Hepatitis B therapy FOCUS ON VIRAL HEPATITIS. Hellan Kwon and Anna S. Lok

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1 FOCUS ON VIRAL HEPATITIS Hepatitis B therapy Hellan Kwon and Anna S. Lok Abstract The goal of hepatitis B treatment is to prevent cirrhosis, liver decompensation and hepatocellular carcinoma. In clinical practice, treatment response is determined by suppression of serum HBV DNA levels, hepatitis B e antigen seroconversion to hepatitis B e antibody, hepatitis B surface antigen loss, normalization of alanine aminotransferase levels and improvement in liver histology. Patients with life-threatening liver disease, and those with high levels of HBV replication and active or advanced liver disease, should be treated. Other patients should be monitored so that treatment can be initiated when indicated. Currently, seven medications are approved for the treatment of hepatitis B: two formulations of interferon and five nucleos(t)ide analogues. Interferon is administered for a finite duration while nucleos(t)ide analogues are usually administered for many years. Antiviral drug resistance is a major limiting factor to the success of nucleos(t)ide analogue treatment; therefore, treatment should be initiated with drugs that have a high genetic barrier to resistance (that is, a low potential for drug resistance). In addition, treatment response should be closely monitored to detect virologic breakthroughs, and the importance of medication adherence should be emphasized. Management of patients with treatment failure should be tailored according to the type of treatment failure (lack of initial response versus virologic breakthrough), the treatment that the patient is receiving, history of prior treatment, and the pretreatment characteristics of both the patient and the disease. Kwon, H. & Lok, A. S. Nat. Rev. Gastroenterol. Hepatol. 8, (2011); published online 22 March 2011; doi: /nrgastro Introduction Substantial progress has been made in the treatment of hepatitis B in the past decade. The availability of medications that have potent antiviral activity and are safe for use in patients with cirrhosis has broadened the indications for hepatitis B treatment. However, current treatments do not eradicate the virus. Given that hepa titis B treatment is expensive and may be associated with drug resistance and adverse effects, and because not all patients with chronic HBV infection progress to cirrhosis, liver failure or hepatocellular carcinoma (HCC), many questions regarding hepatitis B treatment remain. First, who should be treated? Second, which medication to start with? Third, when can treatment be stopped? Finally, how should treatment failure be managed? This Review discusses the natural history of chronic HBV infection and the safety and efficacy of approved treatments before addressing these questions. Natural history of chronic HBV infection Phases of HBV infection The natural course of chronic HBV infection consists of four phases, although not all patients go through all phases (Figure 1). 1,2 Competing interests A. S. Lok declares associations with the following companies: Abbott, Bayer, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Innogenetics, Roche/Genentech, Schering/Merck. See the article online for full details of the relationships. H. Kwon declares no competing interests. Immune tolerant phase The immune tolerant phase is characterized by the presence of hepatitis B e antigen (HBeAg), high serum HBV DNA levels and persistently normal levels of alanine aminotransferase (ALT). Most patients in the immune tolerant phase have minimal liver injury and prognosis is favorable during follow-up of up to 10 years. 3 Immune clearance phase The immune clearance phase (or HBeAg-positive chronic hepatitis) is characterized by the presence of HBeAg, high serum HBV DNA levels, persistently or intermittently increased ALT levels and active inflammation in the liver. During this phase, spontaneous HBeAg seroconversion occurs at a rate of 10 20% per year. HBeAg sero conversion is frequently but not always accompanied by a sudden increase in ALT levels. 4,5 Patients who undergo spontaneous HBeAg seroconversion before the age of 40 have a good prognosis. 6 Inactive phase The inactive (carrier) phase is characterized by the absence of HBeAg, presence of HBe antibody (anti-hbe), persistently normal ALT levels and low or undetectable levels of serum HBV DNA. Patients in this phase have a favorable prognosis. 7 Reactivation phase The reactivation phase (also known as HBeAg-negative chronic hepatitis B) is characterized by the absence of HBeAg, presence of anti-hbe, intermittently or Division of Gastroenterology and Hepatology, University of Michigan Health System, 1500 E. Medical Center Drive, 3912 Taubman Center, SPC 5362, Ann Arbor, MI 48109, USA (H. Kwon, S. A. Lok). Correspondence to: A. S. Lok aslok@umich.edu NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY VOLUME 8 MAY

2 REVIEWS Key points Indication for hepatitis B treatment is determined by HBV replication status and the activity and stage of liver disease Patient age, hepatitis B e antigen status, and other circumstances such as family history of HCC, occupational requirement, need for immunosuppressive or cancer chemotherapy, and pregnancy plans should also be considered when deciding on treatment Patients with chronic HBV infection need life-long monitoring because the status of the disease can change with time There are seven approved treatments for hepatitis B: two formulations of interferon (conventional and pegylated), and five nucleos(t)ide analogues (lamivudine, entecavir, tenofovir disoproxil, adefovir dipivoxil and telbivudine) PEG-IFN, entecavir and tenofovir disoproxil are the preferred first-line treatments for hepatitis B Antiviral drug resistance is a major limiting factor to the success of nucleos(t)ide analogue therapy; treatment should be initiated with drugs that have a high genetic barrier to resistance and virologic response should be closely monitored HBV DNA HBeAg Anti-HBe Box 1 Factors associated with disease progression Viral Persistent presence of HBeAg Persistently high levels of HBV DNA HBV genotype C rather than genotype B Core promoter mutations* Host Male gender Increasing age Recurrent ALT flare Persistently increased ALT levels Cirrhosis* Diabetes* Environment Heavy drinking Cigarette smoking* Aflatoxin* HCV, HDV or HIV coinfection *Factors shown to be associated with an increased risk of HCC only. Abbreviations: ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma. ALT Immune tolerant 0 20 Immune clearance (HBeAg-positive chronic hepatitis) Time (years) Inactive carrier phase Reactivation (HBeAg-negative chronic hepatitis) Figure 1 Natural course of chronic HBV infection. The natural course of chronic HBV infection consists of four phases: the immune tolerant phase; the immune clearance phase (HBeAg-positive chronic hepatitis); the inactive carrier phase; and the reactivation phase (HBeAg-negative chronic hepatitis). ALT levels may be intermittently or persistently increased during the immune clearance and reactivation phases. HBV DNA levels are high during the immune tolerant phase. They decrease during the immune clearance phase and the inactive carrier phase, but may increase again during the reactivation stage. HBeAg seroconversion to anti-hbe occurs during the immune clearance phase (intermittently or persistently). Abbreviations: ALT, alanine aminotransferase; anti-hbe, hepatitis B e antibody; HBeAg, hepatitis B e antigen. Permission obtained from Elsevier Ltd Lok, A. S. Gastroenterology 132, (2007). persistently elevated serum HBV DNA and ALT levels, and active inflammation in the liver. Patients in this phase are usually older and have more advanced liver disease than patients in the other phases of the disease. In addition, most of these patients have precore or core promoter HBV variants that prevent or decrease the production of HBeAg. 8 Factors associated with disease progression Host, viral and environmental factors contribute to progression from chronic hepatitis to cirrhosis, liver failure and HCC (Box 1). Studies have demonstrated that persistently high levels of serum HBV DNA are associated with an increased risk of cirrhosis, HCC and liverrelated mortality. 9,10 This finding has led to an increased reliance on the HBV DNA level as an indication for hepatitis B treatment. Safety and efficacy of approved treatments Currently, seven treatments are approved for hepatitis B, including two formulations of interferon (IFN) (conventional IFN and PEG-IFN) and five nucleos(t)ide analogues (lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil). The goals of hepatitis B treatment are to achieve sustained suppression of HBV replication and remission of liver disease. The ultimate goal is to prevent cirrhosis, liver failure and HCC. As clinical outcomes can take decades to evolve, assessment of treatment response relies on intermediate outcomes, including a decrease in levels of serum HBV DNA, loss of HBeAg with or without seroconversion to anti-hbe, loss of hepatitis B surface antigen (HBsAg) with or without seroconversion to HBs antibody (anti-hbs), normalization of serum ALT levels, and a decrease in hepatic inflammation. Interferon IFN has both antiviral and immunomodulatory activity. Long-term follow-up of patients treated with conventional IFN therapy showed that responders had a decreased incidence of decompensation and HCC and improved overall survival compared with nonresponders PEG-IFN has superseded conventional IFN because it can be administered once a week instead of daily or three times a week and because it is associated with a higher rate of response. Response in HBeAg-positive chronic hepatitis A 1 year course of PEG-IFN resulted in HBeAg seroconversion in approximately 30% of HBeAg-positive 276 MAY 2011 VOLUME 8

3 FOCUS ON VIRAL HEPATITIS Table 1 Response rates (%) to approved therapies for HBeAg-positive and HBeAg-negative chronic hepatitis B Treatment response parameters Lamivudine Adefovir dipivoxil Approved therapies Entecavir Telbivudine Tenofovir disoproxil PEG-IFN* PEG-IFN plus lamivudine* HBeAg-positive patients at week 48 or 52 Histologic improvement Undetectable HBV DNA HBeAg seroconversion HBsAg loss < HBeAg-positive patients during extended treatment Undetectable HBV DNA NA 39(5.0) 94(5.0) 79(4.0) 77(4.0) 13 (4.5) 26 (4.5) HBeAg seroconversion 47 (3.0) 48 (5.0) 41 (5.0) 42 (4.0) 31 (3.0) 37 (4.5) 36 (4.5) HBsAg loss 0 3 ( ) 2(5.0) 5 (2.0) 1 (2.0) 10 (4.0) 8 (4.5) 15 (4.5) HBeAg-negative patients at week 48 or 52 Histologic improvement Undetectable HBV DNA HBsAg loss <1 NA <1 < HBeAg-negative patients during extended treatment Undetectable HBV DNA 6 (4.0) 67 (5.0) NA 84(4.0) 86(3.0) 18 (4.0) 13 (4.0) HBsAg loss <1 (4.0) 5 (5.0) NA <1 (2.0) 0 (4.0) 8 (4.0) 8 (4.0) Data obtained from several sources ,29 40,42,44 46,47,59 *Liver biopsy performed 24 weeks after stopping treatment. Histologic improvement defined as a >2-point decrease in the necroinflammatory score and no worsening of the fibrosis score. The time point at which response was assessed in years is shown in brackets. Assessment performed off treatment. Abbreviations: HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; NA, not available. patients when assessed 24 weeks after completion of treatment (Table 1) The addition of lamivudine led to a greater decrease in serum HBV DNA levels during treatment but did not increase the rate of HBeAg seroconversion. Follow-up of patients in one trial for a mean of 3.5 years after completion of PEG-IFN with or without lamivudine found that 37% had lost HBeAg and 11% had lost HBsAg (28% among those with genotype A infection and 3% among those with nongenotype A infection). 19 Response in HBeAg-negative chronic hepatitis A 1 year course of PEG-IFN resulted in undetectable serum HBV DNA and normalization of ALT levels in 15% of HBeAg-negative patients when assessed 24 weeks after completion of treatment. 20 Addition of lamivudine led to a greater decrease in serum HBV DNA levels during treatment but did not increase the rate of offtreatment virologic response. 3 years after completion of treatment, serum HBV DNA remained undetectable in 16% versus 6% of patients, ALT levels remained normal in 31% versus 18% of patients, and HBsAg loss occurred in 8% versus 0% of patients, of patients who received PEG-IFN with or without lamivudine versus lamivudine alone, respectively. 21 Predictors of response Among HBeAg-positive patients, the most reliable predictor of HBeAg seroconversion is increased levels of ALT prior to treatment. 22 Other predictors include a high histologic activity index, low serum HBV DNA levels, and infections with HBV genotypes A or B. 23,24 Among HBeAg-negative patients, a more marked decline in the serum HBsAg titer or a lower HBsAg titer at week 12 seems to be associated with a higher rate of sustained virologic response. 25,26 Adverse effects The most common adverse effect of IFN is an initial flu-like illness. Other common adverse effects include fatigue, anorexia, a mild increase in hair loss, emotional lability, bone marrow suppression, and unmasking or exacerbation of autoimmune illnesses. IFN is contraindicated in patients with decompensated cirrhosis because of the risk of sepsis and worsening liver failure. 27 IFN should also not be used in patients with HBV-related acute liver failure or severe exacerbations of chronic hepatitis B. IFN has, however, been shown to be safe in carefully selected patients who have compensated cirrhosis (those whose laboratory tests indicate normal hepatic synthetic function and who have no evidence of portal hypertension). 28 Dose regimen The approved dose of PEG-IFN-α2a is 180 μg weekly, administered subcutaneously. PEG-IFN-α2b is approved for the treatment of chronic hepatitis B in many countries but not in the US. Various doses of PEG-IFN-α2b ( μg/kg body weight weekly) have been used in clinical trials. Nucleos(t)ide analogues The five approved nucleos(t)ide analogues can be divided into three groups: l nucleosides (including lamivudine and telbivudine); acyclic nucleoside phosphonates NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY VOLUME 8 MAY

4 REVIEWS Terminal protein Spacer HBV polymerase POL/RT RNaseH 3 years demonstrated a reduction in both inflammation and fibrosis, indicating that antiviral therapy can reverse liver damage I (G) Nucleos(t)ide analogue L-Nucleoside Lamivudine Telbivudine Acyclic phosphonate Adefovir dipivoxil Tenofovir disoproxil D-Cyclopentane Entecavir* II (F) A POL/RT domains B C D E Amino acid substitution rta181t/v rta181t/v rta181t/v rta194t? rtt184 A/L/F/M/C/G/S/I rtm204v/i rtm204i rtm204v/i rts202g/c rtn236t rtm250v/l/i Figure 2 Mutations in the reverse transcriptase region of HBV polymerase that are associated with resistance to nucleos(t)ide analogue therapy. The HBV polymerase consists of four domains: terminal protein, spacer, POL/RT and RNaseH. The POL/ RT domain itself has seven domains (A, B, C, D, E, F and G), and it is amino acid substitutions in these domains that confer nucleos(t)ide analogue resistance. *Multiple amino acid substitutions at positions 184, 202 and 250 have been reported to be associated with resistance to entecavir. Abbreviations: A181T/V, alanine to threonine or valine; A194T, alanine to threonine substitution; M204V/I, methionine to valine or isoleucine; N236T, asparagine to threonine; rtt184a/l/f/m/c/g/s/i, threonine to alanine, leucine, phenylalanine, methionine, cysteine, glycine, serine or isoleucine; rts202g/c, serine to glycine or cysteine; rtm250v/l/i, methionine to valine, leucine or isoleucine. Permission obtained from John Wiley and Sons Lok, A. S. et al. Hepatology 46, (2007). (including adefovir dipivoxil and tenofovir disoproxil); and deoxyguanosine analogues (including entecavir). Upon entry into the hepatocyte nucleus, HBV DNA is transformed into a fully double-stranded DNA known as covalently closed circular DNA (cccdna). This cccdna serves as the template for transcription of the pregenomic RNA and messenger RNAs. The pre genomic RNA is reverse transcribed into HBV DNA in the hepato cyte cytoplasm. The HBV polymerase is divided into several domains; the POL/RT domain functions as a reverse transcriptase as well as a DNA polymerase. Currently approved nucleos(t)ide analogues act primarily by inhibiting the reverse transcription of the pregenomic HBV RNA to the first strand of HBV DNA. These agents do not have any direct inhibitory effect on cccdna; viral relapse is common, therefore, when treatment is stopped. HBeAg-positive chronic hepatitis A 1 year course of treatment with nucleos(t)ide analogues results in high rates of undetectable serum HBV DNA (21 76%), normalization of ALT levels (41 77%), and histologic improvement (49 74%), but only 12 22% of patients achieve HBeAg seroconversion and only 0 3% lose HBsAg (Table 1) Continuing treatment for 12 months after confirmation of HBeAg seroconversion consolidates the response and reduces the likelihood of HBeAg seroreversion. 35 Extending the duration of nucleos(t)ide treatment beyond 1 year results in increasing rates of HBeAg seroconversion to 40 50% after 5 years of treatment but rates of HBsAg loss remain below 10% Follow-up liver biopsies performed in patients who had maintained viral suppression for HBeAg-negative chronic hepatitis A 1 year course of treatment with nucleos(t)ide analogues results in very high rates of undetectable serum HBV DNA (51 93%), normalization of ALT levels (62 78%), and histologic improvement (60 72%), but <1% lose HBsAg (Table 1). 33,34,44 46 Viral relapse occurs in almost all patients when treatment is discontinued. Extending treatment with adefovir dipivoxil or tenofovir disoproxil to 4 5 years results in a high rate of maintained viral suppression (67 86%), but the rate of HBsAg loss remains low (0 5%). 42,47 Antiviral drug resistance Antiviral drug resistance is a major limitation to the long-term success of nucleos(t)ide analogue treatment. 48 Emergence of antiviral resistance is initially manifested as virologic breakthrough, which is defined as an increase in serum HBV DNA levels by >1 log from nadir, or the redetection of HBV DNA after it had become undetectable. Virologic breakthrough may be followed by biochemical breakthrough (increased ALT levels in a patient who previously had normalized ALT levels), hepatitis flares and hepatic decompensation if salvage therapy is not initiated. Signature mutations in HBV polymerase that are associ ated with resistance to the approved nucleos(t)ide analogues are shown in Figure The reported incidence of genotypic resistance to the five approved nucleos(t)ide analogues varies from 0 25% at 1 year to 1 70% at 5 years (Table 2). 36,39,40,42,47,49 Some mutations confer resistance to more than one drug; for example, a methionine to valine or isoleucine substitution (rtm204v/i), which is associated with lamivudine resistance, also confers resistance to telbivudine and decreases susceptibility to entecavir. 50 This finding explains the high rate of drug resistance in patients with previous treatment failure. 49,51 It is important to initiate treatment with a drug that has a high genetic barrier to resistance (low potential for drug resistance) because sequential monotherapy may result in the selection of multidrug resistance mutations. 52 Predictors of response Among HBeAg-positive patients, high pretreatment levels of serum ALT are the strongest predictor of treatment response. 22,53 For HBeAg-negative patients, there is no consistent predictor of treatment response. Unlike IFN treatment, virologic response to nucleos(t)ide analogues is similar across all the major HBV genotypes. 54 Adverse effects Nucleos(t)ide analogues for hepatitis B are very well tolerated. Adefovir dipivoxil and tenofovir disoproxil are reportedly associated with nephrotoxicity, which manifests as an increase in serum creatinine levels in 3% of patients after 3 5 years of continuous treatment, as well as renal tubular dysfunction, including Fanconi 278 MAY 2011 VOLUME 8

5 FOCUS ON VIRAL HEPATITIS syndrome. 37,40,42,47,55 Tenofovir disoproxil has also been reported to decrease bone mineral density, particularly in children. 56 Telbivudine may cause myopathy and peripheral neuropathy, especially when used in combination with PEG-IFN. 39 In one case series, entecavir was shown to be associated with lactic acidosis in patients who had severe liver dysfunction. 57 These data indicate that although nucleos(t)ide analogues for hepatitis B have excellent short-term safety, the long-term safety of these drugs has not been established. Dose regimen Nucleos(t)ide analogues for hepatitis B are administered orally as a single pill once a day. Doses of all the approved nucleos(t)ide analogues should be adjusted in patients who have impaired renal function. Who should be treated? The availability of multiple safe and efficacious drugs has expanded the indications for therapy in patients with hepatitis B. Thus, the question is no longer who should be treated but rather owing to the fluctuating course of chronic HBV infection when should treatment be initiated? The decision to start or to defer treatment should balance the activity and stage of liver disease, HBV replica tion status at the time of assessment and the predicted risk of cirrhosis and HCC in the foreseeable future with the risks of treatment (adverse effects, drug resistance and costs) and the likelihood of spontaneous remission. Guidelines on when to start treatment have been developed by the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, the Asian Pacific Association for the Study of Liver and an NIH Consensus Development Conference Situations in which treatment is clearly indicated Acute liver failure or decompensated cirrhosis In patients who have life-threatening liver disease, such as acute liver failure or decompensated cirrhosis, treatment with nucelos(t)ide analogues should be initiated as soon as possible. Although evidence supporting a benefit of treatment in these conditions is scanty, there is much to gain and very little to lose. Antiviral treatment also reduces the risk of recurrent hepatitis B should these patients require liver transplantation. Nucleos(t)ide analogue treatment has been shown to stabilize liver disease and in some cases reverse liver failure, allowing patients to be removed from the transplant waiting list. 63,64 Survival is also improved compared with historical controls. 63,64 Compensated cirrhosis Treatment should also be initiated in patients who have advanced fibrosis or compensated cirrhosis and high serum HBV DNA levels, because antiviral therapy has been shown to prevent disease progression in a prospective, randomized, double-blind, placebo-controlled trial. 65 In this trial, 651 patients who were HBeAg positive and/or had high serum HBV DNA levels (~150,000 IU/ml) with Table 2 Genotypic resistance to approved HBV nucleos(t)ide analogues Approved HBV nucleos(t)ide analogue Nucleos(t)ide analogue naive patients Incidence of genotypic resistance (%) Year 1 Year 2 Year 3 Year 4 Year 5 Lamivudine ~ Telbivudine NA NA NA Adefovir dipivoxil Entercavir* 0 ~ Tenofovir disoproxil NA Patients with lamivudine resistance Adefovir dipivoxil ~5 ~20 NA NA NA Entecavir Data obtained from several sources. 36,39,40,42,47,49 *Entecavir 1.0 mg daily after year 2 (previously 0.5 mg daily). Most patients with detectable HBV DNA at week 72 received additional treatment with emtricitabine. Abbreviation: NA, not available. bridging fibrosis or cirrhosis were randomly allocated to receive lamivudine or placebo. 65 This trial was terminated after a median duration of 32 months because treated patients had significantly lower rates of disease progression (defined as an increase in Child Turcotte Pugh score by 2 points, HCC, renal insufficiency, bleeding varices, spontaneous bacterial peritonitis and liver-related death) (7.8% versus 17.7%, P = 0.001) and HCC (3.9% versus 7.5%, P = 0.047) compared with patients who received placebo. Although patients in this trial had very high serum HBV DNA levels, the current recommendation for compensated cirrhosis is to initiate treatment in those who have serum HBV DNA levels >2,000 IU/ml, because studies have demonstrated that the risk of cirrhosis and HCC increases with serum HBV DNA levels >10,000 copies/ml (that is, ~2,000 IU/ml). 9,10 Patients receiving immunosuppressive therapy Prophylactic antiviral therapy is recommended for HBsAg-positive persons who will be receiving cancer chemotherapy or immunosuppressive therapy for other medical conditions to prevent reactivation of HBV replica tion. 58,60,66 A review of 14 studies found that antiviral therapy initiated before or at the onset of chemotherapy or immunosuppressive therapy reduced the incidence of HBV reactivation, HBV-related hepatitis, HBV-related liver failure, and HBV-related death by %. 67 Reactivation of HBV replication can also occur in patients who have serologic evidence of past HBV infection (presence of hepatitis B core antibody with or without anti-hbs) but the incidence is lower compared with patients who are HBsAg positive, and the need for prophylactic antiviral therapy is unclear. Situations in which treatment should be considered The decision regarding when to start treatment in patients who have compensated precirrhotic liver disease is complex because of the fluctuating course of chronic HBV infection. In general, patients who have persistently high serum HBV DNA levels and active liver disease should be treated. Other factors such as patient age, HBeAg status, family history of HCC, occupational NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY VOLUME 8 MAY

6 REVIEWS requirements (health-care workers engaged in exposureprone procedures), family planning (women of reproductive age contemplating pregnancy in the near future) and patient preference may influence the decision to start or to defer treatment. HBeAg-positive chronic hepatitis HBeAg-positive patients who have ALT levels persistently more than two times the upper limit of normal or histologic evidence of moderate or severe inflammation or advanced fibrosis should be considered for treatment. Patients who are jaundiced or who present with a severe flare of hepatitis B (that is, with coagulopathy or an increase in bilirubin levels) should begin treatment immediately. The remaining patients should be monitored for 3 6 months and treatment initiated only in those who fail to achieve spontaneous HBeAg sero conversion. Owing to the strong association between adverse outcomes and high serum HBV DNA levels or the presence of HBeAg, patients who remain HBeAg positive, as well as those who have high serum HBV DNA levels beyond the age of 40, regardless of ALT level, should be considered for treatment. Studies suggest that there may be a role for antiviral prophylaxis starting in the second or third trimester of pregnancy in carrier mothers who have high serum HBV DNA levels to further reduce the risk of maternal infant transmission in babies who will be receiving hepatitis B immuno globulin and HBV vaccine; however, when antiviral therapy should be started and when it can be stopped has not been established. 68,69 HBeAg-negative chronic hepatitis Patients who have HBeAg-negative chronic hepatitis should be considered for treatment. Given that sustained spontaneous remission is rare, a period of pretreatment observation is not necessary. Situations in which treatment may be deferred Treatment may be deferred in some patients but these patients should continue to be monitored so that treatment can be initiated at a later stage if HBV replication or liver disease becomes more active. Immune tolerant phase Treatment may be deferred in young (<40 years) HBeAgpositive patients who are in the immune tolerant phase. These patients generally have no or minimal fibrosis on liver biopsy and have a favorable prognosis during follow-up of up to 10 years. 3 Another reason for deferring treatment in these patients is the low likelihood of treatment-related HBeAg seroconversion. A third reason for deferring treatment is that some of these patients will undergo spontaneous HBeAg seroconversion with time. Continued monitoring of these patients allows timely initia tion of treatment if they fail to undergo spontaneous HBeAg seroconversion. Inactive carrier phase Treatment may be deferred in inactive carriers; however, determination of inactivity should only be made after the patients have been observed for at least 1 year with HBV DNA and ALT levels tested on three or four occasions. Which medication to start with? The decision to start treatment with PEG-IFN or a nucleos(t)ide analogue is based upon patient characteristics and preference. The main advantage of IFN is that it is administered for a finite duration. Another advantage of IFN is the high rate of HBsAg loss, particularly among HBeAg-positive patients who have a genotype A infection compared with patients who are infected with other HBV genotypes. A study has also found that IFNinduced HBeAg seroconversion is more durable than nucleos(t)ide-induced HBeAg seroconversion. 70 The main disadvantages of IFN are the need for parenteral administration and the adverse effects. Nucleos(t)ide analogues are administered orally and are well tolerated but viral relapse is common when treatment is stopped, which necessitates long durations of treatment with the associated risks of antiviral drug resistance, high costs, problems with adherence and the potential for adverse effects. Clinical studies have shown that the combination of PEG-IFN and lamivudine results in a more marked decline in serum HBV DNA levels during treatment but no difference in the rate of sustained virologic response compared with PEG-IFN alone. 16,20 Studies comparing a combination of two nucleos(t)ide analogues have shown no benefit of these combinations compared with either drug alone regarding antiviral efficacy. 71,72 The main advantage of combination therapies is a reduction in the rate of lamivudine resistance compared with lamivudine monotherapy. Owing to the low rate of antiviral resistance associated with entecavir or tenofovir disoproxil monotherapy, the benefit of de novo combination therapy involving either of these two drugs is limited. Currently, monotherapy with a nucleos(t)ide analogue or PEG-IFN is recommended as the initial therapy. IFN is not recommended for patients who have hepatic decompensa tion, immunosuppression or medical or psychi atric contraindications. IFN may be used in patients with compensated cirrhosis who have normal synthetic function and no evidence of portal hypertension. IFN is most appropriate for young patients, those who are reluctant to commit to a long duration of treatment, and HBeAg-positive patients who have high pretreatment ALT levels or genotype A infection. 24 Nucleos(t)ide analogues are most appropriate for patients who have decompensated liver disease, patients with contraindications to IFN, and those who are willing to commit to long durations of treatment. Of the five approved nucleos(t)ide analogues, entecavir and tenofovir disoproxil have the best profile regarding safety, efficacy and drug resistance. Tenofovir disoproxil is preferred in patients who might be contemplating pregnancy and in those who might have been exposed to lamivudine or telbivudine in the past. Entecavir is preferred in patients who have other medical conditions that are associated with increased risks of renal insufficiency. Lamivudine and telbivudine should not be used 280 MAY 2011 VOLUME 8

7 FOCUS ON VIRAL HEPATITIS as initial therapy because of the high rates of drug resistance unless cost is a limiting factor. Adefovir dipivoxil should not be used as initial therapy because of its weak antiviral activity. Tenofovir disoproxil and telbivudine are categorized as class B regarding safety in pregnancy and the other HBV drugs as class C. Lamivudine and tenofovir disoproxil have not been shown to be associated with fetal abnormalities even when used during the first trimester of pregnancy. 73 When can treatment be stopped? Ideally, antiviral therapy should be continued until HBsAg loss. However, the likelihood that this will occur is low: 0 10% after 4 5 years of continuous nucleos(t)ide analogue therapy 36 40,42,47 and approximately 10% 3 5 years after completing a 1 year course of PEG-IFN. 19 PEG-IFN PEG-IFN is administered for 48 weeks to both HBeAgpositive and HBeAg-negative patients. Preliminary data from two clinical trials indicate that response rates were lower in HBeAg-positive patients who received 24 versus 48 weeks PEG-IFN, and data from another trial indicate that response rates were higher in HBeAg-negative patients who received 96 versus 48 weeks PEG-IFN Nucleos(t)ide analogues Nucleos(t)ide analogues are administered until the desired end point is achieved. For patients who had decompensated cirrhosis, life-long treatment is recommended because of concerns about fatal flares when treatment is discontinued. For patients who had compensated cirrhosis, life-long treatment is generally recommended; however, discontinuation of treatment may be considered in patients who have lost HBsAg or who have completed adequate duration of consolidation therapy after HBeAg seroconversion (for those who were HBeAg positive before treatment) provided that these patients are closely monitored so that treatment can be promptly reintroduced if there is viral rebound or an ALT flare. For HBeAg-positive patients who have precirrhotic liver disease, treatment should be continued until the patient has achieved HBeAg seroconversion (HBeAg negative, anti-hbe positive and undetectable serum HBV DNA) and completed 12 months of consolidation therapy. One study found that the 5 year cumulative rate of relapse after discontinuation of lamivudine was 62% in patients with <12 months of consolidation therapy versus 9% in patients with 12 months of consolidation therapy. 35 For HBeAg-negative patients who have precirrhotic liver disease, the therapeutic end point is unclear. Most experts recommend life-long treatment or until HBsAg loss. Preliminary data from one small study found that among 33 patients who discontinued treatment after 4 5 years of adefovir dipivoxil therapy and had undetectable serum HBV DNA for at least 3 years, 18 had longterm clinical remission and nine lost HBsAg during 5 year post-treatment follow-up. 77 These data suggest that treatment may be stopped in some patients who maintain viral suppression for a few years. How should treatment failure be managed? For patients who have clear indications for treatment, salvage therapy is generally recommended with a nucleos(t)ide analogue for which there is no crossresistance. For patients who do not have clear cut indications for treatment, discontinuation of treatment and continued monitoring may be appropriate. Lack of initial response The criteria for initial response to IFN therapy have not been established. Data suggest that monitoring the HBsAg titer may be more accurate than monitoring serum HBV DNA levels for predicting long-term response to IFN therapy, and it may be possible to define early stop rules with high negative predictive values. 25 These concepts need to be validated in prospective clinical studies. Inadequate or slow decline in serum HBV DNA levels during the first weeks of nucleos(t)ide analogue therapy has been shown to be associated with an increased risk of antiviral drug resistance during continued therapy. 24,78 These findings prompted the development of the road-map approach, in which a second nucleos(t)ide analogue is given to patients who have inadequate initial response. 79 However, this concept was derived from studies of lamivudine and telbivudine, which are both drugs that have a very low genetic barrier to resistance. Studies of entecavir and tenofovir disoproxil, which are more potent and have lower rates of drug resistance, found that serum HBV DNA levels continued to decline in most patients who remained on the same treatment and overall rates of antiviral resistance were very low or nonexistent. 80,81 These data indicate that patients receiving nucleos(t)ide analogues that have a low genetic barrier to resistance should receive additional therapy if initial viral decline is inadequate, but patients receiving nucleos(t)ide analogues that have a high genetic barrier to resistance may remain on the same drug provided that serum HBV DNA levels continue to decline. Virologic breakthrough after initial response Serum HBV DNA levels can occasionally increase during IFN treatment after an initial decline, particularly if the dose of IFN is reduced, but a correlation with IFN resistance has not been examined. Virologic breakthrough during nucleos(t)ide analogue treatment may be a result of antiviral drug resistance or medication nonadherence. Patients with virologic breakthrough should be counseled regarding medication adherence and breakthrough confirmed by retesting for serum HBV DNA levels after 1 3 months. Salvage therapy should be initiated immediately in patients who have decompensated liver disease or severe hepatitis flares, but in other patients it can be deferred until after virologic breakthrough is confirmed to avoid unnecessary changes in medications. NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY VOLUME 8 MAY

8 REVIEWS Table 3 Salvage therapies for antiviral drug-resistant HBV Drug to which resistance has developed Preferred treatment Alternative treatment Lamivudine or telbivudine Switch to or add tenofovir disoproxil Add adefovir dipivoxil Stop lamivudine or telbivudine, switch to Truvada * Adefovir dipivoxil Switch to or add entecavir Add lamivudine or telbivudine Stop adefovir dipivoxil, switch to Truvada Entecavir Switch to or add tenofovir disoproxil Stopr entecavir, switch to Truvada Tenofovir disoproxil Switch to or add entecavir Stop tenofovir disoproxil, switch to Truvada *Truvada (Gilead Sciences Inc., Foster City, CA) is a combination pill with emtricitabine and tenofovir; it is not currently approved for the treatment of HBV infection. Limited clinical data. The choice of salvage therapy depends on current and prior treatment if any, the pattern of drug-resistance mutations if known, and the susceptibility of these mutations to other nucleos(t)ide analogues. Testing for drugresistance mutations is particularly important for patients who have been exposed to multiple drugs. Table 3 summarizes the recommendations for salvage therapies. For patients who have lamivudine or telbivudine resistance, tenofovir disoproxil is the preferred treatment in countries where it is available because it has more potent antiviral activity than adefovir dipivoxil. Initial studies showed that add-on adefovir dipivoxil is preferred to switching to adefovir dipivoxil monotherapy in preventing adefovir dipivoxil resistance. 51,82 Whether continuation of lamivudine or telbivudine is necessary when tenofovir disoproxil is used as salvage therapy remains to be determined. 51,82,83 Although a higher dose of entecavir (1.0 mg daily) is approved for lamivudine-resistant HBV, entecavir is not an optimal salvage therapy because the pre-existing presence of lamivudine resistance mutations increases the risk of subsequent entecavir resistance. 49,50 For patients with adefovir dipivoxil resistance, entecavir is the preferred treatment. Switching to tenofovir disoproxil in these patients has been shown to lead to a decline in serum HBV DNA levels because the approved dose of tenofovir disoproxil (300 mg daily) has more potent antiviral activity than the approved dose of adefovir dipivoxil (10 mg daily). However, patients with adefovir dipivoxil resistance mutations have decreased susceptibility to tenofovir disoproxil and clinical studies have shown that these mutations persist after switching to tenofovir disoproxil. 83,84 For patients with entecavir resistance, the preferred treatment is tenofovir disoproxil although in vivo efficacy data are limited. For patients with tenofovir disoproxil resistance, the preferred treatment is entecavir. Truvada, which is a coformulation of emtricitabine and tenofovir disoproxil, may be used as rescue therapy for patients with lamivudine, telbivudine, adefovir dipivoxil or entecavir resistance. 48 Conclusions Substantial progress has been made in the treatment of hepatitis B in the past decade. Many safe and effective drugs are now available. These drugs suppress but do not eradicate HBV. To optimize treatment response, treatment should be initiated at an appropriate time using the best available drugs, and the response should be closely monitored so that treatment can be modified in patients with treatment failure. Review criteria A PubMed search of articles published between January 1985 and September 2010 was conducted using the following terms: hepatitis B, treatment, interferon, antiviral therapy, lamivudine, adefovir, entecavir, telbivudine, and tenofovir. In addition, abstracts presented at European Association for the Study of the Liver and American Association for the Study of Liver Diseases meetings in 2009 and 2010 were reviewed. 1. Yim, H. J. & Lok, A. S. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in Hepatology 43, S173 S181 (2006). 2. Fattovich, G., Bortolotti, F. & Donato, F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J. Hepatol. 48, (2008). 3. Chu, C. M., Hung., S. J., Lin, J., Tai, D. I. & Liaw, Y. F. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels. Am. J. Med. 116, (2004). 4. Liaw, Y. F. et al. Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis. Gastroenterology 84, (1983). 5. Lok, A. S., Lai, C. L., Wu, P. C., Leung, E. K. & Lam, T. S. Spontaneous hepatitis B e antigen to antibody seroconversion and reversion in Chinese patients with chronic hepatitis B virus infection. Gastroenterology 92, (1987). 6. Chen, Y. C., Chu, C. M. & Liaw, Y. F. Age-specific prognosis following spontaneous hepatitis B e antigen seroconversion in chronic hepatitis B. Hepatology 51, (2010). 7. Manno, M. et al. Natural history of chronic HBV carriers in northern Italy: morbidity and mortality after 30 years. Gastroenterology 127, (2004). 8. Chotiyaputta, W. & Lok, A. S. Hepatitis B virus variants. Nat. Rev. Gastroenterol. Hepatol. 6, (2009). 9. Iloeje, U. et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 130, (2006). 10. Chen, C. J. et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295, (2006). 11. van Zonneveld, M. et al. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology 39, (2004). 12. Niederau, C. et al. Long-term follow-up of HBeAgpositive patients treated with interferon alfa for chronic hepatitis B. N. Engl. J. Med. 334, (1996). 13. Brunetto, M. R. et al. Outcome of anti-hbe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study. J. Hepatol. 36, (2002). 14. Papatheodoridis, G. V., Manesis, E. & Hadziyannis, S. J. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B. J. Hepatol. 34, (2001). 15. Lampertico, P. et al. Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy. Hepatology 37, (2003). 282 MAY 2011 VOLUME 8

9 FOCUS ON VIRAL HEPATITIS 16. Lau, G. K. et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAgpositive chronic hepatitis B. N. Engl. J. Med. 352, (2005). 17. Janssen, H. L. et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 365, (2005). 18. Chan, H. L. et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann. Intern. Med. 142, (2005). 19. Buster, E. H. et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon a 2b. Gastroenterology 135, (2008). 20. Marcellin, P. et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N. Engl. J. Med. 351, (2004). 21. Marcellin, P. et al. Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2a. Gastroenterology 136, e1 4 (2009). 22. Perrillo, R. P. et al. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology 36, (2002). 23. Wai, C. T., Chu, C. J., Hussain, M. & Lok, A. S. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C. Hepatology 36, (2002). 24. Buster, E. H. et al. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. Gastroenterology 137, (2009). 25. Rijckborst, V. et al. Early on-treatment prediction of response to peginterferon alfa-2a for HBeAgnegative chronic hepatitis B using HBsAg and HBV DNA levels. Hepatology 52, (2010). 26. Moucari, R. et al. Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology 49, (2009). 27. Hoofnagle, J. H., Di Bisceglie, A. M., Waggoner, J. G. & Park, Y. Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B. Gastroenterology 104, (1993). 28. Buster, E. H. et al. Peginterferon alpha-2b is safe and effective in HBeAg-positive chronic hepatitis B patients with advanced fibrosis. Hepatology 46, (2007). 29. Dienstag, J. L. et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N. Engl. J. Med. 341, (1999). 30. Lai, C. et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N. Engl. J. Med. 339, (1998). 31. Marcellin, P. et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N. Engl. J. Med. 348, (2003). 32. Chang, T. T. et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N. Engl. J. Med. 354, (2006). 33. Marcellin, P. et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N. Engl. J. Med. 359, (2008). 34. Lai, C. L. et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N. Engl. J. Med. 357, (2007). 35. Lee, H. W. et al. Lamivudine maintenance beyond one year after HBeAg seroconversion is a major factor for sustained virologic response in HBeAg-positive chronic hepatitis B. Hepatology 51, (2010). 36. Lok, A. S. et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 125, (2003). 37. Marcellin, P. et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology 48, (2008). 38. Chang, T. T. et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigenpositive chronic hepatitis B. Hepatology 51, (2010). 39. Liaw, Y. F. et al. 2 Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology 136, (2009). 40. Heathcote, E. J. et al. Long term (4 year) efficacy and safety of tenofovir disoproxil fumarate (TDF) treatment in HBeAg-positive patients (HBEAG+) with chronic hepatitis B (Study 103): preliminary analysis (abstract 477). Hepatology 52, 556A 557A (2010). 41. Dienstag, J. L. et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 124, (2003). 42. Hadziyannis, S. et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 131, (2006). 43. Chang, T. T. et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 52, (2010). 44. Tassopoulos, N. C. et al. Efficacy of lamivudine in patients with hepatitis B e antigen-negative/ hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. Hepatology 29, (1999). 45. Hadziyannis, S. J. et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N. Engl. J. Med. 348, (2003). 46. Lai, C. L. et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N. Engl. J. Med. 354, (2006). 47. Marcellin, P. et al. Continued efficacy and safety through 4 years of tenofovir disoproxil fumarate (TDF) treatment in HBeAg-negative patients with chronic hepatitis B (study 102): preliminary analysis (abstract 476). Hepatology 52, 555A 556A (2010). 48. Lok, A. S. et al. Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology 46, (2007). 49. Tenney, D. J. et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology 49, (2009). 50. Tenney, D. J. et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine. Antimicrob. Agents Chemother. 48, (2004). 51. Rapti, I., Dimou, E., Mitsoula, P. & Hadziyannis, S. J. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAgnegative chronic hepatitis B. Hepatology 45, (2007). 52. Yim, H. J. et al. Evolution of multi-drug resistant hepatitis B virus during sequential therapy. Hepatology 44, (2006). 53. Wu, I. C. et al. Efficacy of entecavir in chronic hepatitis B patients with mildly elevated alanine aminotransferase and biopsy-proven histological damage. Hepatology 51, (2010). 54. Westland, C. et al. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil1. Gastroenterology 125, (2003). 55. Verhelst, D. et al. Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am. J. Kidney Dis. 40, (2002). 56. Purdy, J. B., Gafni, R. I., Reynolds, J. C., Zeichner, S. & Hazra, R. Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus. J. Pediatr. 152, (2008). 57. Lange, C. M. et al. Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology 50, (2009). 58. Lok, A. S. & McMahon, B. J. Practice guidelines: chronic hepatitis B. Hepatology 45, (2007). 59. Lok, A. S. & McMahon, B. J. Chronic hepatitis B: update American Association for the Study of Liver Diseases [online], aasld.org/practiceguidelines/documents/ Bookmarked%20Practice%20Guidelines/ Chronic_Hep_B_Update_2009%208_24_2009. pdf (2009). 60. Sorrell, M. F. et al. National Institutes of Health Consensus Development Conference Statement: management of hepatitis B. Ann. Intern. Med. 150, (2009). 61. EASL Clinical Practice Guidelines: management of chronic hepatitis B. J. Hepatol. 50, (2009). 62. Liaw, Y. F. et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol. Int. 2, (2008). 63. Fontana, R. J. et al. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology 123, (2002). 64. Yao, F. Y., Terrault, N. A., Freise, C., Maslow, L. & Bass, N. M. Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort. Hepatology 34, (2001). 65. Liaw, Y. F. et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N. Engl. J. Med. 351, (2004). 66. Hoofnagle, J. H. Reactivation of hepatitis B. Hepatology 49, S156 S165 (2009). 67. Loomba, R. et al. Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann. Intern. Med. 148, (2008). 68. Shi, Z., Yang, Y., Ma, L., Li, X. & Schreiber, A. Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a systematic review and meta-analysis. Obstet. Gynecol. 116, (2010). 69. Han, G., Zhao, W., Cao, M., Jiang, H. & Pan, C. A prospective and open-label study for the efficacy and safety of telbivudine(ltd) in pregnancy for the prevention of perinatal transmission of hepatitis B virus (HBV) to the infants (abstract 212). Hepatology 52, 427A 428A (2010). 70. Reijnders, J. G., Perquin, M. J., Zhang, N., Hansen, B. E. & Janssen, H. L. Nucleos(t)ide analogues only induce temporary hepatitis B e NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY VOLUME 8 MAY