2008美国乙肝治疗指南

A em In pd EM B. EU *Div tanfo Yor s, Los Me es, Un Ser Ch lem rit ou the dis no a b of for age alg usi lac sus du tec lev ba sur alf 2a, ap dis sel are for resistance, method of administration, and cost. Chronic hepatitis B (CHB) remains an important public bid ma inf cad Un Mi enc a h inc 1.2 inc tio up com bid CH as pan 20 new bet ava nu CH in Ad str the sta dem apy add for spe spe an exi pre tre tion in the United States. The panel used the same methods of evaluation as for the previous algorithm by reviewing the liter- ature and current international guidelines.6,8–10 A comprehen- CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;xx:xxx ARTICLE IN PRESS health problem and a leading cause of liver-related mor- ity and mortality worldwide.1 In the United States, an esti- ted 1.25 million individuals, or 0.4% of the population, are ected with hepatitis B virus (HBV).2 During the last 2 de- es, the influx of foreign-born persons immigrating to the ited States from areas of high endemicity, including Asia, the ddle East, and Africa, has contributed to an increased pres- e of CHB, particularly in urban areas and communities with igh immigrant population.3,4 Thus, it is likely that the idence of CHB is considerably higher than the estimated 5 million. When left untreated, individuals with CHB are at reased risk for developing cirrhosis, hepatic decompensa- n, and hepatocellular carcinoma (HCC). It is estimated that sive, structured literature review was conducted by using the PubMed computerized bibliographic database for English-lan- guage articles published between August 1, 2005 and March 28, Abbreviations used in this paper: AFP, alpha-fetoprotein; anti-HBc, antibody to hepatitis B core antigen; anti-HBe, antibody to hepatitis B e antigen; anti-HBs, antibody to hepatitis B surface antigen; cccDNA, covalently closed circular DNA; CDC, Centers for Disease Control and Prevention; CHB, chronic hepatitis B; FDA, Food and Drug Administra- tion; HCC, hepatocellular carcinoma; HIV, human immunodeficiency virus; HR, hazard ratio; PCR, polymerase chain reaction; REVEAL, Risk Evaluation Viral Load Elevation and Associated Liver Disease; RR, relative risk; ULN, upper limit of normal. Treatment Algorithm for the Manag fection in the United States: 2008 U MET B. KEEFFE,* DOUGLAS T. DIETERICH,‡ STEVEN-HUY GENE R. SCHIFF,¶ and HILLEL TOBIAS# ision of Gastroenterology and Hepatology, Stanford University Medical Center, S k, New York; §Division of Digestive Diseases, University of California, Los Angele dical College of Cornell University, New York, New York; ¶Center for Liver Diseas vice, New York University Medical Center, New York, New York ronic HBV infection is an important public health prob- worldwide and in the United States. A treatment algo- hm for the management of this disease, published previ- sly by a panel of U.S. hepatologists, has been revised on basis of new developments in the understanding of the order, the availability of more sensitive molecular diag- stic tests, and the licensure of new therapies. In addition, etter understanding of the advantages and disadvantages new treatments has led to the development of strategies reducing the rate of resistance associated with oral nts and optimizing treatment outcomes. This updated orithm was based primarily on available evidence by ng a systematic review of the literature. Where data were king, the panel relied on clinical experience and consen- expert opinion. The primary aim of antiviral therapy is rable suppression of serum HBV DNA to low or unde- table levels. Assays can now detect serum HBV DNA at els as low as 10 IU/mL and should be used to establish a seline level, monitor response to antiviral therapy, and vey for the development of drug resistance. Interferon a-2b, lamivudine, adefovir, entecavir, peginterferon alfa- telbivudine, and tenofovir are approved as initial ther- y for chronic hepatitis B and have certain advantages and advantages. Although all of these agents can be used in ected patients, the preferred first-line treatment choices entecavir, peginterferon alfa-2a, and tenofovir. Issues consideration for therapy include efficacy, safety, rate of to 5000 people die each year in the United States of these plications of HBV infection.1 The cumulative rate of mor- ent of Chronic Hepatitis B Virus ate HAN,§ IRA M. JACOBSON,� PAUL MARTIN,¶ rd, California; ‡Department of Medicine, Mount Sinai Medical Center, New Angeles, California; �Division of Gastroenterology and Hepatology, Weill iversity of Miami School of Medicine, Miami, Florida; and #Liver Transplant ity and mortality from cirrhosis and liver cancer related to B is highest among individuals who acquire HBV infection neonates or in early childhood.1 To help guide clinicians in treating patients with CHB, a el of U.S. hepatologists published a treatment algorithm in 04,5 which was subsequently revised in 2006 on the basis of developments in the field.6 These advances have included a ter understanding of the natural history of CHB and the ilability of more sensitive molecular diagnostic tests. The mber of antiviral agents for the treatment of patients with B has expanded from 5 to 7 with the approval of telbivudine 2006 and tenofovir in 2008 by the U.S. Food and Drug ministration (FDA). In addition, there are now better defined ategies for optimizing patients’ responses to oral antiviral rapy.7 Emerging data on promising antiviral therapies in late ges of clinical development, along with the potential likely onstration of the safety and efficacy of combination ther- , suggest that there will be future management options in ition to the agents that are currently used as monotherapy the treatment of CHB. Finally, data are accumulating on cial patient populations who pose unique challenges and cial requirements for antiviral therapy. In light of these advances, the panel met again to reassess d revise its recommendations. The aim was to build on the sting algorithm, preserving its practical approach and com- hensiveness, and update the guidelines for the diagnosis, atment, and monitoring of patients with chronic HBV infec- © 2008 by the AGA Institute 1542-3565/08/$34.00 doi:10.1016/j.cgh.2008.08.021 20 rev the 20 An the Asi 200 sol reli vid scr alg wh the tio the ito the gro rev chr me tio sta eva the gar na com the of gre Ta Imm p sent Imm p p ry Ina c y , ry Res sis Rea ( C sis ry aLiv bM rom H 2 KEEFFE ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. xx, No. x ARTICLE IN PRESS 08 that addressed the treatment of CHB. The panel also iewed abstracts from the following conferences and included m in the evidence table: Digestive Disease Week 2006 and 07, the American Association for the Study of Liver Diseases nual Meeting 2006 and 2007, the European Association for Study of the Liver Annual Meeting 2007 and 2008, and the an Pacific Association for the Study of Liver Disease 2007 and 8. Where possible, the panel based their recommendations idly on evidence, but where data were lacking, panel members ed on their own clinical experience and expert opinion. The goal of the revised algorithm presented here is to pro- e physicians with the most current information on the eening, diagnosis, and treatment of CHB. Specifically, the orithm provides answers to several practical questions: (1) ich patients are candidates for antiviral therapy?, (2) what are advantages and disadvantages of available treatment op- ns?, (3) when should therapy be initiated?, (4) when can rapy be stopped?, (5) what is the role of on-treatment mon- ring?, and (6) which strategies should be used to modify rapy to decrease the risk for antiviral resistance? As a back- und to an application of the recommendations, this article iews the current understanding of the clinical aspects of onic HBV infection and presents updated algorithm recom- ndations for the management of CHB. Natural History of Chronic Hepatitis B Virus Infection The accurate and early diagnosis of chronic HBV infec- n is an important step in patient management. An under- ble 1. Phases of Chronic HBV Infection Phase ALT Liver histology une tolerance hase Normal or minimally elevated Minimal activity; ab or scant fibrosis une clearance hase (HBeAg- ositive CHB) Elevated, usually persistently or with intermittent elevations Active; liver biopsy showing chronic hepatitis (necroinflammato score �4)a ctive HBsAg arrier state Persistently normal Inactive; liver biops showing variable usually minimal fibrosis (necroinflammato score �4)a olution Normal Inactive; scant fibro ctivation phase HBeAg-negative HBb) Elevated, often fluctuating levels Active; liver biopsy showing variable amounts of fibro (necroinflammato score �4)a er biopsy optional. ost of these patients have precore or core promoter variants. Data f nding of the natural history of CHB is fundamental to the luation and management of CHB, playing a critical role in assessment of patient status and in guiding decisions re- ding candidacy for treatment and treatment end points. The p Res h tural course of HBV infection is a dynamic interplay of plex interactions involving the virus, the hepatocyte, and host immune response, which, together with the influence various external factors, determine disease severity and pro- ssion.11–15 The natural history of HBV infection can be di- ed into distinct phases: immune tolerance, immune clear- ce, inactive carrier of HBsAg, and reactivation.16,17 Each phase haracterized by distinct patterns of serologic markers, HBV A levels, and changes in serum levels of ALT and AST that icate the immunologic and necroinflammatory status of the ient. The clinical terms and definitions used to characterize stages of CHB adopted at the National Institutes of Health ference on the Management of Hepatitis B are summarized Table 1.18 Other clinical terms relating to HBV infection are marized in Table 2. ble 2. Definitions of Clinical Terms Used in the Course of HBV Infection te exacerbation or flare of hepatitis B: intermittent increase of minotransferase activity to �10 � ULN and �2 � baseline ctivation of hepatitis B: reappearance of active ecroinflammatory disease of the liver in a person known to be in he inactive HBsAg carrier state or to have resolved hepatitis B eAg clearance: loss of HBeAg in a person who was previously BeAg-positive eAg seroconversion: loss of HBeAg and detection of anti-HBe in person who was previously HBeAg-positive and nti-HBe–negative, associated with a decrease in serum HBV NA to �20,000 IU/mL eAg reversion: reappearance of HBeAg in a person who was HBV DNA HBeAg HBsAg High levels: serum HBV DNA �20,000 IU/mL Positive; anti-HBe– negative Positive �6 mo High levels: serum HBV DNA �20,000 IU/mL Positive; anti-HBe– negative Positive �6 mo Low or undetectable levels: serum HBV DNA negative or �2000 IU/mL Negative; anti-HBe– positive Positive �6 mo No detectable serum HBV DNA (low levels might be detectable in the liver) Negative; anti-HBe– positive Negative Moderate, often fluctuating levels: serum HBV DNA �2000 IU/mL Negative; anti-HBe– positive Positive �6 mo oofnagle et al18 and Yim and Lok.17 vid an is c DN ind pat the con in sum Ta Acu a Rea n t HB H HB a a D HB reviously HBeAg-negative, anti-HBe–positive olution: loss of HBsAg and no further virologic, biochemical, or istologic evidence of active virus infection or disease wil bir per bef sio in no by DN stu era log ph siti tua ati mi im HB an ally lev are Th fro alt ph the mu hep DN no 0.4 res pro rev eit yea of cov der to a r ten Th vat sel red gu pre cod pro mu nu do tio ati to an par wit ter HB lat stu wh neg a c app HB 1.1 yea the bec lev wh HB HB ria con po bet on the itiv 4-f pen ser dis in Liv tha HB an dev pro stu HC cop Ho cop pat per est fro HC cop sen for Month 2008 A TREATMENT ALGORITHM FOR CHRONIC HEPATITIS B 3 ARTICLE IN PRESS The clinical course of CHB is variable, and not all patients l experience every phase of infection. Acquisition of HBV at th or in early childhood is associated with a long latency iod of immune tolerance, which might last for 2–3 decades ore immune clearance characterized by HBeAg seroconver- n to antibody to HBeAg (anti-HBe), whereas infection later life is associated with a very short immune tolerance phase or ne at all.16,19 The onset of chronic HBV infection is marked the continued presence of HBsAg, high levels of serum HBV A, and the presence of HBeAg in serum. A 5-year follow-up dy involving HBsAg-positive individuals in the immune tol- nce phase found that these patients exhibit minimal histo- ic changes, and those remaining in the immune tolerance ase experience no or minimal disease progression.17,20 Tran- on to the immune clearance phase is characterized by fluc- ting or generally high HBV DNA levels, with frequent hep- tis flares or ongoing hepatic necroinflammatory damage that ght lead to variable degrees of fibrosis or cirrhosis. The mune clearance phase ends when the patient undergoes eAg seroconversion, with loss of HBeAg and development of ti-HBe. Loss of HBeAg and seroconversion to anti-HBe usu- are preceded by a marked decrease in serum HBV DNA els to �20,000 IU/mL, although often still detectable, and typically followed by the normalization of ALT levels.21 us, HBeAg seroconversion usually represents a transition m the immune clearance phase to an inactive carrier state, hough some patients directly transition to the reactivation ase clinically called HBeAg-negative CHB and associated with presence of the precore and/or double basal core promoter tant virus. During the inactive carrier state, there is little evidence of atitis by clinical and laboratory evaluation, and serum HBV A levels are markedly reduced or undetectable.17,22–24 A mi- rity of patients (annual incidence, 0.1%–0.8% for Asians and %–2% for whites) will lose HBsAg, which is referred to as olution of the carrier state. It is not uncommon for a small portion of patients in the inactive carrier state to experience ersion back to HBeAg positivity or reactivation of disease, her spontaneously or through immune suppression after rs of inactivity.25,26 This is most likely caused by the presence detectable HBV DNA levels in the liver in the form of alently closed circular DNA (cccDNA).27 These findings un- score the fact that even HBsAg clearance is not tantamount the complete resolution of HBV infection. In addition, one third or more of inactive carriers experience eturn of high levels of HBV DNA and persistent or intermit- t increases in ALT levels, despite the absence of HBeAg.22,28,29 is form of chronic HBV infection, referred to as the reacti- ion phase or HBeAg-negative CHB, is associated with the ection of viral mutants that fail to produce HBeAg or have uced HBeAg production.30 The most common mutation is a anine to adenine substitution at nucleotide 1896 in the core region. This mutation results in a TAG stop codon at on 28 of the precore protein, thereby preventing HBeAg duction, and is termed the precore mutant. A second dual tation, the double basal core promoter mutant involving 2 cleotide substitutions (A1762T and G1764A), leads to the 31 wn-regulation of HBeAg production. Alone or in combina- n, these mutations account for the majority of HBeAg-neg- ve CHB. The HBeAg-negative form of CHB has been reported occur more frequently in patients with HBV genotypes B, C, HC fou cop d D compared with genotype A, with genotype D having a ticularly strong association with the precore mutation.32 Sustained spontaneous remission is uncommon in patients h HBeAg-negative CHB (incidence, 6%–15%), and the long- m prognosis is reportedly poorer compared with that for eAg-positive patients, although this might in part reflect a er stage of HBV infection.29 A recent long-term follow-up dy involving 1965 asymptomatic inactive HBsAg carriers o were followed for 20,298 person-years showed that HBeAg- ative hepatitis recurred at an annual incidence of 1.5%, with umulative probability of 10% at 5 years, 17% at 10 years, and roximately 20% after 15 years.33 In this study, spontaneous sAg seroclearance occurred at an annual incidence of up to 5%, with a cumulative probability of 8% at 10 years, 25% at 20 rs, and 45% at 25 years of follow-up. It is unclear whether se results can be universally applied to all inactive carriers, ause this was a special group of patients with normal ALT els and serum HBV DNA was not routinely tested. Patients o lose HBsAg have a much better prognosis than do their sAg-persistent counterparts.34 Long-term follow-up of sAg-positive, HBeAg-negative individuals, involving the se- l testing of HBV DNA and ALT levels, is recommended to firm that the inactive carrier state is maintained.8 Hepatitis B Virus DNA and Disease Progression Large, long-term population-based studies of HBsAg- sitive individuals have demonstrated a strong relationship ween the risk of progression to cirrhosis, HCC, or both and going HBV replication.12,35–37 In both natural history and rapeutic studies, patients with cirrhosis who are seropos- e for HBeAg, HBV DNA, or both have an approximately old higher risk of further disease progression to decom- sation, HCC, and death than do patients who are HBeAg onegative.15,38–40 The relationship between serum HBV DNA levels and risk of ease progression has been most convincingly demonstrated the Risk Evaluation Viral Load Elevation and Associated er Disease (REVEAL) study, a large, prospective cohort study t assessed the natural history of CHB in 3653 untreated sAg-positive Asian individuals.12 Patients were followed for average of 11.4 years, during which 164 study participants eloped HCC. The cumulative incidence of HCC increased gressively in a direct relationship to HBV DNA levels at dy entry. The multivariable-adjusted relative risk (RR) of C increased from 1.1 at HBV DNA levels of 300 to �104 ies/mL to 6.1 at HBV DNA levels of �106 copies/mL.12 wever, patients with HBV DNA levels of �104 to �105 ies/mL also were at a significant risk of HCC (RR, 2.3), and ients with increasing levels of HBV DNA over time or with sistently increased levels during follow-up were at the high- risk for HCC. In contrast, a lowering of HBV DNA levels m the highest levels was linked with a reduction in risk of C, but only when the HBV DNA level decreased to �104 ies/mL. Reanalysis of the REVEAL study data with more sitive real-time polymerase chain reaction (PCR) methods quantifying serum HBV levels showed an increasing risk of 6 41 C up to �10 copies/mL. In a recent subanalysis of the REVEAL cohort, Ileoje et al35 nd that individuals with low levels of HBV DNA (�104 ies/mL), who are often classified as having “inactive” disease, are wit vol tie du HB dev lev oth pan cir coh neg Th pat tie the sta vir chr ral dis na dis enc cop (H adv an rep dis res im ate (pa esp qu an rev (CD sho hep for enz cau me HB tio CH inc par can tes an oth cir con pat lev lar no Scr ua als mi sho hea Ab cir no CD an mo fol inc HB Ta Ind f ● A ● M ● E P ● I ● S ● E f ● C Oth ● H ● P ● P t ● M ● I ● I ● I ● P ● P Da 4 KEEFFE ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. xx, No. x ARTICLE IN PRESS also at an increased risk for HCC development, compared h uninfected (HBsAg-negative) individuals. This analysis in- ved 3584 HBsAg-positive and 18,541 HBsAg-negative pa- nts as controls who were followed for 12 years. Moreover, ring follow-up, individuals with persistently low levels of V DNA (�300 to �104 copies/mL) had an increased risk of eloping HCC, compared with patients whose HBV DNA els were persistently undetectable (�300 copies/mL). An- er analysis of the REVEAL cohort, involving 3582 partici- ts, found a positive direct relationship between the risk of rhosis and serum HBV DNA levels.36 More than 90% of the ort had serum ALT levels �45 U/L; 85% were HBeAg- ative, a