The ultimate goal of hepatitis B treatment is to prevent

Transcription

1 GASTROENTEROLOGY 2007;132: Navigating the Maze of Hepatitis B Treatments ANNA SUK FONG LOK Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan The ultimate goal of hepatitis B treatment is to prevent cirrhosis, hepatic failure, and hepatocellular carcinoma (HCC). Because clinical outcomes arise only after decades of infection, surrogate end points are used to determine the success of hepatitis B treatment. Standardized definitions of treatment response were discussed in detail at the 2006 National Institutes of Health Workshop on Management of Hepatitis B. 1 Currently, there are 6 approved therapies for hepatitis B virus (HBV) infection including 2 formulations of interferon, standard interferon -2b (IFN- -2b) and pegylated interferon -2a (pegifn- -2a), and 4 nucleos(t)ide analogues, lamivudine (Epivir), adefovir (Hepsera), entecavir (Baraclude), and telbivudine (Tyzeka). Despite these advances, approved treatments for hepatitis B do not eradicate hepatitis B virus. Thus, clinical benefit is dependent on the ability to maintain sustained suppression of HBV replication. However, long-term treatment with nucleos(t)ide analogues is associated with increasing rates of drug resistance, and the safety and efficacy of these therapies beyond 1 5 years have not been established. This review aims to help the reader navigate the maze of hepatitis B treatments. New therapies and molecular mechanisms of antiviral resistance are discussed in an accompanying article by Ghany and Liang. 2 Efficacy of Approved Therapies The short-term goals of hepatitis B treatment are to achieve suppression of HBV replication and to induce remission of liver disease. Table 1 summarizes the rates of response to the 6 approved therapies in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients Nucleos(t)ide analogues are more effective in decreasing serum HBV DNA levels, but they are less likely to lead to loss of HBeAg or hepatitis B surface antigen (HBsAg). A higher rate of HBeAg and HBsAg loss associated with IFN therapy, despite its less potent antiviral activity, is related to its ability to down-regulate viral protein expression and to achieve immune clearance of infected hepatocytes. Response after IFN therapy is also more durable than response after nucleos(t)ide analogue therapy. Among the nucleos(t)ide analogues, entecavir and telbivudine are more potent, followed by lamivudine and then adefovir. For HBeAg-positive patients, a 1-year course of pegifn is associated with HBeAg seroconversion in approximately 30% of patients compared with 12% 22% after a 1-year course of nucleos(t)ide analogue therapy. 5,7 10,13 15 Furthermore, 6 months after discontinuation of treatment, HBeAg seroconversion rate increases slightly in patients who received pegifn, whereas 20% 50% of patients who received nucleos(t)ide analogues revert back to HBeAg positivity. 5,7,16 18 The difference in HBeAg seroconversion rate between IFN and nucleos(t)ide analogue therapy is eliminated during subsequent years because nucleos(t)ide analogues are usually administered beyond 1 year. Thus, HBeAg seroconversion rates increase to 40% and 48% after 5 years of lamivudine and adefovir, respectively, and to 39% after 3 years of entecavir However, 50% of patients who meet stringent criteria for inclusion in clinical trials achieve HBeAg seroconversion after 5 years of continued therapy. For HBeAg-negative patients, virologic response rates during treatment are high, but posttreatment relapse occurs in 90% of patients who discontinue nucleos- (t)ide analogue therapy and in approximately 80% of patients who discontinue IFN after 1 year of therapy. 23,24 Continued treatment with lamivudine results in a progressively lower percentage of patients with maintained virologic response because of drug resistance, and continuation of adefovir leads to a slight increase in the percentage of patients with maintained virologic response up to year 4. 25,26 Efficacy of Combination Therapies Combination therapy has been advocated to improve antiviral activity and/or prevent drug resistance. Three studies evaluated the combination of nucleos(t)ide analogues. One study compared combination of lamivudine and adefovir to lamivudine alone in 115 HBeAgpositive patients. 27 Responses at weeks 52 and 104 were not different between the 2 groups. Lamivudine-resistant mutations were detected in 15% and 43% of patients after 2 years of combination therapy and lamivudine monotherapy, respectively. 28 Another study showed that combination of lamivudine and telbivudine was worse than telbivudine alone. 29 A third study reported that combi- Abbreviations used in this paper: HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; IFN- -2b, standard interferon -2b; pegifn- -2a, pegylated interferon -2a by the AGA Institute /07/$32.00 doi: /j.gastro

2 April 2007 HEPATITIS B TREATMENTS 1587 Table 1. Responses to Approved Antiviral Therapies Among Nucleoside-Naive Patients Lamivudine 100 mg qd Wk Placebo Adefovir 10 mg qd 48 Wk Placebo Entecavir 0.5 mg qd 48 Wk Telbivudine 600 mg qd 52 Wk Peg-IFN- 180 g qw 48 Wk HBeAg-positive patients Loss of serum HBV DNA a 40% 44% 16% 21% 0 67% 60% 25% Loss of HBeAg 17% 32% 6% 11% 24% 11% 22% 26% 30% HBeAg seroconversion 16% 21% 4% 6% 12% 6% 21% 22% 27% Loss of HBsAg 1% % 0 3% Normalization of ALT 41% 75% 7% 24% 48% 16% 68% 77% 39% Histologic improvement b 49% 56% 23% 25% 53% 25% 72% 65% 38% Durability of response a 50% 80% 90% 69% 80% na HBeAg-negative patients Loss of serum HBV DNA 60% 73% na 51% 0 90% 88% 63% Normalization of ALT 60% 79% na 72% 29% 78% 74% 38% Histologic improvement 60% 66% na 64% 33% 70% 67% 48% b Durability of response 10% 5% na na 20% NOTE. Adapted from Lok AS and McMahon. 53 qd, 4 times daily; qw, 4 times weekly; na, not available. a Lamivudine and entecavir: no or short duration of consolidation treatment; adefovir and telbivudine: most patients had consolidation treatment. b Posttreatment biopsies obtained on treatment for nucleos(t)ide analogues and 24 weeks after treatment for peg-ifn. nation of emtricitabine and adefovir was superior to adefovir alone, but the results likely reflect more potent antiviral activity of emtricitabine vs adefovir. 30 The lack of additive or synergistic antiviral activity in these studies may be related to the common target (HBV polymerase) of the drugs used in combination. Studies comparing combination of pegifn and lamivudine to pegifn monotherapy and lamivudine monotherapy showed that combination therapy resulted in more marked on-treatment viral suppression, but responses assessed 6 months after discontinuation of treatment were similar to treatment with pegifn alone and superior to that of lamivudine alone. 5 7 Lamivudine resistance was less frequent but not completely prevented in the combination therapy group. Efficacy of Investigational Therapies in Phase III Clinical Trials Among the investigational therapies, tenofovir disoproxil fumarate, a nucleotide analogue that is structurally similar to adefovir, holds the most promise. In vitro studies showed that tenofovir and adefovir are equipotent and have activity against wild-type as well as lamivudine-resistant HBV and entecavir-resistant HBV. 31 The approved dose of tenofovir is 30-fold higher than adefovir, accounting for its greater antiviral activity in vivo. 32,33 Tenofovir, alone and in combination with emtricitabine as a single pill, has been approved for the treatment of human immunodeficiency virus (HIV) infection. Emtricitabine (FTC) is structurally similar to lamivudine (3TC) and is approved for the treatment of HIV infection. Clinical trials in patients with hepatitis B showed that FTC and 3TC have similar efficacy and resistance rates and select for the same resistant mutations. 34 Clevudine is unique because viral suppression persists for up to 24 weeks even after very short courses of treatment. 35 However, phase II clinical trials found that HBeAg seroconversion rate in clevudine-treated patients was not different compared with those who received placebo, 36 and in vitro studies suggest that clevudine is not effective against lamivudine-resistant HBV. Safety of Approved Therapies IFN therapy is associated with many adverse effects, notably fatigue, bone marrow suppression, mood changes, and unmasking or exacerbation of autoimmune illnesses. The most dreaded adverse event is a severe hepatitis flare that is believed to be immune mediated and can lead to hepatic failure, particularly in older patients and those with cirrhosis or advanced hepatic fibrosis. 37,38 Nucleos(t)ide analogue therapies for hepatitis B have been very well tolerated even in patients with decompensated cirrhosis. 39 Adefovir and tenofovir have been associated with renal dysfunction. Nephrotoxicity defined as an increase in serum creatinine by 0.5 mg/dl on 2 consecutive occasions has been reported in 3% of patients with compensated liver disease after 4 5 years of adefovir therapy. 40 Antiviral Resistance A major concern with long-term nucleos(t)ide analogue treatment is the selection of antiviral-resistant mutations. The rate at which resistant mutants are selected is related to pretreatment serum HBV DNA level, rapidity of viral suppression, prior exposure to other HBV treatments (and presence of cross-resistant mutations), medication compliance, and potency of the drug

3 1588 ANNA SUK-FONG LOK GASTROENTEROLOGY Vol. 132, No. 4 Table 2. Rates of Antiviral-Resistant HBV Mutations Reported in Clinical Trials Antiviral therapy Rates of genotypic resistance Nucleoside-naïve patients Lamivudine 15% 30% after 1 yr, 70% after 5 yr Adefovir 0% after 1 yr, 30% after 5 yr Entecavir 0% after 1 yr, 1% after 2 and 3 yr Telbivudine 5% 11% after 1 yr Lamivudine-resistant patients Adefovir 20% after 2 yr Entecavir 1%, 9%, 17% after 1, 2, and 3 yr, respectively and its genetic barrier to resistance. Table 2 summarizes the rates at which antiviral-resistant HBV mutants are detected in clinical trials. 19,40 42 It should be pointed out that the reported rates vary with the sensitivity of the methods used for detection of the mutants and the patient population studied. Antiviral resistance is manifested as virologic breakthrough, increase in serum HBV DNA level by 1 log (10-fold) above nadir during treatment, in a medication compliant patient. Serum HBV DNA levels tend to be low initially because most antiviral-resistant mutants have decreased replication fitness compared with wild-type HBV. However, compensatory mutations that can restore replication fitness frequently emerge during continued treatment, leading to a progressive increase in serum HBV DNA that may exceed pretreatment levels. Biochemical breakthrough, defined as elevation in alanine aminotransferase (ALT) during treatment in a patient who had achieved initial normalization, can occur simultaneously with or months to years after virologic breakthrough. Emergence of antiviral-resistant mutations can lead to hepatitis flares and hepatic failure. 19 A potential consequence of antiviral resistance is the selection of mutations that are cross-resistant to other drugs, limiting future treatment options. For example, patients with lamivudine-resistant HBV are more likely to acquire resistance to entecavir. 43 Once selected, antiviralresistant mutations are archived and can reemerge within a few months of reexposure to the same drug. In addition, sequential nucleos(t)ide monotherapy has been reported to result in the selection of multidrug-resistant mutants. 44 Impact of Antiviral Therapy on Clinical Outcome Follow-up studies of patients who previously received IFN therapy showed that responders had better survival and survival free of hepatic failure, but a benefit on overall survival was not demonstrated One study from Asia reported a reduction in HCC development among IFN-treated patients, but this effect was not confirmed by another Asian study. 49,50 A landmark double-blind, randomized controlled trial demonstrated that lamivudine treatment significantly decreased disease progression in patients with cirrhosis or advanced fibrosis and active HBV replication (HBeAgpositive and/or serum HBV DNA 700,000 genome equivalents/ml). 51 Disease progression defined as increase in Child-Pugh score, liver failure, or HCC development occurred in 7.8% of treated patients and in 17.7% of controls (P.001). Patients with maintained viral suppression derived the greatest benefit. Natural Course of Chronic HBV Infection An understanding of the natural history of chronic HBV infection is critical in deciding whom and when to treat. Figure 1 depicts the natural course of chronic HBV infection, 52 and it should be recognized that not all patients go through all 4 phases. In patients with perinatally acquired HBV infection, the first phase (immune tolerance) is characterized by the presence of HBeAg, high levels of serum HBV DNA, normal serum ALT, and minimal or no inflammation on liver biopsy. During this phase, which may last 1 4 decades, spontaneous and treatment-induced HBeAg seroconversion is infrequent, and prognosis is generally favorable. The second phase (immune clearance or HBeAg-positive chronic hepatitis) is characterized by the presence of HBeAg, high or fluctuating serum HBV DNA and ALT levels, and active inflammation on liver biopsy. A hallmark of this phase is flares of ALT, which may precede Figure 1. Natural course of chronic HBV infection showing 4 phases: immune tolerance, immune clearance (HBeAg-positive chronic hepatitis), inactive carrier state, and reactivation (HBeAg-negative chronic hepatitis). Not all patients go through all 4 phases. Immune tolerance phase may be short-lived or nonexistent in patients with adult acquired HBV infection. Immune clearance phase may be brief or protracted; in the latter case, serious liver damage with progression to cirrhosis and hepatocellular carcinoma may occur even while the patient is still HBeAg positive. Prognosis of inactive carriers is favorable if liver damage accrued during the immune clearance phase is mild and if the patient remains in this phase. Not all patients progress to HBeAgnegative chronic hepatitis. Patients in this last phase tend to be older and have more advanced liver disease. Adapted from Yim and Lok. 52

4 April 2007 HEPATITIS B TREATMENTS 1589 HBeAg seroconversion, but many flares only result in transient decrease in serum HBV DNA levels without loss of HBeAg, and some flares may lead to hepatic decompensation. The third phase (inactive carrier state) is characterized by the absence of HBeAg, persistently normal ALT, and low or undetectable serum HBV DNA ( 10 3 IU/mL). Liver biopsy usually shows mild hepatitis and minimal fibrosis, but inactive cirrhosis may be observed if there had been severe liver injury prior to HBeAg seroconversion. The inactive carrier state may persist indefinitely, in which case the prognosis is generally favorable, particularly if this state is reached early, but some inactive carriers have reactivation of HBV replication, either spontaneously or as a result of immunosuppression. The fourth phase (reactivation of HBV replication or HBeAg-negative chronic hepatitis) is characterized by absence of HBeAg, high HBV DNA ( 10 3 IU/mL), elevated ALT, and continued necroinflammation. The hallmark of this phase is its fluctuating course, but sustained remission is rare. Most patients are found to have mutations in the basal core promoter or precore region of the HBV genome that down-regulate or abolish HBeAg production. Treatment Algorithm Multiple therapies that suppress, but not eradicate HBV, are expensive and have limited long-term safety and efficacy data are available. These pose a major challenge to the treatment of hepatitis B. Because most patients will require long-term treatment (years, decades, and possibly lifelong) and sequelae of chronic HBV infection may not occur until years or decades later if at all, the long-term benefits must be balanced against the long-term risks. Treatment is indicated if the risk of liver-related morbidity or mortality in the next 10 years is high. 53 Treatment can be deferred if the risk of liver-related morbidity or mortality in the next 20 years and the likelihood of achieving a sustained response after a defined course of treatment are low. 53 Many hepatitis B patients will fall between these 2 extremes, and the decision on treatment will need to be individualized based on the patient s age, family history of HBV-related liver disease, and patient preference. In view of the fluctuating course of chronic HBV infection, the risk of liverrelated morbidity and mortality and the likelihood of response may vary as the patient progresses through the course of chronic HBV infection. Moreover, new treatment options and additional data on approved therapies may change the landscape of hepatitis B treatment. Thus, all HBV carriers who are not deemed to be treatment candidates at presentation and those who elect to defer treatment should be monitored. Whom to Treat? Currently, the indications for hepatitis B treatment are primarily based on activity (ALT 2 upper limit of normal [ULN] or modest/severe necroinflammation on liver biopsy) or stage of liver disease (cirrhosis or advanced fibrosis). The rationale is that these patients are more likely to achieve HBeAg seroconversion or to develop progressive liver disease. Recently, these dogmas have been challenged. Several studies including a large community-based study in Taiwan found that high serum HBV DNA level was associated independently with an increased risk of cirrhosis and HCC. 54,55 These studies recommended that indication for treatment should be based on HBV DNA and not ALT. Several small studies also found that, among HBV carriers with normal ALT who underwent liver biopsies, as many as 40% had moderate-severe inflammation and up to 20% had advanced fibrosis or cirrhosis. Furthermore, it has been suggested that the ULN for ALT should be decreased to 30 U/L for men and 19 U/L for women. 56 Finally, some experts questioned the predictive value of pretreatment ALT on response to newer treatments that are more potent. There is no doubt that a high HBV DNA level, particularly if persistent, is a risk factor for adverse outcome. However, the prognostic value of 1 high serum HBV DNA level in an individual patient is uncertain. Furthermore, risk factors in cohort studies are not necessarily accurate prognostic tools for individual patients. 57 Most of the subjects in the Taiwan study likely acquired HBV infection perinatally and had been infected for more than 4 decades at enrollment. Data from this and similar studies may not be applicable to individuals with adult acquired HBV infection or persons with perinatally acquired HBV infection who are younger than 40 years of age. Many studies reporting abnormal liver histology or increased liver-related mortality among HBV carriers with normal ALT included a small number of patients who had normal ALT on a few occasions. Indeed, some of these studies found that severe inflammation or advanced fibrosis was associated with older age and intermittently elevated ALT. Finally, post hoc analysis of the phase III clinical trial of entecavir the most potent HBV treatment at this time confirmed that patients with pretreatment ALT 2 ULN were less likely to undergo HBeAg seroconversion or to have undetectable serum HBV DNA. 58 Based on our current understanding of the natural history of chronic HBV infection 52 and the available treatment options, the indications for HBV treatment should be predicated on serial assessment of HBeAg, HBV DNA, and ALT with or without liver histology as well as the patient s age. The question is not so much who should be treated but whether treatment should be initiated at presentation. Patients who do not have indications for immediate treatment and those who elect to defer treatment should continue to be monitored because treatment may be indicated at a later stage because of changes in HBV replication status and/or activity of liver disease or availability of new treatments. Table 3

5 1590 ANNA SUK-FONG LOK GASTROENTEROLOGY Vol. 132, No. 4 summarizes suggested treatment recommendations for chronic hepatitis B. 53 A clear plan regarding what to do if the patient fails to achieve initial response, experiences serious adverse events, becomes pregnant, or develops drug resistance should be in place prior to initiating treatment. What Should Be the Primary Treatment? In deciding which antiviral agent should be the first-line treatment, the long-term safety (adverse effects and drug resistance) should be balanced against the longterm efficacy (likelihood of sustained virologic response after a defined course of therapy or of maintained virologic response during continued treatment) and costs of the treatment (medications, monitoring tests, and clinic visits), as well as patient preference. The advantages and disadvantages of the approved treatments are summarized in Table 4. IFN is particularly attractive for young patients who have no cirrhosis and no contraindications to the use of IFN and do not wish to be committed to many years of treatment. Among HBeAg-positive patients, those with more markedly elevated ALT ( 5 ULN) and those with HBV genotype A and to a lesser extent genotype B are more likely to undergo IFN-related HBeAg seroconversion, 5,59,60 but it should be pointed out that high ALT is also a predictor of spontaneous or nucleos(t)ide analogue treatment-related HBeAg seroconversion. Testing for HBV genotype may be useful in patients who are contemplating IFN treatment, but there is no role for routine genotyping of all HBV carriers. PegIFN has superseded standard IFN because of its more convenient dosing schedule. Table 3. Recommendations for HBV Treatments HBeAg HBV DNA (IU/mL) ALT Treatment strategy Positive 20,000 2 ULN Low efficacy with current treatment Observe; consider treatment when ALT becomes elevated Consider biopsy in persons 40 yr of age, ALT persistently high normal (or 1 ULN), or with family history of HCC Consider treatment if HBV DNA 20,000 IU/mL and biopsy shows moderate/severe inflammation or significant fibrosis Positive 20,000 2 ULN Observe for 3 6 months and treat if no spontaneous HBeAg loss Consider liver biopsy prior to treatment if compensated Immediate treatment if icteric or clinical decompensation IFN- /peg- IFN-, LAM, ADV, ETV, or LdT may be used as initial therapy LAM and LdT not preferred because of high rate of drug resistance End point of treatment: seroconversion from HBeAg to anti-hbe Duration of therapy: IFN- : 16 weeks Peg-IFN- : 48 weeks LAM/ADV/ETV/LdT: minimum 1 year, continue for at least 6 months after HBeAg seroconversion Negative 20,000 2 ULN IFN- /peg-ifn-, LAM, ADV, ETV, or LdT may be used as initial therapy. LAM and LdT not preferred because of high rate of drug resistance End point of treatment: not defined Duration of therapy: IFN- /peg-ifn- : 1 year LAM/ADV/ETV/LdT: 1 year IFN- nonresponders/contraindications to IFN- ADV/ETV Negative to 2 ULN Consider liver biopsy and treat if liver biopsy shows moderate/severe necroinflammation or significant fibrosis Negative 2000 ULN Observe, treat if HBV DNA or ALT becomes higher Positive/negative Detectable Cirrhosis Compensated: HBV DNA 2000 IU/mL: treat. LAM/ADV/ETV/LdT may be used as initial therapy. LAM and LdT not preferred due to high rate of drug resistance HBV DNA 2000 IU/mL: consider treatment if ALT elevated Decompensated: coordinate treatment with transplant center, LAM (or LdT) ADV or ETV preferred. Refer for liver transplant Positive/negative Undetectable Cirrhosis Compensated: observe Decompensated: refer for liver transplant NOTE. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. from Yim and Lok. 52 Copyright 2006 American Association for the Study of Liver Diseases. ALT, alanine aminotransferase; ULN, upper limit of normal; IFN-, interferon ; peg-ifn-, pegylated IFN ; LAM, lamivudine; ADV, adefovir; ETV, entecavir; LdT, Telbivudine.

6 April 2007 HEPATITIS B TREATMENTS 1591 Table 4. Comparison of Approved Treatments of Chronic Hepatitis B Peg-IFN- Lamivudine Adefovir Entecavir Telbivudine Duration of treatment HBeAg chronic hepatitis 1 Yr 6 Mo after confirmed HBeAg seroconversion HBeAg chronic hepatitis 1 Yr Until HBsAg loss Route Subcutaneous Oral Oral Oral Oral Adverse effects Many Negligible Nephrotoxicity Negligible Negligible Resistant mutations None Very high Moderate Low High Annual cost ($) 18, Among the nucleos(t)ide analogues, lamivudine and telbivudine are associated with very high rates of drug resistance, and resistant mutants to these drugs are crossresistant to other L-nucleosides and predisposes to resistance to entecavir. Thus, these 2 compounds should not be used as monotherapy, except when only a short course of therapy is planned. Adefovir at the approved dose of 10 mg has weak antiviral activity and should not be used in patients in whom rapid viral suppression is needed, such as patients with severe hepatitis flare or decompensated cirrhosis, and in those with very high pretreatment serum HBV DNA levels. Entecavir is the most potent approved oral therapy for hepatitis B and has a very low rate of drug resistance in nucleos(t)ide-naïve patients, but its long-term safety and resistance profile have not been established. Tenofovir is the most promising among the investigational therapies. In theory, combination therapy should be more efficacious and may prevent antiviral resistance, but the optimal combination therapy and the cost-effectiveness of de novo combination therapy vs potent monotherapies with high genetic barriers to resistance have not been established. Management of Antiviral-Resistant HBV Hepatitis B patients receiving antiviral treatment should be monitored regularly for initial response, adverse events, and breakthroughs. Patients with virologic breakthrough should be checked for medication compliance. When possible, testing for resistance mutation should be performed. This is particularly important in patients who have been exposed to more than one nucleos(t)ide analogue therapy. Management of patients with antiviral-resistant HBV depends on prior treatment received, pattern of mutations found, and knowledge of any cross-resistance with other antiviral agents. Recent studies demonstrated that rescue therapy is more effective if initiated early at the time of virologic breakthrough, and, in most instances, rescue therapy should be added to the original therapy. 61,62 The management of antiviral-resistant HBV is summarized in Table 5. When to Stop Treatment When to stop treatment is the most difficult question in hepatitis B treatment. IFN is administered for a finite duration, and response is assessed typically at the end of treatment and again 6 months after stopping treatment. If response is not achieved, patients may be considered for nucleos(t)ide analogue therapy if indicated. Nucleos(t)ide analogues are administered until a therapeutic end point is achieved. For HBeAg-positive patients, relapse is universal if treatment is discontinued prior to HBeAg loss, even if serum HBV DNA has been undetectable for years. Response is durable in 70% 90% of patients if treatment is continued for at least 6 months after confirmed HBeAg seroconversion (2 consecutive tests at least 1 month apart). 16,22,63 For HBeAg-negative patients, virologic relapse (redetection of serum HBV DNA by polymerase chain reaction assay) is frequent, even if treatment is discontinued after serum HBV DNA has remained undetectable for 1 4 years. 64 Treatment may be discontinued in patients who clear HBsAg, but only 5% of patients will achieve this end point after 5 years of treatment. Pilot studies showed that clinical relapse (serum HBV DNA 4- to 5-log 10 copies/ml and ALT elevation) is less common when treatment is discontinued after 2 5 years of therapy, but these data need to be confirmed. For patients with compensated cirrhosis, it is not clear whether treatment must be continued for life or whether treatment can be withdrawn after achieving therapeutic end points such as HBeAg seroconversion, HBsAg loss, or histologic confirmation of reversal of Table 5. Treatment of Patients With Antiviral-Resistant HBV Drugs Lamivudine or Telbivudine resistance Adefovir-resistance Entecavir-resistance Treatment Add adefovir (or tenofovir) (Stop lamivudine, switch to Truvada a ) Stop lamivudine, switch to entecavir (preexisting lamivudine-resistant mutation predisposes to entecavir resistance) Add lamivudine (Stop adefovir, switch to Truvada a ) Switch to or add entecavir Switch to or add adefovir (or tenofovir) NOTE. Emtricitabine, tenofovir, and Truvada are approved for HIV but not approved for HBV treatment. a Truvada, combination pill with emtricitabine and tenofovir.

7 1592 ANNA SUK-FONG LOK GASTROENTEROLOGY Vol. 132, No. 4 cirrhosis. For patients who had decompensation and for liver transplant recipients, lifelong treatment is recommended. For patients who have primary nonresponse, less than 2-log decrease in HBV DNA and to a level 4-log 10 IU/mL after 6 months of therapy, a phenomenon that occurs in up to 50% of patients receiving adefovir 61 and in 5% 30% of patients receiving lamivudine, entecavir, or telbivudine, alternative or additional treatment should be considered to prevent drug resistance. Summary and Future Directions Substantial advances have been made in the treatment of hepatitis B in the past decade. The availability of multiple treatment options that are more potent, better tolerated, and more conveniently administered has enabled more patients with hepatitis B to benefit from treatment. Nevertheless, current treatments do not eradicate HBV, and long-term safety data are lacking. Given the need for long durations, and in many instances lifelong treatment with its associated risks of drug resistance, adverse events, and costs, physicians should know how to navigate the maze of HBV treatments before recommending their patients to enter. References 1. Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok ASF. Management of hepatitis B: summary of a Clinical Research Workshop. Hepatology In press. 2. Ghany M, Liang TJ. Drug targets and molecular mechanisms of drug resistance in chronic hepatitis B. Gastroenterology 2007; 132: Wong DK, Cheung AM, O Rourke K, Naylor CD, Detsky AS, Heathcote J. Effect of -interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis (comments). Ann Intern Med 1993;119: Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, Chutaputti A, et al. Peginterferon -2a (40 kda): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat 2003;10: Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352: Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, Lu ZM, 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 2004;351: Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, Simon C, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005;365: Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group (comments). N Engl J Med 1998;339: Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, Crowther L, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341: Marcellin P, Chang T, Lim SG, Tong M, Sievert W, Schiffman M, Jeffers L, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348: Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003;348: Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006;354: Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, et al. A comparison of entecavir and lamivudine for HBeAgpositive chronic hepatitis B. N Engl J Med 2006;354: Schalm SW, Heathcote J, Cianciara J, Farrell G, Sherman M, Willems B, Dhillon A, et al. Lamivudine and interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial (comments). Gut 2000;46: Lai C, Gane E, Liaw Y-F, Thongawat S, Wang Y, Heathcote E, Rasenack J, et al. Telbivudine (LDT) vs. lamivudine for chronic hepatitis B: first-year results from the International Phase III Globe Trial. Hepatology 2005;42:748A. 16. Dienstag JL, Cianciara J, Karayalcin S, Kowdley KV, Willems B, Plisek S, Woessner M, et al. Durability of serologic response after lamivudine treatment of chronic hepatitis B. Hepatology 2003;37: Song BC, Suh DJ, Lee HC, Chung YH, Lee YS. Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea. Hepatology 2000;32: Ryu SH, Chung YH, Choi MH, Kim JA, Shin JW, Jang MK, Park NH, et al. Long-term additional lamivudine therapy enhances durability of lamivudine-induced HBeAg loss: a prospective study. J Hepatol 2003;39: Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, Dienstag JL, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 2003;125: Chang TT, Lai CL, Chien RN, Guan R, Lim SG, Lee CM, Ng KY, et al. Four years of lamivudine treatment in Chinese patients with chronic hepatitis B. J Gastroenterol Hepatol 2004;19: Marcellin P, Chang T, Lim SG, Sievert W, Tong M, Arterburn S, Borroto-Esoda K, et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B (CHB) patients (abstr 969). Hepatology 2006;44:548A. 22. Chang T, Chao Y-C, Kaymakoglu S, Cheinquer H, Pessoa M, Gish R, Poordad F, et al. Entecavir maintained virologic suppression through 3 years of treatment in antiviral naive HBeAg( ) Patients (ETV 022/901) (abstr 109). Hepatology 2006;44:229A. 23. Hadziyannis S, Tassopoulos N, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, et al. 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Gastroenterology 1995;109: Fontana RJ, Hann HW, Perrillo RP, Vierling JM, Wright T, Rakela J, Anschuetz G, et al. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology 2002;123: Hadziyannis S, Tassopoulos N, Chang TT, Heathcote J, Kitis G, Rizzetto M, Marcellin P, et al. Long-term adefovir dipivoxil treatment induces regression of liver fibrosis in patients with HBeAgnegative chronic hepatitis B: results after 5 years of therapy. Hepatology 2005;42:754A. 41. Colonno R, Rose R, Pokornowski K, Baldick C, Klesczewski K, Tenney D. Assessment at three years shows high barrier to resistance is maintained in entecavir-treated nucleoside naive patients while resistance emergence increases over time in lamivudine refractory patients (abstr 110). Hepatology 2006;44: 229A 230A. 42. Lai C, Gane E, Hsu C-W, Thonsgawat S, Wang Y, Chen Y, Heathcote E, et al. 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9 1594 ANNA SUK-FONG LOK GASTROENTEROLOGY Vol. 132, No. 4 HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype. Am J Gastroenterol 2006;101: Fung SK, Chae HB, Fontana RJ, Conjeevaram H, Marrero J, Oberhelman K, Hussain M, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol 2006;44: Lampertico P, Vigano M, Manenti E, Iavarone M, Lunghi G, Colombo M. Adefovir rapidly suppresses hepatitis B in HBeAgnegative patients developin genotypic resistance to lamivudine. Hepatology 2005;42: Gish R, Chang TT, de Man R, Gadano A, Sollano J, Han KH, Lok A, et al. Entecavir results in substantial virologic and biochemical improvement and HBeAg seroconversion through 96 weeks of treatment in HBeAg( ) chronic hepatitis B patients (Study ETV- 022). Hepatology 2005;42:267A. 64. Fung SK, Wong F, Hussain M, Lok AS. Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigennegative chronic hepatitis B. J Viral Hepat 2004;11: Address requests for reprints to: Anna Lok, MD, Division of Gastroenterology, University of Michigan Medical Center, 3912, Taubman Center, Ann Arbor, Michigan aslok@umich.edu; fax: (734) Supported in part by NIH contract N01 DK and grants U01 DK57577 and U01 DK Financial disclosure: A.S.L. serves on the advisory board and receives research support from GlaxoSmithKline, Bristol-Myers Squibb, Gilead, Idenix, Roche, Pharmasset, and Innogenetics.