The role of creatine kinase levels monitoring dubious, as most patients with elevated creatine kinase do not have myopathy. Patients treated with adefovir or tenofovir should have renal function and phosphate level monitoring. There is currently insufficient data to support routine bone mineral density assessment. Combination Treatment Combination treatment may be in the form of NA plus interferon or using two NAs together. In the pivotal peginterferon studies, although the combination of peginterferon and lamivudine resulted in greater HBV DNA reduction during treatment, there was no meaningful advantage over peginterferon monotherapy in ALT normalization, HBeAg seroconversion, posttreatment HBV DNA level, and histological improvements. 18,19,21,22 Studies combining peginterferon and more potent NAs (entecavir and tenofovir) are under way. De novo combination of lamivudine and adefovir does not improve viral suppression over lamivudine alone, although this reduces, but not abolishes lamivudine resistance. 52 Furthermore, adefovir resistance was not reported in this study. Combining telbivudine and lamivudine again does not

5 126 Chronic Hepatitis B: A Treatment Update Wong, Chan Table 2 Efficacy of tenofovir in adefovir suboptimal responders Author/Year Study design N Patient composition Treatment effects van Bommel et al Retrospective cohort study Tan et al Berg et al van Bommel et al Retrospective cohort study Randomized controlled trial Retrospective cohort study Patterson et al Prospective cohort study 20 on tenofovir All had previous lamivudine resistance HBV DNA > 5logcopies/ ml while on adefovir 4 had rtv173v, rtl180m, and rtm204v 1 had rtm204v; 1 had rtm204i. 10 on tenofovir 3ontenofovirþ emtricitabine 53 on tenofovir 52 on tenofovir þ emtricitabine HBV DNA > 4logcopies/ ml or virological breakthrough during adefovir treatment 2 had rta181v; 1 had rta181v and rtn236t; 4 more patients had adefovir resistance on cloning. 1 had rtm204i and rtl180m; 1 had rtl80i, rtm204i and rtl180m. HBV DNA >1,000 copies/ ml while on adefovir 10% had rtn236t and/or rta181v/t. 12% had rtm204v/i, rtl180m, and/or rtv173l. 131 on tenofovir HBV DNA 4logcopies/ ml while on other NAs. 19% had rta181v/t and/or rtn236t. 62% had rtm204v/i, rtl180m, and/or rtv173l (1 patient had rtm204v, rtl180m, and rts202g from previous entecavir treatment). 38 on tenofovir 22 on tenofovir þ lamivudine (16 on tenofovir monotherapy initially were added lamivudine at week 24) All had previous lamivudine resistance HBV DNA > 5logcopies/ ml in HBeAg-positive patients or >4 logcopies/ml in HBeAg-negative patients while on adefovir. 20 had rtm204v/i; 21 had rta181t/v and/or rtn236t Abbreviations: HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; NA, nucleos(t)ide analog. 19 had HBV DNA < 400 copies/ml in 1 8 moof treatment 4of19hadHBeAgloss; 1hadHBsAg seroconversion 4hadHBVDNA< 200 copies/ml within 12 mo. 10 had HBV DNA < 200 copies/ml at the last visit. 2of11hadHBeAgloss. 81% in both groups had HBV DNA < 400 copies/ml at week 48. 8% had HBeAg loss. 1 patient had HBsAg loss. Virological response not affected by lamivudine or adefovir resistance at baseline. 90% had HBV DNA < 400 copies/ml at month % had HBeAg seroconversion. 4% had HBsAg loss. 33% with adefovir resistance at baseline and 90% without resistance had HBV DNA < 400 copies/ml at month % and 64% had HBV DNA <15 IU/mL within 48 and 96 wk, respectively. 13% had HBeAg loss at week 96; 0% had HBsAg loss. Virological response not affected by lamivudine or adefovir resistance at baseline. achieve greater reduction in HBV DNA than telbivudine monotherapy, but may even increase the risk of telbivudine resistance. 53 This suggests that NAs with the same resistance pattern should not be combined. Research in this disappointing field is reignited when new and potent NAs become available. Combination of entecavir and tenofovir is highly effective in patients with multidrug resistance, though it is uncertain if tenofovir monotherapy may be as good. 54 In a recent clinical trial, 379 treatmentnaïve patients were randomized to receive entecavir monotherapy (n ¼ 186) or entecavir plus tenofovir (n ¼ 198). 55 By week 96, 76% in the monotherapy arm and 83% in the combination arm had HBV DNA below 50 IU/mL (p ¼ 0.088). In a post hoc subgroup analysis, combination

6 Chronic Hepatitis B: A Treatment Update Wong, Chan 127 therapy was superior to entecavir monotherapy in patients with positive HBeAg and baseline HBV DNA over 8 log IU/mL. However, because the subgroup analysis was not planned a priori, the findings can only be considered exploratory and have to be confirmed in another study focusing on patients with high viral load. The efficacy of tenofovir monotherapy and higher dose entecavir (1.0 mg) has to be evaluated before combination therapy can be recommended for this group of patients. Stopping Treatment Although NAs are largely safe and effective during long-term treatment, patients may wish to stop for convenience and financial reasons. Currently guidelines recommend that it is possible to stop NAs in HBeAg-positive chronic hepatitis B after sustained HBeAg seroconversion and undetectable HBV DNA for at least 6 to 12 months In HBeAg-negative cases, the risk of virological relapse is high. NAs can only be stopped after HBsAg seroclearance. The Asian Pacific guideline is unique in recommending stopping NAs after at least 2 years of treatment if HBV DNA remains undetectable for at least three visits 6 months apart. 14 However, observational studies consistently showed that a significant proportion of patients would still have relapse despite fulfilling the guideline criteria. 8,10 Currently, there is limited knowledge on the predictors of virological relapse. For HBeAg-positive disease, a longer duration of consolidation antiviral therapy after HBeAg seroconversion can reduce the chance of relapse. 9 In a small retrospective study of 53 HBeAg-negative patients who stopped lamivudine after treatment for 12 to 76 months, all patients who had HBsAg below 100 IU/mL and decline of > 1 log continued to have suppressed HBV DNA 12 months later. 56 In contrast, all patients with HBsAg above 100 IU/mL and less than 1 log decline developed virological relapse. The results have to be replicated and tested in other NAs in a prospective manner before they can be applied in the clinic. Future Challenges Current antiviral treatment for chronic hepatitis B is effective, but imperfect. Peginterferon is a finite treatment but is only successful in a minority of patients and carries numerous side effects. NAs are well-tolerated, but often require long-term treatment. Besides, some patients may still develop HCC and cirrhotic complications despite complete viral suppression. To further improve patient outcomes, we need new treatment strategies. On one hand, future drugs should have improved tolerability and durability. Treatment that can increase the chance of HBsAg seroclearance would be an immediate goal. On the other hand, treatment would have to target beyond the virus. For example, new insights in the pathogenesis of liver fibrosis may offer new therapeutic targets for cirrhosis regression. Conflict of Interests Vincent Wong is in the advisory boards of Gilead and Otsuka, and has served as a speaker for Gilead, Novartis, Roche, Bristol-Myers Squibb, and Abbott Diagnostics. Henry Chan is a consultant for Abbott, Bristol-Myers Squibb, Gilead, Merck, Novartis, and Roche, and has received lecture fees from Abbott, Bristol-Myers Squibb, Echosens, Gilead, Glaxo-Smith-Kline, Merck, Novartis, and Roche. References 1 Liaw YF, Sung JJ, Chow WC, et al; Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351 (15): Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: Treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther 2008;28(9): Wong GL, Yiu KK, Wong VW, Tsoi KK, Chan HL. Meta-analysis: reduction in hepatic events following interferon-alfa therapy of chronic hepatitis B. 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7 128 Chronic Hepatitis B: A Treatment Update Wong, Chan 18 Lau GK, Piratvisuth T, Luo KX, et al; Peginterferon Alfa-2a HBeAg- Positive Chronic Hepatitis B Study Group. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352(26): Marcellin P, Lau GK, Bonino F, et al; Peginterferon Alfa-2a HBeAg- Negative Chronic Hepatitis B Study Group. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351 (12): Liaw YF, Jia JD, Chan HL, et al. Shorter durations and lower doses of peginterferon alfa-2a are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B virus genotypes B or C. Hepatology 2011;54(5): Janssen HL, van Zonneveld M, Senturk H, et al; HBV Study Group; Rotterdam Foundation for Liver Research. 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