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between this versionandtheVersionrecord. Pleasecitethis articleasdoi:10.1002/hep.28280. through thecopyediting, typesetting, paginationandproofreadingprocess, whichmayleadtodifferences This istheauthormanuscript acceptedforpublicationandhasundergone full peerreviewbuthasnotbeen [email protected] [email protected] Brian J. McMahon, MD McMahon, BrianJ. [email protected] Lok,MD AnnaSF Authors [email protected] MPH MBBCh, KhaledMohammed, [email protected] MPH MD, Hassan Murad, Mohammad [email protected] ZhenPh.D Wang, [email protected] Larry, J MLS Prokop [email protected] M.B.,B.Ch Dabrh, Abu Moain Abd [email protected] MohamedA. Essa [email protected] MD Singh, Siddharth [email protected] MD Mouchli, A. Mohamed [email protected] Benkhadra, M.D Khalid [email protected] FaresAlahdab,M.D [email protected] M.D Almasri, Jehad [email protected] Farah, Wigdan MBBS [email protected] MBBCh Ahmed, T. Ahmed B. MD Wong, John [email protected] MPH MD, Brown, S. Jr., Robert : :
Accepted Article Inf B Virus Hepatitis forChronic Therapy Antiviral
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8 1
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5,6 5,6
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This article isprotected by copyright. All rights reserved.
7 5,6 A Systematic Review and Meta Analysis Meta Analysis and Review A Systematic
3
6 5,6,10
5,6,10
Hepatology
ection in Adults: Adults: in ection
September September 2015 15, USA USA 3 2 1 Affiliations Health and Nutrition Examination Surveys (NHANES). Surveys (NHANES). Examination andHealth Nutrition Up (ALT), Aminotransferase Alanine surface(HBsAg), Hepatiti (HCC), Carcinoma IFN),Hepatocellular (Peg trials (RCT Controlled Randomized Diseases(AASLD), Abbreviations of List [email protected] 5362 SPC Center, Taubman 3912 Drive, CenterMedical author Corresponding Keywords USA 10 9 8 7 6 5 4 Library Public Services, Mayo Clinic, Rochester, MN Rochester, Mayo Clinic, LibraryServices, Public MayoC andof Hepatology, Gastroenterology Division clinic Internal Mayo of Hospital Medicine, Division May Delivery, Care Health of forCenter Science the Clin Mayo Program, Research Evidence BasedPractice Making,Medical Tufts ofDecision Clinical Division Weill andof Hepatology, Gastroenterology Division Native Program, Alaska Liverand Hepatitis Diseases Univer andof Hepatology, Gastroenterology Division Division of Preventive, Occupational andAerospace Occupational of Preventive, Division : cirrhosis, hepatocellular carcinoma, interferon, carcinoma, hepatocellular cirrhosis, :
Accepted Article :
. Tel: 734 936 7511. Fax: 734 936 7392. 734 936 7392. Fax: 734 936 7511. Tel: . : Hepatitis B virus (HBV), American Association for American Association B: (HBV), virus Hepatitis : Anna S. Lok, MD, University of Michigan Health Sy Health of Michigan Lok,University : Anna S. MD, This article isprotected by copyright. All rights reserved. Hepatology Hepatology , Rochester, Minnesota, USA USA Minnesota, Rochester, , o Clinic, Rochester, MN, USA USA MN, Rochester, Clinic, o Center, Boston, Massachusetts, USA USA Massachusetts, Boston, Center, Cornell Medical College, New York, NY, College,Medical NewCornell York, Tribal Health Consortium, AK, USA AK, USA Consortium, Health Tribal s B e antigen (HBeAg), Hepatitis B Hepatitis B s (HBeAg), e antigen , USA USA , sity of Michigan, Ann Arbor, MI, USA Arbor, USA MI, Ann sityof Michigan, Medicine, Mayo Clinic, Rochester, MN, MN, Rochester, Clinic, Mayo Medicine, per limit of normal (ULN), National (ULN), National of normal perlimit linic, Rochester, MN, USA MN, Rochester, linic,
s), Interferon (IFN), Pegylated interferon interferon InterferonPegylated (IFN), s), , Ann Arbor, MI 48109. Email: Email: Arbor, Ann 48109. , MI ic, Rochester MN, USA USA RochesterMN, ic, nucleos(t)ide analogues analogues nucleos(t)ide the Study of Liver of Study the stem, 1500 E E 1500 stem,
2
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September September 2015 15, served on advisory board ofGlaxoSmithKline Gilead, board servedadvisory on Brist from grants research received Lokhas AnnaSF Disclosures Murad(Mayo Clinic M to LiverDiseases of Study the Support Financial icoue. disclosures. Murad M Z Larry,Wang, R ADabra, Mohamed, E Singh, Almasri, F A Farah, J W Ahmed, A Wong, BJ McMahon, Gilead. Gi from grants research received Brown S has Robert
Accepted Article
: This study was supported by a contract from the A the from acontract by This : study was supported
This article isprotected by copyright. All rights reserved. Hepatology Hepatology ol Myers Squibb and Gilead, and Gilead, has and ol MyersSquibb lead and has served as a consultant for a consultant as leadand served has and Merck. and Merck. ). , K Mohammed do not have any not do KMohammed , lahdab, K Benkhadra, M Mouchli, S S Mouchli, Benkhadra,M K lahdab, merican Association for Association merican 3
positive patients who seroconverted from HBeAg to H to HBeAg from seroconverted who patients positive September September 2015 15, American Association for the Study of LiverDisease of Study the for AmericanAssociation appropriate, an most is medication which initiated, provid help to are needed guidelines Evidence based a remains (HBV) infection B virus hepatitis Chronic Abstract clinical challenging and encountered othercommonly c active of phases immune the on literaturefocuses level low with cirrhosis compensated in antivirals du viremia persistent with patients secondagent in HBeAg therapy in antiviral continuing vs. stopping and indire Non comparative entecavirtenofovir. vs. antivi continuing vs. discontinuing about questions therapy. Only antiviral with outcomes intermediate qu moderate patients, Inimmune tolerant carcinoma. de cirrhosis, of reducingrisk the in HBVinfection t of antiviral effectiveness the evidencesupported rep studies) observational 44 and RCTs (15 59 which indep of pairs wasdone by extraction therapy.Data c with years diagnosed ≥18 old adults enrolled that trials controlled databases for randomized multiple a prior developed a protocol committees andwriting
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology herapy in patients with immune active chronic active chronic immune with herapy patients in compensated liver disease, and hepatocellular and hepatocellular disease, liver compensated viremia. ring treatment; and the effectiveness of effectiveness and the ringtreatment; d when treatment can safely be stopped. The stopped. cansafely be when treatment d (RCTs) and controlled observational studies studies observational and controlled (RCTs) hronic HBV infection who received antiviral antiviral received who infection HBV hronic ral therapy in hepatitis B e antigen (HBeAg) (HBeAg) e antigen B ralhepatitis therapy in hronic HBV infection. Decision making in in Decision making infection. HBV hronic endent reviewers. We included 73 studies; of studies; 73 included We reviewers. endent very low quality evidence informed the the informed evidence quality low very ct evidence was available for questions about about for questions available was evidence ct negative patients; monotherapy vs. adding a adding vs. monotherapy patients; negative i for this systematic review. We searched We review. systematic for i this significant global health problem. problem. health global significant ers determine when treatment should be should treatment erswhen determine s (AASLD) HBV guideline methodology methodology guideline HBV (AASLD) s ality evidence supports improved improved supports alityevidence orted clinical outcomes. Moderate quality Moderate outcomes. clinical orted settings depends on indirect evidence. indirect on depends settings Be antibody and about the safety the of about Beand antibody
Conclusion : Most of the current Most current of the :
4
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provides a useful framework when developing amanag when developing framework a useful provides Surveys ( Examination Nutrition andHealth National September September 2015 15, however, the absolute number of persons chronically of persons number absolute however, the in 4.2% from slightly, declined only has infection decades, forthree vaccines HBV of availability the a remains (HBV) infection B virus hepatitis Chronic Introduction infection. infection. fu been not have each phase during HBV responsesto IU/ml. generally2,000 below DNA disea liver concomitant of other absence ALT the in ofh andof presence HBeAg absence by characterized generallya DNA and HBV inflammation activehepatic in by are characterized hepatitis, negativechronic active phases, Theimmune IU/ml. over well 20,000 levels (ALT) aminotransferase alanine normal HBeAg, phas tolerant The immune active (4). phases immune im (HBeAg) positive antigen B e hepatitis tolerant, consist HBV infection chronic courseof Thenatural chronicHBV havemay of 730,000) (instead residents end from immigration for accounting groups,when so However, (2). be0.27% to was estimated infection ( In2005. States in United the million 240 to 1990
Accepted Article :
This article isprotected by copyright. All rights reserved.
Although not all patients go through each phaseandeach go patients through all Althoughnot Hepatology Hepatology termittently or persistently elevated ALT with with ALT elevated or persistently termittently 1990 to 3.7% in 2005 (1). Worldwide, (1). Worldwide, 2005 in 3.7% to 1990 US), based on 1999 2006 data the from 1999 2006 basedon US), the global prevalence of chronic HBV chronic HBV of global the prevalence mune active, inactive, and HBeAg negative andHBeAg negative active, inactive, mune ses, and undetectable or low levels of HBV of HBV levels low or and undetectable ses, NHANES under sampled high prevalence high prevalence under sampled NHANES significant global health problem. Despite Despite problem. health global significant s of four characteristic phases: immune immune phases: of four s characteristic infected has increased from 223 million in in million 223 from increased has infected also called HBeAg positive or HBeAg called HBeAg positive also NHANES), the prevalence of chronic HBV chronicHBV of prevalence the NHANES), e is characterized by the presence of presence bythe characterized eis infection (3). (3). infection lly characterized, this classification schema schema classification this llycharacterized, epatitis B e antibody (anti HBe), normal (anti HBe),normal antibodyB e epatitis emic countries, as many as 2.2 million US US million as 2.2 asmany countries, emic and high levels of HBV DNA usually DNA of HBV and high levels ement approach for chronic HBV chronicHBV for approach ement bove 2,000 IU/ml. The inactive phase is is The phase inactive IU/ml. 2,000 bove immune immune 5
September September 2015 15, IFN is given for a finite duration, nucleos(t)ide a nucleos(t)ide duration, givena finite for IFN is inf and ameliorate hepatic replication HBV suppress adef entecavir, telbivudine, lamivudine, analogues: and peg (IFN) standard of interferon formulations treat are for approved medications Currently,seven Eligibility Criteria: Criteria: Eligibility of ALT. andnormalization DNA, ofHBV of hepatit loss seroconversion, durabilityof HBeAg (intermedi surrogate data unavailable, were outcome and [HCC] carcinoma hepatocellular decompensation, we of interest Theoutcomes Table 1). (Supplemental Intervent key 7 for Population developeda protocol state (PRISMA) Meta analysis and Reviews Systematic standards the follows review of Thethis reporting prot developed a committees and writing methodology LiverDis for of Study the Association TheAmerican Methods: be safely can treatment appropriate, and when most whentreatme determine providers help guidelinesto Ther cost. and increased resistance,non adherence, ass are of treatment Longdurations oftenfor life.
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology nalogues are administered for many yearsand many for administered are nalogues ociated with risks of adverse reactions, drug drug reactions, of adverse risks with ociated set in the Preferred Reporting Items for Preferred the Reporting in set ovir and tenofovir. These medications medications These and tenofovir. ovir ylated (Peg IFN), and five nucleos(t)ide andIFN),five ylated (Peg efore, there is a need to have evidence based have evidence based to a need is there efore, ment of chronic HBV infection: two two HBVofinfection: chronic ment is B surface (HBsAg), long term suppression suppression long term B is surface (HBsAg), questions (PICO) Outcome Comparison ion stopped. stopped. lammation but do not eradicate HBV. While not While do eradicateHBV. but lammation ate) outcomes were sought, specifically specifically sought, were ate) outcomes is medication which beinitiated, should nt re clinical outcomes (cirrhosis, liver liver (cirrhosis, outcomes clinical re eases (AASLD) HBV guideline HBV eases(AASLD) ocol a priori for this systematic review. systematicreview. for a ocol this priori all cause mortality); however, when such however, mortality); all cause ment (5). The committee identified and identified committee (5). The ment 6
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patients who were pregnant, patients co infected wi co infected patients pregnant, were who patients September September 2015 15, immunodeficiency virus, patients receiving corticos receiving patients virus, immunodeficiency incl that studies excluded We therapyas treatment. chroni with yearsdiagnosed old ≥18 adults enrolled and (RCTs) trials controlled randomized included We during each screening level to assess agreement bet agreement assess to level duringscreening each Inter reviewer. by a third or arbitration consensus duplicate. screenedin and abstractsretrieved were Evidence (DistillerSR, system referencemanagement abs and titles screened independently reviewers Two Studyselections: Tablespecifies 2 Supplemental studies. additional an methodology guideline HBVAASLD the from Members for chronic hepat antivirals of comparativestudies with vocabulary supplemented Controlled 2014. 16th, an Reviews, of Systematic Database Cochrane Trials, Coc EMBASE, MEDLINE, Citations, Non Indexed &Other co a librarianconducted Clinic experiencedMayo An Search strategy: question. eachkey Tablesummarizes 1 groups.Supplemental comparison pat and hemodialysis recipients therapy,transplant
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology reviewer agreement (Kappa) was calculated calculated was (Kappa) revieweragreement itis B. No language restrictions were used. B. language No restrictions itis Disagreements were resolved by seeking byseeking resolved were Disagreements ients, as well as studies without control or control without as studies as well ients, the detailed search strategy. strategy. search detailed the uded patients with acute HBV infection, HBVacute infection, with uded patients ween reviewers. For PICO questions where questions ForPICO weenreviewers. th hepatitis C or D or human or Dor human C hepatitis th c HBV infection who received antiviral antiviral received who cHBV infection teroids, chemotherapy or immunosuppressive orimmunosuppressive chemotherapy teroids, tracts for potential eligibility using an online an online eligibility using tractsfor potential d Scopus from early 1988 to September September to 1988 early from Scopus d mprehensive search of Medline In Process Medline of search mprehensive controlled observational studies that that studies observational controlled keywords was used to search to for keywordswas used Partners, Inc.). Full text of the included included of the Inc.).text Full Partners, the inclusion and exclusion criteria for criteria and for exclusion inclusion the d writing committees helped identifyhelped committees writing d hrane Central Register of Controlled Controlled Register of Central hrane 7
September September 2015 15, Data Extraction: DataExtraction: gen in andwere narratively were studies summarized uncontrolle forsearches manual performed committee fou were criteria meeting predefined the studies no heterogeneity, we conducted subgroup analysis for s for analysis subgroup conducted heterogeneity,we Co LP, (StataCorp 13 version STATA, conductedusing the heterogeneit overall the measure To model. Haenszel est and models Lairdrandom effects and DerSimonian log the pooled then We distribution. using binomial ratio risk we calculated outcomes, Fordichotomized analysis: Statistical and publi (heterogeneity) inconsistency intervals), (surrog indirectness bias, of risk were ofevidence app (GRADE) and Evaluation Development, Assessment, eva was estimates) the in (i.e.,certainty evidence and observ RCTs in of bias risk the assess (NOS)to a tool of Bias assessment Cochrane the used Risk We assessment: of bias risk and quality Methodological intervent characteristics, patient characteristics, pilo using a standardized, was done Dataextraction I² I²
statistic, where statistic, Accepted Article I² I² >50% suggests high degree of heterogeneity. All sta All of heterogeneity. high degree >50%suggests This article isprotected by copyright. All rights reserved. Hepatology Hepatology ions details and outcomes of interest. interest. of and outcomes details ions luated using the Grading of Recommendations ofRecommendations Grading using the luated ate outcomes), imprecision (wide confidence (wide confidence imprecision ateoutcomes), cation bias (6). (6). bias cation nd, the AASLD HBV guideline methodology methodology guideline HBV AASLD the nd, ted form. We extracted data on study dataon extracted We form. ted transformed risk ratios using the ratios risk transformed
ational studies, respectively. Quality of respectively. Quality studies, ational tudies enrolling patients with more advanced moreadvanced with enrolling patients tudies (95%CI) intervals confidence and 95% s eral consistent with low quality evidence. quality evidence. low with consistent eral y across the included studies, we calculated we calculated studies, y included the across nd modified Newcastle Ottawa Scale Newcastle OttawaScale modified nd d observational studies. Data from these Data from studies. observational d imated heterogeneity using the Mantel Mantel the heterogeneity using imated llege Station, TX). To explore explore To TX). llegeStation, roach. Criteria used to evaluate quality evaluate to quality used Criteria roach. tistical analyses were analyses were tistical 8
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provides the GRADE summary of the evidence. evidence. the of summary GRADE the provides September September 2015 15, outcome was available and heterogeneity was low (7) low heterogeneity was and was available outcome if plots funnel constructing and by asymmetrytest of pub impact the explored B. We chronichepatitis fai liver acute chronic on cirrhosis, decompensated for analysis stratified we disease; liver performed studies (28, 40 45) compared entecavir vs. no treat no vs. entecavir 40 45)compared (28, studies (24 39) c studies 16 IFNtreatment; no comparedvs. co therapy vs. antiviral comparing Amongstudies 42 infection: compared to therapy antiviral of Effectiveness 1.1 another. agent vs. antiviral compared one studies c Forty two studies outcomes. clinical andreported observationa and 44 RCTs (15 studies 59 included We infection p in therapy antiviral of 1: Effectiveness Question in are and 7 summarized 6 4, questions relevantto questi availablefor only were of interest outcomes was 0.78 for study Kappa selection weighted Average descr 1 Figure included. were studies of 73 Atotal Results:
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology the following groups: compensated cirrhosis, cirrhosis, compensated groups: following the atients with immune active chronic HBV active immune HBV chronic with atients ibes the details of the selection process. selection of the details the ibes ons 1, 2, 3 and 5. Uncontrolled studies that are that studies Uncontrolled and 5. 3 2, 1, ons control in patients with chronic hepatitis B B hepatitis chronic with patients in control ment;1 study each compared telbivudine (44) (44) telbivudine compared study eachment;1 a sufficient number of studies (>20) per (>20) per of studies anumber sufficient lure, and severe acute exacerbations of exacerbations acute lure, and severe Supplemental File 3. Supplemental table 4 4 table FileSupplemental 3. Supplemental ompared antiviral therapy vs. control and 18 and18 control therapy vs. antiviral ompared lication bias by using the Egger regression Egger regression the by bias using lication ompared lamivudine vs. no treatment; 7 7 treatment; no vs. omparedlamivudine ntrol in 62,731 patients, 16 studies (8 23) studies 16 patients, 62,731 in ntrol . . . Controlled studies that reported studies the Controlled . l studies) that evaluated antiviral therapy antiviral evaluated that studies) l 9
chronic hepatitis B and 21 studies enrolled patient studies B and 21 chronichepatitis onl enrolled studies 3 disease, decompensatedliver chronic failure, liver on acute with only patients wi onlyenrolled patients Eleven studies treatment. (47 49 studies and 3 placebo vs. (46) andtenofovir reduce the risk of decompensated liver disease (6 s (6 disease liver of decompensated risk reducethe I I 0.7), 0.4 (95%CI, control therapy vs. antiviral that analysisshowed patien 59,201 involving studies Inobservational 35 group. obser were events no but as outcomes decompensation exam (29) RCT moderate.One to was low evidence the I 1.3), all in found were differences 0.8)).significant No a 0.7)) 0.3 (95% CI, 0.4 RR disease liver (1 RCT, 2) significan (Figure control therapy vs. antiviral su 3,463 involving 46) 33, 29, (8,23 25, InRCTs 7 Risk ascertainment. outcome and exposure inadequate description of clear lack to due highof bias risk used method blinding the reported and 6 concealment randomizatio reported the RCTs included of asthe 2 of Risk Table 1. in illustrated are characteristics September September 2015 15, 2 =92.3%) and cirrhosis (4 studies, RR 0.6 (95% CI,0. 0.6 RR studies, (4 and cirrhosis =92.3%) 2
Accepted0. (95% CI, 0.6 RR incidence (3 RCT, HCC =72.9%)or Article 2 =87.4%), all cause mortality (23 studies, RR 0.6 (9 0.6 RR studies, (23 mortality all cause =87.4%), This article isprotected by copyright. All rights reserved. Hepatology Hepatology bias assessment for RCTs was low to moderate to waslow for RCTs assessment bias of the selection process of the population and population of the process selection the of 2 studies enrolled only patients with with onlyenrolled patients studies 2 tly decreased the overall risk of decompensated of decompensated risk overall the decreased tly decreased the risk of HCC (23 studies, RR 0.5 0.5 RR studies, (23 of HCC risk decreased the cause mortality (4 RCTs, RR 0.5 (95% CI, 0.5 0.2 RR (4 RCTs, causemortality s with stable chronic hepatitis B. Study chronic hepatitis stable with s th compensated cirrhosis, 5 studies enrolled studies 5 cirrhosis, compensated th tudies, RR 0.7 (95% CI, 0.3 1.9), I 1.9), 0.3 (95% CI, 0.7 RR tudies, ) compared a variety of oral antiviral vs. no no vs. oralantiviral of a variety )compared nd cirrhosis (1 RCT, RR 0.4 (95% CI,0.2 (95% CI,0.2 0.4 RR (1 RCT, cirrhosis nd y patients with severe acute exacerbations of exacerbations yacute severe with patients ts with mean follow up of 60 months, meta months, of 60 up mean follow with ts bjects with mean follow up of 28 months, months, of 28 up mean follow with bjects n method, 2 reported utilization of allocation of allocation reported 2 utilization method, n . Most of the observational studies were studies at observational of the Most . 4 0.8), I 0.8), 4 of bias is described in Tables 2 3. 2 3. Tables in described is of bias ved in either the intervention or control or control intervention either the vedin ined adverse events including death and deathincluding events adverse ined 2 =0%) but did not significantly significantly not did but =0%) 3 1.1), I 3 1.1), 5% CI, 0.5 0.8), CI, 0.5 5% 2 =0%). The quality of The quality =0%). 2 =96.5%) 10
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patients included had compensated cirrhosis. Reduc cirrhosis. had compensated included patients hepatitis B B hepatitis t compared therapy antiviral of Effectiveness 1.1.1 CI. narrowyielding95% and precise up, large included numb studies these however, waslow; a 4 3, (Figures controls untreated to whencompared or decompensated liver disease (1 study, RR 0.7 (95 0.7 RR (1 study, disease liver ordecompensated I CI,0.4 0.9), decrea significantly treatment no to alphacompared (Fi 41) 38, 35, 26, (25, studies Inobservational 5 I I CI,0.4 0.8), t therapy decreased antiviral months), 60 up follow pa 3) involving (Figure studies Inobservational 10 CI (95% 0.1 (RR mortality all cause reduced control wi patients cirrhotic 222 (25) enrolling InRCT one cirrhosis: compensated and compared to therapy antiviral of Effectiveness 1.2 mortality. all cause in reduction obse 11 in HCC in reduction and only RCT 1 in shown stabl with patients enrolled that studies Of21 the September September 2015 15, 2 =67.2%) and all cause mortality (3 studies, RR 0.5 0.5 RR (3 studies, mortality and all cause =67.2%)
2 2 =36.3%), decompensated liver disease (2 studies, RR (2 studies, disease liver =36.3%),decompensated =0%) but not of all cause mortality (1 study, RR 0. (1 study, RR of all cause not mortality =0%) but Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology gure 4) with mean follow up of 84 months, IFN months, of 84 up follow mean gure4) with e chronic hepatitis B, 0 to 91% of the 54,719 54,719 of the 91% B, to 0 echronic hepatitis o control in the sub group with stable chronic chronic stable with sub group the in control o control in patients with chronic HBV infection infection HBV chronic with patients in control tients with compensated cirrhosis (mean cirrhosis compensated with tients he risk of HCC (10 studies, RR 0.6 (95% 0.6 RR studies, (10 of HCC herisk th follow up of 53 months, lamivudine vs. vs. lamivudine months, of 53 up follow th sed the risk of HCC (5 studies, RR 0.6 (95% 0.6 RR studies, (5 of HCC risk the sed nd 5). The quality of this evidence overall evidence overall of this 5).The quality nd % CI, 0.3 1.5). %CI, 0.3 1.5). tion in risk of decompensated cirrhosis was cirrhosis of decompensated risk in tion , 0.1 0.3), moderate quality evidence). evidence). quality moderate 0.1 0.3), , (95% CI,0.4 0.6), I (95%CI,0.4 0.6), ers of patients with long duration of follow long duration with ersof patients rvational studies. No studies demonstrated demonstrated studies No studies. rvational 7 (95% CI, 0.5 2.4), I 0.5 2.4), (95% CI, 7 0.5 (95% CI,0.2 0.9), (95% CI,0.2 0.9), 0.5 2 =0%). =0%). 2 =56.9%) =56.9%) 11
cirrhosis followed for a mean of 52 months, entecav months, meanof 52 a for followed cirrhosis (95% CI, 0.3 0.3 0.5). RR disease liver (1 study, I 0.4 0.96), t reduced significantly treatment no vs. lamivudine (Figure 41) 38, 35, (26, studies Inobservational 4 with severe acute exacerbations: exacerbations: severeacute with compared to therapy antiviral of Effectiveness 1.5 (44). (95% CI, 0.4 0.2 0.9) (RR I l therapies including evaluating individual studies I CI,0.6 0.8), (95% 0.7 (RR mortality the antiviral months, of26 up mean follow with 44) eviden moderate quality (95% CI, 0.5 0.3 0.99), (RR a for followed patients 26 In(46) involving RCT 1 failure: liver chronic acute on experiencing compared to therapy antiviral of Effectiveness 1.4 (95% CI, 0.5 0.3 RR (2 studies, all causemortality mon of 29 up follow with studies Inobservational 2 cirrhosis: decompensated and compared to therapy antiviral of Effectiveness 1.3 0 (95% CI, 0.6 death (RR and 0.1 0.5)) (95% CI, 0.3 September September 2015 15, 2 =50.2%) (28, 37, 44), entecavir (RR 0.7 (95% CI, 0. (95% CI, 0.7 (RR entecavir 44), 37, (28, =50.2%)
2
Accepted Article(95% 0.4 RR (1 study, mortality all cause =49.9%),
This article isprotected by copyright. All rights reserved. 2 =5.4%). Similarly, reduced mortality was also found also was mortality reduced =5.4%).Similarly, Hepatology Hepatology 5) with mean follow up of 45 months, months, of45 up mean follow 5) with In 1 cohort study (40) of 1,980 patients with with patients 1,980 In(40) of study cohort 1 amivudine (RR 0.8 (95% CI, 0.7 0.9), (95% CI, 0.8 0.7 0.9), (RR amivudine control in patients with chronic HBV infection infection HBV chronic with patients in control infection HBV chronic with patients in control infection HBV chronic with patients in control 0.8) I 0.8) he risk of HCC (4 studies, RR 0.6 (95% CI, 0.6 RR (4 studies, of HCC herisk year, tenofovir reduced all cause mortality all cause mortality year,reduced tenofovir rapy vs. no therapy reduced all cause all cause reduced therapy no rapyvs. ths (27, 32), lamivudine vs. control reduced reduced control vs. lamivudine 32), (27, ths ir vs. control reduced the risk of HCC (RR (RR of HCC risk the reduced control vs. ir .3 0.98)). .3 0.98)). ce). In 4 observational studies (28, 37, 42, 42, 37, (28, studies Inobservational 4 ce). 6 0.8), I 6 0.8), 2 =0%). =0%). 2 =0%) (28, 42, 44) and telbivudine and44) telbivudine 42, (28, =0%) CI, 0.3 0.6) and decompensated and decompensated CI,0.3 0.6) in in 12
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0.5 1.9), I 0.5 1.9), 0.2 (95% CI, 0.5 (RR agents: lamivudine individual I (95% CI, 0.9 0.5 1.5), (RR statisti no showed control therapy vs. ofantiviral moret with 45) 43, (30, studies Inobservational 3 lamivudine (56), and telbivudine vs. lamivudine, re lamivudine, vs. (56), and telbivudine lamivudine en compared Three RCTs months). 28 up (meanfollow chronic HBV with patients 607 enrolled Fourstudies (95% CI, 0.4 (1 study, RR entecavirlamivudine vs. in reduction with outcome in significantdifference res lamivudine, vs. and(66); telbivudine tenofovir ent (58); lamivudine vs. compared entecavir studies ade (55) compared RCT 1 months), 22 up (meanfollow chron with patients 3,300 enrolling Amongstudies 5 of bias. risk descr 1 2Tables up. follow and inadequate outcomes character of the bydescription unclear limited the follow to and loss blinding concealment, allocation du of bias risk have high 55 57)to (52, theseRCTs antivira compared one that patients enrolling6,737 patients 2,318 (50 57) enrolling RCTs 8 included We antiv individual comparing head studies Headto 1.6 September September 2015 15, 2
Accepted Article 45). (43, =71.3%)
This article isprotected by copyright. All rights reserved. 2 =54.5%) which was consistent with studies evaluatin studies with wasconsistent which =54.5%) Hepatology Hepatology cally significant reduction in all cause mortality all cause in mortality reduction callysignificant istics for cohort selection, ascertainment of the ascertainment for selection, cohort istics han 12 month mean follow up, meta analysis meta analysis up, mean follow month han12 pectively (61). Only 1 study (58) showed a showed (58) study 1 (61). Only pectively all cause mortality in patients who received received who patients in all cause mortality l agent with another. We considered most of most considered another. We agent with l up. The observational studies were studies also The observational up. spectively (50); and one cohort study (59) study cohort andone (50); spectively e to unclear randomization methods, methods, randomization unclear eto ecavir vs. telbivudine (65); lamivudine vs. vs. lamivudine (65); ecavirtelbivudine vs. 0.3 0.6), very low quality of evidence). of evidence). quality low very 0.3 0.6), 1.7) (30) and entecavir (RR 0.9 (95% CI, 0.9 (RR andentecavir (30) 1.7) ic HBV infection and compensated cirrhosis cirrhosis compensated and HBVic infection agents: iral infection and decompensated cirrhosis cirrhosis and decompensated infection ibe the details of the included studies and studies included of the details the ibe and 10 observational studies (28, 58 66) (28, studies observational and 10 fovir vs. lamivudine, and 4 observational observational and 4 lamivudine, vs. fovir tecavir vs. adefovir (57), adefovir vs. vs. (57),adefovir adefovir vs. tecavir g the effectof g the 13
Three cohort studies (28, 62, 63) that enrolled 508 enrolled that 63) 62, (28, studies cohort Three entecavir. received who patients in entecavi study comparing cohort the in wasobserved CI, 0 (95% 0.4 adefovir(RR vs. entecavir comparing ris in Reduction lamivudine. vs. entecavir compared indirectness and imprecision. and imprecision. indirectness qual The 0.3 3.9)). (95%CI, 1.0 (RR HBsAg clearance seroc 2.2)), HBeAg (95%CI, 0.3 0.03 (RR loss HBeAg eviden moderate quality 1.8), (95%CI, 1.4 1.1 (RR a showed statistica tenofovir vs. andemtricitabine long term Althoughno weeks. for 192 (62 patients) a to (64 patients) tenofovir (67) compared OneRCT of and risk characteristics Detailedstudy levels. i therapy antiviral evaluated (67) (68) studies Two infection p in therapy antiviral of Effectiveness 2. Question mortality. effecton fol B (mean hepatitis of chronic acuteexacerbation entecavir compared that 64) (60, studies cohort Two all causemortality. 32 up (mean follow lamivudine to entecavir compared September September 2015 15,
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology bias are described in Tables 1 2. 1 2. Tables are in described bias atients with immune tolerant chronic HBV HBV chronic tolerant immune with atients lly significant increase in viral suppression suppression viral in increase llysignificant patients with acute on chronic liver failure and failure liver acute chronic on with patients n HBeAg positive patients with normal ALT normal with patients HBeAg positive n low up 32 months) showed no significant significant no showed months) 32 up low k of HCC was observed in the RCT (57) RCT the in was observed of HCC k ce) but no statistically significant increase in in significantincrease ce)statistically no but tenofovir reported, were outcomes clinical vs. lamivudine in 320 patients with severe with patients 320 in lamivudine vs. combination of tenofovir and emtricitabine and emtricitabine of tenofovir combination .2 0.8), and reduction in all cause mortality all cause in mortality reduction and .2 0.8), r vs. lamivudine (RR 0.4 (95% CI, 0.3 0.7) 0.3 0.7) (95% CI, 0.4 (RR lamivudine rvs. months), showed no significant effect on effecton significant no showed months), ity of evidence was low due to due to waslow ity of evidence onversion (RR 0.1 (95%CI, 0.01 2.8)) or 0.01 2.8)) (95%CI, 0.1 (RR onversion 14
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bias, indirectness and imprecision. Additional non non Additional and imprecision. indirectness bias, Question 3: Discontinuing compared to continuing an continuing compared to 3: Discontinuing Question study nature of the observational to rated down due 337. (95% CI, 20.3 1.2 (RR loss and666.9)) HBeAg H ratesof improved significantly untreatedcontrol postpar positive HBeAg 68 of (68) Inastudy cohort immune active chronic HBV infection infection HBV chronic active immune antivir continuing compared to Stopping 4. Question File 3. Supplemental in summarized evi of The quality reported. were outcomes clinical incidence anda cumulative study 1 in (69) months 6 I antivira stopped who patients in relapseof viremia q therapy, very low antiviral continued to Compared 3. and 1 Tables in illustrated Characte 1 55) months. (range was 12 seroconversion of consoli duration median and months (range2 120) median (1 120) was21 months, seroconversion HBeAg me the studies, For both therapy. receiveantiviral to seroconversion HBeAg after therapy(61 patients) patient compared 70) (69, studies observational Two anti HBe HBeAgto seroconverted from who September September 2015 15, 2
AcceptedHBeA of The rate flares. ALT effect on no with =0%) Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology dian (range) duration of therapy leading to of to therapy leading (range) duration dian l therapy RR 94.4 (95% CI, 13.3 670.7), CI,13.3 670.7), (95% 94.4 therapy RR l BeAg seroconversion (RR 41.8 (95% CI, 41.8 2.6 (RR seroconversion BeAg comparative and indirect evidence is andindirect comparative dence was very low due to increased risk of risk increased to due very dencelow was , risk of bias and imprecision. and imprecision. of bias risk , tum women, Peg IFN and adefovir IFN vs. and Peg women, tum of 9% at 5 years in another study (70). No yearsstudy another in 5 at of 9% uality evidence suggests increased risk of risk increased suggests ualityevidence to patients) (128 continued who those s with chronic hepatitis B who stopped B stopped who chronic hepatitis with s al therapy in HBeAg negative adults with with negativeadults HBeAg in therapy al dation treatment after HBeAg HBeAg after treatment dation ristics and risk of bias for both studies are studies for both of bias risk and ristics 7)). The quality of evidence was very low, very low, was evidence of 7)).The quality tiviral therapy in HBeAg positive patients patients HBeAg positive in therapy tiviral g seroreversion was 8% after a median ofa after8%median was gseroreversion follow up after stopping therapy was 40 was 40 therapy stopping after up follow 15
Question 5. Safety of entecavir compared to tenofov to entecavir compared of Safety 5. Question relapselower. were when relapse of viral rate a indicate high studies may that evidence indirect and studies uncontrolled for this studies comparative find to were We unable antiviral therapy. Supplemental File 3 summarizes u File summarizes 3 therapy. Supplemental antiviral o on studies comparative identify to were We unable IU/ml) <2000 (HBV DNA level viremia low and chro with patients in therapy Antiviral 7. Question entec with monotherapy continuing to agentcompared litt File 3) showed (Supplemental evidence indirect for studies comparative identify to were We unable a infection HBV chronic with tenofovir) patients in compare agent antiviral second a Adding 6. Question forstudy. each Tab density. bone on reported studies No wasshort. or profiles renal safety in andtenofovir entecavir sta no showed included studies of the Meta analysis are of bias described and risk studies included the mean with patients 1,300 in entecavirtenofovir vs. stu observational and 10 (71) (1 RCT Elevenstudies September September 2015 15,
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology hypophosphatemia, but duration of observation of observation duration but hypophosphatemia, treatment was stopped, but rates of clinical rates of clinical but was stopped, treatment in Table 1 2. Table 1 2. in nic HBV infection and compensated cirrhosis cirrhosis compensated and infection HBV nic follow up of 18.6 months. Characteristics of Characteristics months. of 18.6 up follow nd persistent viremia viremia persistent nd le to no benefit in adding a second antiviral antiviral adding benefitin no a second to le address this question. Data from these Data these from question. this address question. Supplemental File 3 summarizes File summarizes 3 Supplemental question. ir ir this question. Uncontrolled studies and studies Uncontrolled question. this reported outcomes describes 4 le detailed the tistically significant difference between between difference significant tistically ncontrolled studies and indirect evidence evidence indirect and studies ncontrolled dies (66, 72 74) (75 80)) compared compared 72 74)(75 80)) (66, dies utcomes of these patients with or without or without with of these patients utcomes d to continuing monotherapy (entecavir or monotherapy continuing to d avir or tenofovir. aviror tenofovir. 16
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practice. The methodologists performed an extensive an performed Themethodologists practice. bias: Publication untreated patients (81). (81). untreated patients differen by beconfounded could results the but HCC of antivira benefit the examined studyspecifically compen Inwith question. patients address this that therapy in reducing adverse outcomes of chronic HBV chronic of outcomes adverse reducing therapyin lo to Moderate evaluation. and review availablefor active ch immune with patients therapy in Antiviral e and non comparative indirect identified committee 2,00 below levels HBV DNA and cirrhosis compensated antiviral and whether alone, eitherof thesedrugs suppr to fail who persons in tenofovir entecaviror HBeAg n are who infection HBV active chronic immune questi three remaining forthe absent wassparse or wasfound evidence comparative evidence.Sufficient ou andclinical data on group a comparison included th questions key clinical developed seven Guideline co and writing methodology AASLD of Thethe members Discussion for outcome. each studies due to bias publication evaluate to were We unable September September 2015 15,
Accepted Article:
This article isprotected by copyright. All rights reserved.
Hepatology Hepatology therapy should be used in patients with with patients in beused should therapy l therapy and found a decrease in incidence of incidence in a found decrease therapy and l ess HBV DNA to undetectable levels with with levels undetectable DNAto HBV ess sated cirrhosis and low level viremia, one viremia, level and low satedcirrhosis ons: when to stop therapy in persons with with persons therapy in stop when to ons: w quality evidence supported the benefit of benefit the supported wquality evidence ronic HBV infection had 59 published studies studies published had 59 infection ronicHBV high heterogeneity and small number of number small and highheterogeneity at challenge clinicians and patients in daily in and patients challengeat clinicians tcomes, and then rated the quality the of the rated and then tcomes, vidence (Supplemental File 3). File3). (Supplemental vidence ces in the characteristics of treated versus of treated characteristics the ces in literature search, selected studies that that studies selected literature search, for four of the key questions, but evidence but key questions, the for four of infection including progression to to progression including infection 0 IU/ml. For these three questions, the the three IU/ml.For questions, these 0 egative, the benefit of adding either of adding benefit egative,the mmittees for the HBV Practice for the mmittees 17
particularly if it occurs before the development of development the before occurs it if particularly d provided cirrhosis no with predominantly patients for the significant benefit of antiviral treatment treatment of antiviral benefit forsignificant the fol and longer sizes sample larger These imprecise. were studies sufficiently observational 35 from HCC follow and longer 3,463) vs. (59,201 more patients morta and all cause decompensation liver cirrhosis, HBsAg loss; and HBsAg loss has been shown to be ass be to has been shown loss and HBsAg HBsAgloss; precedes suppression HBV DNA example, For outcome. t of steps a series and represent outcomes clinical bee have outcomes These intermediate orregression. HBeAg seroconversio normalization, ALT suppression, rely o to has cirrhosis without patients therapyin evi Thus, infeasible. and likely beunethical would group control the unti in treatment andwithholding require would thousa cirrhosis and no HBVinfection therapy improves antiviral that evidencesupport to no with mostly patients or only enrolled infection RCT Indeed,most failure. chronic liver oracute on com with disease: moreadvanced patients to limited outc clinical on treatment antiviral benefitof the ofinfection, chronic HBV nature indolent the Given RCTs. the in not but studies September September 2015 15,
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology on HCC and mortality found in the observational observational the in found and mortality HCC on omes was found only when the analysis was analysis the when only was found omes n intermediate outcomes such as HBV DNA DNA as HBV such outcomes intermediate n owards the ultimate goal of improving clinical clinical ofimproving goal owardsultimate the cirrhosis. cirrhosis. cirrhosis, and very few trials that enrolled that few trials and very cirrhosis, dence supporting the benefit of antiviral of antiviral benefit the dencesupporting clinical outcomes in patients with chronic with patients in outcomes clinical s of antiviral therapy in chronic HBV chronicHBV therapy in of antiviral s low up in the observational studies account studies observational the in low up l the completion of the study. Such a study a study.study of the Such completion the l lity. Because the observational studies had studies observational the Because lity. up (60 vs. 28 months), data on mortality and mortality data on months), 28 vs. (60 up ata on clinical outcomes. Provision of Provision outcomes. ataclinical on it is not surprising that evidence supporting evidence surprising that supporting not is it pensated cirrhosis, decompensated cirrhosis cirrhosis decompensated pensatedcirrhosis, precise, whereas data from 7 RCTs were RCTs 7 from data whereas precise, n shown to correlate with improvement in in improvement with correlate to shown n nds of patients followed for many years, for many followed of patients nds ociated with decreased risk of HCC, of HCC, risk decreased with ociated n, HBsAg loss, and cirrhosis prevention prevention cirrhosis and HBsAg n, loss, HBeAg seroconversion which precedes precedes which seroconversion HBeAg 18
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potent antiviral activity and low risk of antiviral risk low and activity antiviral potent not were analoguetherapy nucleos(t)ide on patients lower than those in patients in the HBeAg positive HBeAg positive the in patients in those lower than reported not were outcomes clinical phase, tolerant ex Instudies two the of viremia. highest the level (82 84). mortality and liver related HCC cirrhosis, virem of HBV high levels that showed Recentstudies mineral density. Meta analysis of studies comparing of studies density. mineral Meta analysis includ dysfunction tubular renal renal in function, as first lin used been have andtenofovir Entecavir decompensation. of start the at cirrhosis with forespecially those af closemonitoring treatment, occurstopping after Becausehepa File 3). (see Supplemental possible is sus that but universal is relapse viral that showed and biochemi serologic virologic, the literatureon stoppi comparing directly Studies durableresponse. serocon HBeAg achieving therapy after consolidation 20 from varying seroconversion HBeAg durable showed Other obs stopping. with of viremia of relapse risk therapy, very continued vs. stopped therapyand who seroconv HBeAg achieved who patients HBeAg positive risk comparing the studies observational Intwo the September September 2015 15,
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology therapy who have the highest risk for risk highest the have who therapy drug resistance. Tenofovir can cause impairment can impairment cause Tenofovir resistance. drug tained clinical remission and even HBsAg loss loss even HBsAg and remission clinical tained clusively enrolling patients in the immune immune the in patients clusivelyenrolling ing Fanconi anemia, and decreased bone decreased bone anemia,and Fanconiing cal outcomes of patients who stopped therapy stopped who of patients caloutcomes e nucleos(t)ide analogues because of their their becauseof analogues enucleos(t)ide ervational studies (see Supplemental File 3) Supplemental (see studies ervational Patients in the immune tolerant phaseimmune have the in Patients ter discontinuation of treatment is important, important, is of treatment terdiscontinuation , but rates of intermediate outcomes were were outcomes rates of intermediate but , of viral relapse and HBeAg seroreversion in in seroreversion and HBeAg relapse of viral immune active phase. active phase. immune titis flares and hepatic decompensation may may decompensation flares and hepatic titis found; however, observational studies in the the in studies however, found; observational ng vs. continuing therapy in HBeAg negative HBeAg negative in ngtherapy continuing vs. monotherapy with entecavir or tenofovir did did tenofovir or entecavir with monotherapy low quality evidence suggests an increased suggestsan increased evidence quality low ia are associated with an increased risk of risk an increased with associated areia version, the most consistent predictorof consistent most the version, 90% depending on the duration of duration the on 90%depending ersion during nucleos(t)ide analogue analogue nucleos(t)ide during ersion 19
patients with high baseline serum HBV DNA. Studies Studies DNA. HBV serum high baseline with patients viremia despite being adherent to medication. This This medication. to adherent being despite viremia antiviral have potent entecavir and tenofovir While of however, duration the level; phosphate serum in creatini serum in difference a significant show not monitored. Management of special population such as such ofspecial population Management monitored. who infection HBV chronic with frequently patients therapy,s who antiviral initiate beto used should and laborator clinical what HBV, against vaccinated s be should systematic review: who this in included pr the in beenaddressed had that Severalquestions (81). was started treatment IU/mltime the at 2,000 pat most and in receivetreatment not did who those r who patients but ofHCC, incidence the decreasing therapy antiviral su orIU/ml) without with (<2,000 cir compensated with of patients outcomes comparing es been not DNAhas HBV of levels and low cirrhosis antivir of DNA.The benefit high of HBV levels with ris ahigh have cirrhosis compensated with Patients ac ultimately patients most that showed monotherapy w of patients studies Observational were found. not antiviral asecond adding vs. monotherapy tenofovir September September 2015 15,
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology hould undergo surveillance for HCC, and how and how for HCC, undergosurveillance hould ne level, estimated glomerular filtration rate or rate filtration glomerular neestimated level,
evious AASLD HBV Guidelines were not Guidelines HBV AASLD evious activity, some patients have persistent have persistent patients activity, some k of liver failure and HCC particularly those andHCC failure of liver k ggest a benefit of antiviral therapy in therapy in of antiviral benefit ggesta is more common among HBeAg positive among HBeAg positive morecommon is treatment was short in these studies. thesestudies. in short was treatment ho continued entecavir or tenofovir ortenofovir entecavir continued ho creened for HBV infection, who should be should who infection, HBV creenedfor ients HBV DNA was level was higher than was than higher was HBVlevel ients DNA agent in patients with persistent viremia viremia persistent with patients agent in eceived treatment differed substantially from substantially differed treatment eceived y criteria (levels of HBV DNA and ALT) DNA and HBV yof(levels criteria are not receiving antiviral therapy should be therapy should antiviral arereceiving not al therapy in patients with compensated with patients therapyal in hieved undetectable HBV DNA. DNA. HBV undetectable hieved rhosis and low levels of HBV DNAof HBV levels and low rhosis those with HIV, HCV or HDV HIV, HCV with those tablished. One retrospective study One retrospective tablished. comparing continuing entecavir or or entecavir continuing comparing 20
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Conclusion: Most of the current literature focuses focuses currentof the literature Most Conclusion: He World and the Prevention and Control forDisease prev canthe in befound recommendations Additional studies controlled from data current because review immunosuppressive requiring and those coinfection, updated the in provided are systematic review this adults for of management Recommendations resources. consideratio take into should infection chronicHBV eviden to Inaddition evidence. indirect dependson encoun commonly other in Decision making infection. September September 2015 15,
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology on the immune active phases of chronic HBV HBV of chronic active phases immune the on AASLD guidelines (89). (89). guidelines AASLD ce based data, management of patients with with of patients ce baseddata, management for these patient populations were sparse. populations for these patient n individual patient preference and available and available preference patient individual n therapy were also not addressed the in not also therapywere alth Organization Guidelines (85 88). (85 88). Guidelines Organization alth ious AASLD HBV Guideline, the Centers Centers the Guideline, HBV AASLD ious tered and challenging clinical settings settings clinical andchallenging tered with chronic HBV infection based on basedon chronic HBV with infection 21
patients with chronic hepatitis B. Journal of Viral B. Journal chronic hepatitis with patients 3. Kowdley KV, Wang CC, Welch S, Roberts H, Brosgar H, Roberts S, Welch CC, KV, Wang Kowdley th in living persons B foreign born among hepatitis 3. diseases2010;202:192 201. of infectious Journal EP, Simard W, Kuhnert D, WasleyKruszon Moran A, th in B infection virus of hepatitis The prevalence 2. 2012;30:2212 2219. Globa ST. Wiersma J, GA, Groeger Stevens JJ, Ott HBsAgsero ofage specific new estimates infection: 1. References: Cancer 1998;83:901 909. Cancer1998;83:901 909. G,Fattovich NoventaF, L, L,Chemello Benvegnu the on interferon therapy effect of the analysisof 16. Lia CM, IS, Chu Sheen RN, DI, Tai Chien LinSM, reco alphaand interferon of lymphoblastoid effects 15. 1996;334:1422 14 of Medicine Journal England B. New G, Ni Goldmann LangeS, T, NiederauHeintges C, trea patients HBeAg positive of follow up Long term 14. 2001;34:306 313. Hepatology SJ. Hadziyannis E, GV, Manesis Papatheodoridis HBeAg neg with patients and untreated alphatreated 13. 2001;32:452 458. Health &Public TropicalMedicine chro with patients Thai in carcinoma hepatocellular Klad V, Mahachai D, Thong ngam P, Tangkijvanich the effect of interferon Long term P. Kullavanijaya 12. 2005;16 MolecularMedicine of Journal International T, Hamano K, Ninomiya M, Kato Y, BX, Truong Seo chronic hepatit with patients of Japanese follow up 11. 2007;46:45 52. of Hepatology carcinoma.Journal IS, Sheen R N, Chien LeeC M, M L, Yu LinS M, reduces chronic hepatitis positive HBeAg therapyin 10. Lancet1998;351:1535 1539. Group. Study progressio on of interferon alpha Effect IIHCSG. Internatio study. cohort aretrospective carcinoma: 9. Zuckerman Alexander G, TJ, Harrison AndersonMG, c interferon for of lymphoblastoid trial controlled 8. 2011;343:d4002. BMJ trials. Terrin Jo N, Ioannidis AJ, JP, Sutton JA, Sterne asymmetr plot funnel and interpreting forexamining 7. 2014;312:171 179. JAMA literature. medical the to R, Jaeschke IoannidisJP, VM, Montori MuradMH, a and and meta analysis review read to a systematic 6. DG. Pref Altman J, Tetzlaff A, Liberati MoherD, PL statement. PRISMA the reviewsand meta analyses: B. Hepatol hepatitis Chronic BJ. LokMcMahon AS, 5. 4. 2012;56:422 433. Hepatology September September 2015 15,
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology clinical outcome of patients with viral cirrhosis. viral with of patients outcome clinical hronic active hepatitis B. Gut 1987;28:619 622. 1987;28:619 622. Gut B. active hronic hepatitis Hepatitis 2004;11:349 357. 2004;11:349 357. Hepatitis e United States in the era of vaccination. The ofvaccination. era the in States United e nal Interferon alpha Hepatocellular Carcinoma Carcinoma Interferon alphaHepatocellular nal is B treated with interferon alpha. B interferon alpha. is treated with rapy on incidence of cirrhosis and cirrhosis of rapyincidence on mbinant interferon alpha 2a therapy in in therapy interferon alpha 2a mbinant e United States by country of origin. of origin. country byStates e United nic hepatitis B. Southeast Asian Journal of Journal Asian B. Southeast hepatitis nic pply the results to patient care: users' guides care: users' patient to results pply the progression to cirrhosis and hepatocellular cirrhosis to progression prevalence and endemicity. Vaccine Vaccine endemicity. and prevalence y in meta analyses of randomised controlled controlled of randomised ymeta analyses in ative chronic hepatitis B. Journal of B. Journal hepatitis chronic ative :279 284. :279 284. ted with interferon alfa for chronic hepatitis chronicalfahepatitis for interferon with ted nes DR, Lau J, et al. Recommendations LaunesRecommendations al. et DR, J, oS Medicine 2009;6:e1000097. 2009;6:e1000097. Medicine oS 27. 27. n of cirrhosis to hepatocellular hepatocellular to of cirrhosis n erred reporting items for systematic for items reporting erred The long term outcome of interferon of outcome Thelong term Pontisso P, Alberti A. RetrospectiveA. Alberti P, Pontisso l epidemiology of hepatitis B virus of hepatitis epidemiology l ederau CM, Mohr L, Haussinger D. L,Haussinger ederauMohr CM, w YF. Comparison of long term of long term wYF. Comparison Chu C M, Liaw Y F. InterferonLiaw C M, Y F. Chu ogy 2007;45:507 539. ogy2007;45:507 539. Devereaux PJ, Prasad K, et al. How Prasad al. etK, PJ, Devereaux chareon N, Suwangool P, P, Suwangool N, chareon Katayama M, et al. Long term Long term al. et M, Katayama AJ, Murray Lyon IM. Randomised Randomised IM. Murray Lyon AJ, Finelli L, McQuillan G, Bell B.L, BellG, Finelli McQuillan t CL. Prevalence of chronic of CL. t Prevalence 22
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progression to hepatocellular carcinoma and to deat and to carcinoma hepatocellular to progression of Hepa study. Journal cohort a long term patients: 20. Mahmood S, Niiyama G, Kamei A, Izumi A, Nakata Nakata IzumiA, A,Kamei NiiyamaS, G, Mahmood B of Hepatitis progression genotype the in and load 20. LeandroColo G, B, Coco F, Oliveri BrunettoMR, in B chronic hepatitis positive of anti HBe Outcome 19. Gi Vaccaro A, C, IaconoCamma O, Lo Marco Di V, B. Hepatology hepatitis chronic course of long term 18. (1):4 2006;2 andHepatology study.Gastroenterology fro Death VWC. LM,KB, Tyson Kao Blatt TongMJ, h chronic with patients in carcinoma hepatocellular 17. 32. Manolakopoulos S, Karatapanis S, Elefsiniotis J Elefsiniotis S, Karatapanis S, Manolakopoulos monotherapy lamivudine course of Clinical al. et E, 32. 1722. Z Y,Sc Cui LeungG B, LaiYao N, C L, LokASF, chronic hepat with patients in treatment lamivudine 31. 2002;9:424 428. of ViralHepatitis Journal FKL LeungChan NWY, Y, Hui SWC, HLY,Tsang Chan fl severe in of mortality and predictors lamivudine 30. 1999;341:1256 1263. of Medicine Journal RP, TL, Wright Perrillo ER, Schiff DienstagJL, hepatit for treatment chronic asinitial Lamivudine 29. &Science Diseases Digestive chronicfailure. liver Lei L,Liu X Q, Song Y L, Y B, F, Wang Cui Yan he with of patients prognosis long term the improve 28. 2010;30:1033 1042. International GK, Dhali HembramJR, S, Pal S, DasKDK, Datta of decompensation onset after diseaseand survival 27. &Scie Diseases Digestive cirrhosis. HBsAg positive Hsu HE, Kao Sun JH, JJ, Song C, Hsien TongMJ, 26. Hepatolog cirrhosis. liver carcinomaHBV related in P JW, Choi BIK, Jang TN, LH, LeeKim SH, JR Eun d and adefovir lamivudine Lee effectof The HJ, SH. 25. (3):345 353. Therapy 2007;12 Antiviral Tw AML, Chim JJY. J, Sung H, Niu HLY,Wang Chan B: chronic hepatitis B e antigen negative hepatitis 24. (6):389 397. 1998;5 Hepatitis WG Cooksley G,Farrell HC, Thomas K, Krogsgaard interferon alpha with effect of treatment long term 23. 1997;26:1338 1342. Hepatology R, Corrocher G, Realdi G, Giustina G, Fattovich compen with patients B e antigen–positive hepatitis 22. 1998;82:827 835. study. a pilot Cancer Tsubo M, Kobayashi Y, Suzuki S, IkedaSaitoh K, patients in carcinogenesis decreaseshepatocellular 21. 2005;25:220 225. LiverInternational carcinoma. September September 2015 15,
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology A double blind, placebo controlled trial. trial. placebo controlled Adouble blind, are up of chronic hepatitis B with jaundice. jaundice. B with hepatitis chronic are upof is B in the United States. New England NewEngland States. United B the is in with cirrhosis caused by the hepatitis B virus: B virus: caused hepatitis the cirrhosis bywith 2a in chronic hepatitis B. Journal of Viral B. Journal chronic hepatitis 2a in tology 2002;36:263 270. tology2002;36:263 270. s 2010;55:2373 2380. 2010;55:2373 2380. s epatitis B virus infection: A prospective B infection: virus epatitis in hepatitis B virus related cirrhosis. Liver cirrhosis. B virus related hepatitis in associated liver cirrhosis to hepatocellular to cirrhosis liver associated itis B. 2003;125:1714 Gastroenterology itis sated cirrhosis treated with interferon alfa. interferon alfa. with treated satedcirrhosis h from liver complications in patients with with patients in complications liver from h in patients with decompensated cirrhosis due cirrhosis decompensated with patients in patitis B virus infection associated acute on B infection associated virus patitis 1999;30:257 264. 1999;30:257 264. alpha interferon treated and untreated treated alpha interferon y 2007;46:664A 665A. y2007;46:664A 665A. ipivoxil on preventing hepatocellular preventingon ipivoxil nces 2009;54:1337 1346. nces2009;54:1337 1346. 1 47. 1 47. , Mathou N, Vlachogiannakos J, Iliadou J, , Vlachogiannakos N, Mathou al. et Z, Goodman Hann HW, Schalm SW. Long term outcome of Long term outcome SW. Schalm mbatto P, Gorin JM, Bonino F. JM, Gorin P, mbatto ta A, Fukuda M, et al. Interferon Interferon al. et FukudaA,ta M, L, et al. Factors associated with with L,associated Factors al. et X Z, et al. Nucleoside analogue can analogue X Z, Nucleoside al. et Santra A, Chowdhury A. Course of Course A. Chowdhury A, Santra hiff ER, et al. Long term safety Long term of al. et hiffER, unta M, Martorana G, et al. The al. et G, Martorana M, unta ark YS, Kim KO, LeeKO, KH,Kim Moon arkYS, E, Moroni M, Perez V, et al. The al. etV, Perez M, Moroni E, K, Ikeda H, et al. Influence of viral Influenceof viral al. IkedaetH, K, m liver disease and development of development and disease liver m o year lamivudine treatment for treatment lamivudine o year , Sung JJY. The role of JJY. Sung , 23
patients with chronic hepatitis B live and advanced chronic hepatitis with patients 35. Ma H, Guo F, Wei L, Sun Y, Wang H. The prospect WangY, The H. L,Sun F, Guo H, Ma Wei cirrho and HBeAg positive of HBeAg negative outcome 35. Re Hepatology patients. of 2795 retrospectivestudy Iin M, Omata A,Rokuhara TanakaA, E, Matsumoto carcinoma for hepatocellular preventing lamivudine 34. 2004;351:1521 1531. LeeFarrell C Z Chow G, WC, Sung JJY, LiawY F, 33. 63. J American HBV infection. chronic HBeAg to negative 780. 780. 2011 Hepatology. in appears failure.[Erratum liver BC,K Garg M, Sharma V, Kumar GargSK, Sarin H, o reactivation spontaneous with patients in outcome 46. LiLiGon Liu FZ,QF, HanRH, Yu JH, C, J, Chen & Pancrea B. Hepatobiliary chronichepatitis severe 45. Virology 2009;23:467 469. & Clinical Experimental e H, Cao N, Chen X, Shu Z, L b, Xu Q h, Xu Chen acute on chron with patients in treatment antiviral 44. 2009;23:56 58. Z.LeiYang[Ca W D, C L, K Y,Jia HeG M, Xiao Chinese B]. chronichepatitis severe for treatment 43. (2):460 467. 2013;7 International Zhang Xie S, etX, J, XieXie D, B,CQ, LinPan exa acute the due to failure acute on chronicliver 42. 2013;58:98 107. Hepatology infection. Kawamu Y, Seko M, F, Kobayashi HosakaSuzuki T, carcinom hepatocellular reduces entecavirtreatment 41. 2013;58:1537 1547. Hepatology IpZMLee SK Y, CW H, Mak HL Y, GL H, Wong Chan chro in and deaths events hepatic reduces treatment 40. of disease. Journal liver B virus related hepatitis Leeassessment Risk TN, Lee KS. Kim HJ, JR, Eun response viral on treatment according to carcinoma: 39. 2012;27:1589 1595. &Hepatology Gastroenterology Yim HJ, Kim JD, Jung JY, YS, Seo SH, Um CH, Kim oral eranucleos( the in of cirrhosis related liver 38. 2010;25:583 590. &Hepatology Gastroenterology Infl LiZhao S C. L J, Y H, Kang P, J W, Yu Sun acute on chr with patients for treatment lamivudine 37. Antivira disease. advanced without patients evenin DK Wong K, Tsui DH F, Chow W K, YuenM F, Seto co of long term risk the therapy reduces lamivudine 36. C of NationalJournal Medical [Chinese]. hepatitis. September September 2015 15,
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology t)ide analog antiviral agents. Journal of Journal agents. antiviral analog t)ide Hepatology 2010;53:118 125. 2010;53:118 125. Hepatology cerbation of chronic hepatitis B. Hepatology hepatitis of chronic cerbation ic hepatitis B liver failure]. Chinese Journal of Chinese Journal failure]. B liver hepatitis ic Journal of Experimental & Clinical Virology Virology &of Experimental Clinical Journal r disease. New England Journal of Medicine Journal NewEngland rdisease. hina 2007;87 (26):1832 1835. (26):1832 1835. 2007;87 hina Sep 2;54(3):1114]. Hepatology 2011;53:774 2;54(3):1114]. Sep l Therapy 2007;12:1295 1303. 2007;12:1295 1303. Therapy l nic hepatitis B patients with liver cirrhosis. cirrhosis. liver with B patients hepatitis nic onic hepatitis B liver failure. Journal of Journal failure. B liver hepatitis onic mplications of chronic hepatitis B infection hepatitis of chronic mplications f hepatitis B presenting as acute on chronic asacute on chronic B presenting fhepatitis tic Diseases International 2009;8:261 266. 2009;8:261 266. International Diseases tic search 2005;32 (3):173 184. (3):173 184. search2005;32 during long term lamivudine therapy in therapy in lamivudine during long term a incidence in patients with hepatitis B virus hepatitis with a patients incidence in in chronic hepatitis B: A multicenter B: Amulticenter chronic hepatitis in ournal of Gastroenterology 2004;99:57 of ournal Gastroenterology al. Entecavir improves the outcome of outcome the Entecavir improves al. sis in patients with chronic type B chronic type with patients in sis uential factors of prognosis in in factors uential of prognosis g GZ. Short term entecavir therapy of therapy entecavir gShort term GZ. t al. [The short term efficacy of efficacy short term [The al. t for the development of hepatocellular of for development the se controlled study of entecavir of study se controlled ive study of the clinical features and features clinical the study ive of , Yuen H, et al. Lamivudine for Lamivudine al. et YuenH, , o S, Tanikawa K, et al. Efficacy of Efficacy al. et K, Tanikawa S, o umar A. Tenofovir improves the the improves umarTenofovir A. ra Y, Sezaki H, et al. Long term Long term al. etH, raSezaki Y, et al. Prognosis of hepatitis B of hepatitis Prognosis al. et H, Ngai VW S, et al. Long term al. et VW S, H, Ngai Y, Lam AT H, et al. Entecavir al. et AT H, Lam Y, 24
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New England Journal of Medicine 2005;352 (26):2682 2005;352 Medicine of Journal NewEngland of Hepatology 20 Journal analysis. propensityscore 49. Kumada T, Toyoda H, Tada T, Kiriyama S, Tanikaw S, Kiriyama T, Tada H, Toyoda KumadaT, hepatocarcinogene on therapy analogue nucleos(t)ide 49. 2014;1 Association Gastroenterological American the gastroenterology and hepato Clinical population. US LB,LiHolmberg LameratoRupp LE, J, SC, Gordon and B infection virus chronichepatitis therapyfor 48. 201 study.Gastroenterology cohort B Anationwide Lee e SY, CW, Wang TY, Su Lin HJ, Ho CY, Wu JT, of hepatocellula risk reduced with analoguetherapy 47. 61. Liang J, Han T, Xiao S X. [Telbivudine treatmen [Telbivudine Han S X. Xiao T, LiangJ, 200 TsaChih KanPing Tsang Chung Hua B]. hepatitis 61. 2011;54:236 242. Hepatology Chu AM L, KK L, Chim Yiu GL H, Wong VW S, Wong severe e with acute patients in Entecavirtreatment 60. Therapy 2012;17:605 612. Antiviral C Tseng D S, L R,Perng C Y, Chang Mo Y C, Hsu B of chronic treatment the hepatitis in lamivudine 59. 2014;147:152 161. Gastroenterology lamivudine. LeeD Suh HC, JH, Shim N Y, Heo LimHan S, Y S, ch with among patients carcinoma andhepatocellular 58. Hep open label study. a randomized, decompensation: Sari H, Cheinquer M, Raptopoulou Gigi LiawY F, in adefovir versus entecavir of and safety Efficacy 57. 2009;17:515 519. Chih study of clinical [A D f. Z j, Hu YangGong Q, decompen their in cirrhosis with patients hepatitis 56. 2013; Sciences &Pharmacological for Review Medical e HY, XY,Ma XiePang Q, YY, Yao GB, WangJi H, therapy combined dipivoxil and adefovir lamivudine 55. of Medicin EnglandB. Journal New chronichepatitis Hadziy FarciP, F, Bonino Lau GKK, P, Marcellin com in two alone,and the alone,lamivudine Alfa 2a 54. T P, KangMarcellin XL, T, LauGKK,Piratvisuth combinat and the lamivudine, Alfa 2a, Peginterferon 53. 1020. NewEngland Apr 27;354(17):1863]. 2006 Med. EnglJ Chang AS, T T, Cheinque Lok D, LaiShouval C L, HBeAg negative with for patients lamivudine versus 52. 2006;354:1001 1010. Medicine Gadano Sollano A, R, Man de RG, Gish ChangT T, chronic for HBeAg positive andlamivudine entecavir 51. Vir of Journal cirrhosis. decompensated HBV related P DJ, Suh SK, Sarin EJ, Gane YC, HLY,Chen Chan safety of telbivudine efficacy and trial: clinical 50. September September 2015 15,
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology and lamivudine in treatment naive patients with with patients treatment naive in lamivudine and sation period]. Chung Hua Kan Tsang Ping Tsa Kan Ping Tsang Chung Hua period]. sation development of hepatocellular carcinoma in a in carcinoma of hepatocellular development xacerbation of chronic hepatitis B. Journal of B. Journal hepatitis of chronic xacerbation chronic hepatitis B patients with hepatic with B patients chronic hepatitis patients with hepatic decompensation. hepatic decompensation. with patients r carcinoma in patients with chronic hepatitis chronic hepatitis with patients in rcarcinoma 13;58:427 433. 13;58:427 433. logy : the official clinical practice journal of journal practice clinical official logy the : bination in patients with HBeAg negative patients in bination ion for HBeAg positive chronic hepatitis B. chronic hepatitis for HBeAg positive ion sis in chronic hepatitis B patients: a B patients: chronic hepatitis in sis ronic hepatitis B treated with entecavir vs vs entecavir with B treated ronichepatitis European patients. B hepatitis chronic in 4;147 (1):143 151.e145. (1):143 151.e145. 4;147 e 2004;351 (12):1206 1217. (12):1206 1217. e2004;351 N in appears B.[Erratum chronichepatitis 2012;19:732 743. Hepatitis al 2:885 893. 2:885 893. hepatitis B. New England Journal of Journal England B. New hepatitis atology 2011;54:91 100. 2011;54:91 100. atology 9;17:24 27. 9;17:24 27. adefovir dipivoxil treatment for treatment chronic dipivoxil adefovir 17:636 643. 17:636 643. 2695. 2695. Journal of Medicine 2006;354:1011 of Medicine Journal t on cirrhosis resulting from chronic resulting from cirrhosis on t annis S, Jin R, et al. Peginterferon al. et R, Jin S, annis hongsawat S, Cooksley G, et al. al. etG, Cooksley S, hongsawat n SK, Tanwandee T, Leung N, et al. al. et Leung N, T, Tanwandee SK, n r H, Goodman Z, et al. Entecavir al. et Z, rGoodman H, J, Chao Y C, et al. A comparison of Acomparison al. et Y C, Chao J, SD, Moorman AC, et al. Antiviral Antiviral al. et AC, Moorman SD, iratvisuth T, et al. Randomized Randomized al. et T, iratvisuth a M, Hisanaga Y, et al. Effect of Effect of al. et Y, Hisanaga aM, H, Lo G H, et al. Entecavir versus versus LoEntecavir al. G H,H, et J. Mortality, liver transplantation, Mortality, transplantation, liver J. t al. Two yearsof efficiency Two al. t t al. Association of nucleos(T)ide of nucleos(T)ide Association al. t SH T, Chan H Y, et al. al. et H Y, Chan SH T, 25
65. Tsai MC, Yu HC, Hung CH, Lee CM, Chiu KW, Lin M KW, LeeChiu CH, CM, Hung HC, Yu MC, Tsai 65. (4):1918 1921. 2014;58 Chemotherapy LaiCh KH,Lin HS, HH, Chan PH, WL, Chiang Tsai acutesevere B with chronichepatitis for treatment 64. of Gastroenter Journal World chronicfailure. liver ZhouYang Chen F, TY, S, Zhong XY, Hu Y, Zhang reactiv spontaneous with patients therapyfor naive 63. (6):1 2014;60 of Hepatology Journal decompensation. Wang PL, Hung LinTseng CH, TH, Hu CH, CL, Chen sev with B patients chronic hepatitis in lamivudine 62. B in China. International journal of clinical and e and of clinical journal International BChina. in LinChong G, Y, LiH, Wu X, Shi Y, Jie HuangM, ini fumarate for andentecavir disoproxil tenofovir 75. 2015;28:109 117. Gastroenterology Societyof gastroenterology of Annals cirrhosis. decompensated Vl J, GV, Goulis Papatheodoridis E, Cholongitas nucleos(t) of newer The al. et impact KetikoglouJ, 74. I IntJ real life study. B: a multicenter hepatitis F, F, Karabay Kocak Arslan E, Guclu BatirelA, of respon and predictors entecavir versus tenofovir 73. 2012;23:247 252 of Gastroenterology Journal Turkish MS Akin A, Soylu Y, B,Gumurdulu Kara DoganUB, of nucleo treatment the for and entecavir tenofovir 72. He B disease. liver chronichepatitis decompensated Papathe Akarca US, C M, Lee IS, Sheen LiawY F, emtricitab fumarate (TDF), Tenofovirdisoproxil al. 71. of Gastroenterolog Journal American seroconversion. W Yuen J, M, LaiMizokami Y, Tanaka CL, FungJ, B: cessati hepatitis chronic therapy for lamivudine 70. 2012; Gastroenterology of Clinical therapy.Journal H Nguyen RT, HN, Garcia Trinh Ha NB, Chaung KT, B e hepatitis after viremia of frequency recurrent 69. Int2015;35:1692 1699. Liver DNA. ofLevels HBV etH, Zhang LiuS, Ren X, Du Y, S, Zhang LuJ, with Women HBV Adefovir in Postpartum with Combined 68. 1248. B vir of hepatitis levels and high aminotransferase Ch S, F, Chan Poordad AJ, Hui CK, HL, Chan Chan B e fumarate antigen positi hepatitis in disoproxil 67. &Hepa Gastroenterology Clinical relatedcirrhosis. AS, Koksal M, Demir MT, TunaGulsen Y, S, Koklu t and entecavir, of lamivudine, efficacyand safety 66. 575. of Gastroenterology Journal cirrhosis. compensated n and entecavir of telbivudine outcome andclinical September September 2015 15,
Accepted Article
This article isprotected by copyright. All rights reserved. Hepatology Hepatology nfect Dis 2014;28:153 159. 2014;28:153 159. Dis nfect xperimental medicine 2015;8:666 673. 2015;8:666 673. medicine xperimental antigen seroconversion and consolidation consolidation and antigenseroconversion ve patients with normal levels of alanine of alanine levels normal with ve patients enofovir for treatment of hepatitis B virus hepatitis of enofovirfor treatment tial treatment of patient with chronic hepatitis chronic hepatitis with of patient treatment tial us DNA. Gastroenterology 2014;146:1240 DNA. Gastroenterology us on vs. continuation of treatment after HBeAg HBeAg after of treatment continuation vs. on exacerbation. Antimicrobial Agents and Agents Antimicrobial exacerbation. (16):4745 4752. ology2014;20 s(t)ide naive patients with chronic hepatitis B. chronic hepatitis with s(t)ide naive patients ere acute exacerbation and hepatic and ereexacerbation acute se in treatment naive patients with chronic with patients treatment naive sein ation of hepatitis B presenting as acute on B presenting of hepatitis ation ide analogues on patients with hepatitis B hepatitis with patients analogueson ide aive patients with hepatitis B virus related hepatitis with aive patients 46:865 870. 46:865 870. tology2013;11:88 94. ine/TDF, and entecavir in patients with with patients in entecavir ine/TDF,and patology 2011;53:62 72. 2011;53:62 72. patology and Hepatology (Australia) 2014;29 (3):568 2014;29 (Australia) Hepatology and : quarterly publication of the Hellenicof the publication quarterly : y 2009;104:1940 1946; quiz 1947. quiz y2009;104:1940 1946; 127 1134. 127 1134. . . O, Ozer S, et al. Comparable efficacy of Comparable al. et S, Ozer O, al. Effect of Peg interferon alpha 2a Peg interferon Effect of al. achogiannakos J, Karatapanis S, S, Karatapanis achogiannakosJ, Y. Comparison of the efficacyof of the Comparison Y. Normal Levels of ALT and High ofLevelsandALT High Normal odoridis GV, Suet Hing Wong F,et Wong GV, Suet Hing odoridis ong DKH, Yuen MF. The duration of Theduration MF. ong DKH, Yuen ang TT, et al. Effects of tenofovir oftenofovir Effects al. et ang TT, Kockar MC, et al. Long term Long term al. et Kockar MC, eng JS, et al. Early entecavir Early al. etentecavir engJS, G, et al. Entecavir vs lamivudine lamivudine vs Entecavir al. etG, A, Nguyen KK, et al. High al. et KK, A, Nguyen . Comparison of the efficacyof the of Comparison . JH, et al. Entecavir vs. vs. Entecavir al. et JH, T, et al. Comparing the efficacy the Comparing al. et T, 26
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phosphate handling. Digestive diseasesand sciences Digestive handling. phosphate patients in renal on function inhibitors polymerase Hepatology 2011;55:1235 1240. 2011;55:1235 1240. Hepatology J Henke D, Hueppe N, Filmann Berger F, S, Mauss 78. 1188.e1181. Gastroent Clinical B Monoinfection. Virus Hepatitis Fon A, Vallet Pichard M, Schwarzinger V, Mallet Re on Analogues Nucleotide and Nucleoside Effectof 77. 2015;59:3168 3173. Chemotherapy KM, Kee LeeCH, LuChen SN, CM, HungTH, Hu CH, severe B with hepatitis of chronic treatment the in 76. 2015. HEPATOLOGY Jonas J, Hwang K M, Chang N, Bzowej Terrault N, B. Hepatitis Treatmentof Chronic 89. 2015: Data, Library Cataloguing in Publication WHO andtr care prevention, for the Guidelines WHO. Binfection. 88. CE31 34. Center and reports / Recommendations weeklyreport. and r Recommendations of adults. MMWR. immunization o Committee Advisory of the recommendations States: Bell AlterMJ, Fiore AE, CM, Weinbaum EE, Mast of transmission eliminate strategyto immunization 87. Center and reports / Recommendations weeklyreport. Recommendations MMWR. B infection. virus hepatitis Fine I, Wang EE, SA, Williams CM, Mast Weinbaum healt and public for identification Recommendations B: update hepatitis Chronic BJ. LokMcMahon AS, 86. 85. CL, Chen Jen SL, You J, HI, Su IloejeUH, Yang B Ga load. viral hepatitis of level circulating the 84. 2007;5:921 931. Ame of the journal practice official the clinical : LY,Wang You J, CL,Su HI, Jen IloejeUH, Yang B infec chronic hepatitis with associated mortality 83. LuCL, SN, Yang Jen J, SL, You HI, Su CJ, Chen B v hepatitis of serum gradient acrossa biological 82. 2015;62:694 701. Hepatology YH, GwakK, GY, Paik Kim LeeJ, Goo DH, J, Sinn c compensated B virus infected chronic hepatitis in 81. qu 2012;10:941 946; Association Gastroenterological clin official the : and hepatology gastroenterology M Mangahas RE, Shaw SD, Kane MD, Clark RG, Gish ent or tenofovir with treated patients among events 80. Lee LimS, C, LS, Chan Chang M, JJ, Xu C, Tien B pat hepatitis chronic Asian American in tenofovir 79. September September 2015 15,
http://www.who.int/hiv/pub/hepatitis/hepatitis b gu Accepted Article
This article isprotected by copyright. All rights reserved. http://www.aasld.org/publications/practice guidelin Hepatology Hepatology stroenterology 2006;130:678 686. 2006;130:678 686. stroenterology rican Gastroenterological Association Association Gastroenterological rican acute exacerbation. Antimicrobial Agents and Agents Antimicrobial acuteexacerbation. ical practice journal of the American the of journal ical practice irus DNA level. JAMA 2006;295:65 73. 2006;295:65 73. DNA JAMA level. irus tion. Clinical gastroenterology and hepatology gastroenterology and hepatology Clinical tion. with chronic hepatitis B. Journal of Journal B. chronic hepatitis with ecavir for chronic hepatitis B. Clinical B. Clinical hepatitis forecavirchronic irrhosis patients with low viral load. load. viral low with patients irrhosis hepatitis B virus infection in the United United the in B infection virus hepatitis ients is associated with abnormal renal renal abnormal associated with is ients 2015;60:566 572. 2015;60:566 572. erology and Hepatology 2014;13:1181 and Hepatology erology h management of persons with chronic with of management persons h iz e968. e968. iz s for Disease Control 2006;55:1 33; quiz quiz 2006;55:1 33; Control for s Disease 2008;57:1 20. Control for s Disease nal Function in Patients With Chronic With Patients in Function nal 166. 166. n Immunization Practices (ACIP) Part II: PracticesPart (ACIP) Immunization n eatment of persons with chronic hepatitis hepatitis chronic with of persons eatment and reports : Morbidity and mortality andmortality Morbidity andreports : CJ. Predicting cirrhosis risk based on basedon risk Predictingcirrhosis CJ. taine H, Corouge M, Sogni P, Pol S. S. Pol P, Sogni M, Corouge H, taine et al. Long term treatment with with Long termtreatment al. et et al. Risk of hepatocellular carcinoma carcinoma of hepatocellular Risk al. et eports : Morbidity and mortality and mortality Morbidity : eports SL, Chen CJ. Risk and predictorsRisk of SL,CJ. Chen 2009. Hepatology 2009;50:661 662. 2009;50:661 662. Hepatology 2009. , Hegener P, et al. Effect of HBV Hegener , Effect al. et P, M, Murad H. AASLD Guidelines for Guidelines MuradAASLD H. M, BP, Finelli L, et al. A comprehensive L,Acomprehensive al. et Finelli BP, et al. Hepatocellular carcinoma risk risk carcinoma Hepatocellular al. et lli L, Wasley A, et al. L,al. et A, lli Wasley F, Baqai S. Similar risk of renal risk BaqaiSimilar F,S. et al. Tenofovir versus entecavir entecavir versus Tenofovir al. et idelines/en/ March 2015 ed: Marched: 2015 es 0 . . 27
Question 1: EffectivenessQuestion1: of antiviral therapyin p Characteristics 1: Table of theincluded studies Mahmood, Benvegnu, Benvegnu, Papatheod Anderson, Di Marco, Di Tangkijva Niederau, Niederau, Brunetto, Brunetto, 2006(17) 2001(13) 2005(20) 1998(21) 2004(15) 2007(10) 1998(16) 2002(19) 1999(18) 2001(12) 2005(11) 1996(14) IIHCSG, 1987 Truong, 1998(9) Author name, oridis, Ikeda, Tong, nich, nich, year Lin, Lin,
(8)
Argentina Germany Country Thailand Japanese Italy and Italyand England Taiwan Taiwan Greece Japan aa 9 INapa 1 R R R 81.6 NR NR NR 41 IFN-alpha 94 Japan USA Italy Italy Italy Accepted Article Patients
3 INapa 27 3 15 1 4%>. 81.6±38.4 40% >7.7 112 175± 233 32±7 IFN-alpha 233 378 Control 48 NR NR NR 84 35 35 NR 84 NR NR NR NR 35 NR Control 48 193 Control 378 0 48.8±13.7 10.7 73.2±36 Control 40% >7.7 195 187±109 233 31±8 Control 233 0 INapa 681. 0 46.8±11.3 IFN-alpha 209 103 IFN-alpha 40 0 NR NR 72 38 38 72 NR NR 0 40 IFN-alpha 103 109 IFN-alpha 33 NR NR NR NR NR NR 33 IFN-alpha 109 109 IFN-alpha 31±9 NR NR 31±9 IFN-alpha 109 103 IFN-alpha NR 103 NR NR 50.0 ± 19.8 27 27 ± 50.0 19.8 NR NR 103 NR IFN-alpha 103 ( N ) 8 oto 4 N N N 8 100 84 38 72 NR NR NR NR NR 49 0 Control 40 68 Control 16 61 38.5±18.2 NR NR NR 32±6 53 22. 24 Control 60.1±35.3 NR 14 34 NR Control 74.4±34.8 100 93.3±114.4 53 NR 82.2 72 142.3±152.1 39.9±13.7 NR 20 Control 36.6±10.9 NR 72 Control NR 35 54 Control 97 16 22 IFN-alpha 48 49% NR NR 84 35 35 84 NR NR 49% 48 IFN-alpha 22 3 F-lh 4 N N N 8 100 84 NR NR NR 49 IFN-alpha 23 13 IFN-alpha 57 NR NR NR NR NR NR 57 IFN-alpha 13 7 F-lh 3.±05 7 8.±3. N 59.4±30.9 NR 180.7±137.9 67 36.9±10.5 IFN-alpha 67 7 F-apa 321. 1 286201 R 43 3 84±30 NR 238.6±250.1 17 33.2±10.4 IFN- alpha 27 14 14 9 F-lh 5 N N N 69.6 NR NR NR 54 IFN-alpha 49
Interventions IFN-alpha This article isprotected by copyright. All rights reserved. Control atientswith immune active HBV chronic infection (A oto 6 N N N 7 100 72 NR NR NR 60 Control
(years) Age 36 14 14 36 35 16 16 35
Hepatology Hepatology Positive HBeAg (N) (N) Baseline ALT Baseline 77% elevated 77% 77% elevated 77% (13-1905) (20-1335) 256±232 132±86 (U/L) ALT ALT ALT ALT 112 68 68
ntiviral vsntiviralcontrol):
HBV DNA HBV IU/mL)* Baseline Baseline (log10 NR 92 85 85 92 NR NR 12 20 20 12 NR NR 12 20 20 12 NR NR 84.5 90 90 84.5 NR . 7±24 27.3 72±32.4 5.4 . 7.±68 34.9 73.2±46.8 5.4
Follow upFollow duration (months) 93.6 93.6 72 72
cirrhosis cirrhosis Baseline Baseline 17.9 100 100 (%) 100 8.1 29 29 29 29
.3 2
Page 28of61 Control Control Control Control Control Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort design Study Case Case Case Case RCT Case Case Case Case Case Case
Page 29of61 Chan 2007Chan Krogsgaar Matsumot Manolako Fattovich, Dienstag, 1998(23) 2005(34) 2009(26) 2010(28) 2004(33) 2003(31) 2007(25) 1999(29) 2010(27) 2004(32) 1997(22) 2002(30) poulos, Chan, Chan, Tong, Liaw,
Lok, Eun, (24) Das, Das, Cui, Cui, d, d, o,
national national Europe Multi- Multi- Korea China China Japan Kong Hong India USA USA Italy UK
Accepted Article
2138 151 1 Placebo 215 Placebo 200 100 52.8 NR 46 NR Control 46 NR 102 Control 100 NR 101 84 Placebo 111 NR NR NR 44 Control 219 1 IN–lh 3 210 36 IFN –alpha 210 436 9 Lamivudine 998 5 Lmvdn 40.9±11.0 Lamivudine 657 111 Lamivudine NR NR NR NR NR NR NR NR Lamivudine 111 3 neai 38.4±10.8 Entecavir 33 0 IFN-alpha 40 0 oto 62.8±1.4 Control 30 47.2±14 Control 18 Placebo 41.±11.5 71 Control 39.4±10.6 37 19 Lamivudine 34 15.6 NR 39±11 98 Placebo 36 47 Control 98 Control 50 7 aiuie 40 Lamivudine 27 6 Lamivudine 66 0 aiuie 63.1±1.7 Lamivudine 30 8 aiuie 42.7±13.5 Lamivudine 28 9 aiuie 39±11 Lamivudine 89 and adefovir and Lamivudine Lamivudine This article isprotected by copyright. All rights reserved. Control
37.3±12.4 45 (20–67) (18–73) (15–73) (22-71) (17-74) (15-67) 47 34.5 32.0 44 44 42 43 43 38 38 40 40 ± ± 1.8 2.2
Hepatology Hepatology
22 6.±3. N 7.±6 15.5 74.4±66 NR 163.5±234.3 1272 5 N N 4 100 48 NR NR 45% 124 355 183.4± 211.1 NR NR 211.1 183.4± 355 252 998 200 R R R 36 100 63.6 NR NR NR R R R 56 100 45.6 100 NR 63.6 NR NR NR NR NR 40 40 30 30 11 30 30 50 50 71 71 66 66 10 10 13 13 16 1416.6±577.7 NR 12 NR NR 12 NR 1416.6±577.7 16 4 6 2 1659.5±1928.4 NR 12 NR NR 12 NR 1659.5±1928.4 2 1.6 (0.2–23.4) 1.6 elevatedALT 2.3(0.4-4.14) (0.61 (0.61 (17–2535) (22–2314) (47–2861) (33–592) (46–401) (30-199) (14-959) (26-280) (xULN) (xULN) 2.6±2.3 2.1±1.7 (7-821) (/ULN) (/ULN) 100% 226.5 287 135 125 364 5.3 5.3 5.3 5.3 68 68 80 80 70 70 77 77 xULN) xULN)
(<5.1-10.3) (<5.1-8.9) (4.7–8.1) (4.7–7.8) (4.6-7.6) (4.6-7.9) 4.9 ±0.8 4.9 5 ±0.0.9 120 31 31 120 ±0.0.9 5 5.2±0.8 5.1±0.6 (3.2-7) 5±0.9 NR 15.6 19 19 15.6 NR NR NR R 44 100 74.4 NR R 44 100 74.4 NR 6.6 6.4 4.9 6.5 6.7 6.7 6.6
58.8 ±52.858.8 0.2-41.5 0.2-41.5 0.2-41.5 (0-42) (2-55) (0-42) (3-36) 52.8 120 21 21 120 32 32 22 22 32 32 18 18 12 14 14 12 48 10 10 48 2 6 12 12 13 13 12
14.9 100 100 100 NR NR NR NR NR NR 39 39 31 31
Control Control Control Cohort Cohort Cohort Cohort Cohort Case Case Case Case RCT RCT Case Case RCT RCT RCT
Wu, 2014 2014 Wu, 2013 (49) 2013 2009(44) 2014(48) 2013(40) 2007(36) 2010(39) 2011(46) 2013(42) 2012(38) 2009(37) 2009(43) 2013(41) 2009(45) 2007(35) Kumada, Gordon, Hosaka, Wong, Yuen, Yuen, Chen, Chen, Garg, Xiao, Xiao, Kim, Eun, Eun, Sun, Sun, (47) Lin, Ma, Ma, Xu, Xu,
Taiwan Korea Korea China China China China China China Japan aa 148 Japan Kong Hong Kong Hong India USA
Accepted Article
19 Cnrl 43.6±13.6 Control 21595 21595 13 oto 3±31 398 39±13.1 Control 1143 81 oto NR Control 1851 46 neai 51±12 Entecavir 1466 133 4 Lamivudine 142 1 Cnrl 40.6±10.5 Control 215 41±13 Control 35.5±12.9 424 Control 46.4±10.3 699 Control 45.2±3.6 481 Control 130 Control NR 124 Control 166 7 Lmvdn 40.1±12.2 Lamivudine 872 820 7 Etcvr 21. 219 42±12.4 Entecavir 472 4 Lmvdn 49.6±10.9 Lamivudine 240 3 Lmvdn 44.3±3.5 Lamivudine 130 4 Tenofovir 14 1 aiuie NR Lamivudine 51 3 Entecavir 53 9 neai NR Entecavir 39 5 neai 43.6±10.9 Entecavir 55 3 Placebo 40.3±11.7 13 Control 74 NR Control 39 Control 55 Varietyof oral Varietyof oral varietyof oral Telbivudine, entecavir orentecavir lamivudine This article isprotected by copyright. All rights reserved. antivirals antiviral IFN and antiviral (20.2-54.4) 40.6±11.4 43.5±13.4 (20.8-59) (32–49) (34–47) (16-62) (26-81) (16-67) 47.5 33.9 33.4 NR 53 53 38 38 45 45 40
Hepatology Hepatology
1851 NR NR NR NR 1851 637 280 694 145 820 NR NR NR NR 820 142 155 124 443 NR NR NR NR NR NR NR NR NR NR NR 526.1±688.5 3.8 NR NR NR NR 3.8 526.1±688.5 NR NR NR NR NR NR NR NR NR NR NR NR 534±712.8 4.3 NR NR NR NR 4.3 534±712.8 NR 2 R R 5 100 35 NR NR 12 12 12 13 13 9 R R 5 100 35 NR NR 39 26 26 76 76 16 16 20 20 12 12 25 451.9±464.6 4.4±0.1.1 3 NR NR 3 4.4±0.1.1 451.9±464.6 25 14 14 95 492.3±82.6 > 4.3 3 10 10 3 4.3 > 492.3±82.6 95 90 474.1±83.4 > 4.3 3 10 10 3 4.3 > 474.1±83.4 90 141.3±199.1 (107 (107 –1192) 90.2 ±136.390.2 159 159 ±265.4 (188-1185) (186-2000) 161±183.8 357±405.2 (181–704) (47–514) (47–514) 145±319 (7-1088) (42-163) 84 ±113 84 (20-68) 185 226 179 360 467 125 206 125 65 65 70 70 33 33
(1.9-8.9) (3.3-6.8) (4.6-7.3) (0.8-8.9) (3.5-11) .±. 6.±04 37.2 68.4±50.4 6.7±0.3 .±. 5.±88 47.4 56.4±28.8 7.1±0.4 6.2±0.6 5.3±1.3 .±. 1 32.1 12 5.8±0.8 5.3±0.3 .±. 1 27.3 12 5.3±0.7 5±0.65 3 NR NR 3 5±0.65 NR NR 5.2 3 NR NR 3 5.2 6.3 5.1 5.5 3 NR NR 3 5.5 6.1 143 100 114±31 5 8 6 3 1 100 ±13 36 5 153.6(37.2 153.6(37.2 – (52.8-193.2) (26.5-128.3) (30.9-127.3) (25.2 (25.2 –51.6) (42.5-84) (16.8-66) (36-108) (36-108) (1–124) (2–94) 235.2) 107.8 51.4 46.4 89.9 62.4 62.4 38.4 114 78. 40 40
13.2 32.9 14.6 100 100 14 14 2 Cohort 62 17 17 25 25 0 0 Page 30of61 Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort RCT
Page 31of61 QuestionHead1. to studieshead comparing individu Wong,2011(60) ag 035) China Wang,2013(55) Liang,2009(61) Yang, Yang, 2009(56) hn 025) China Chan, 2012(50) Liaw,2011(57) i,21(8 Korea Lim,2014(58) s,21(9 Taiwan Hsu, 2012(59) Lau,2005(53) Cui, Cui, 2010(28) Lai,2006(52) Marcellin, Marcellin, 2006(51) 2004(54) Chang,
3 Control 637 national national national national Taiwan Multi- Multi- Multi- Multi- China China China Kong Hong
Accepted Article
00 neai 4±1 1168 47±11 Entecavir 2000 34 aiuie 31 2421 43±11 Lamivudine 3374 102 Adefovir 44±9.5 NR NR 44±9.5 Adefovir 102 5 Etcvr 51 38 4.±1. 8913 2 8 12 8.9±1.3 140.5±114.3 348 35±13 Entecavir 354 177 0 Etcvr 112 4 92 11 .±.1 4 100 24 6.8±0.01 99.2± 11.1 54 51±1.2 Entecavir 100 271 117 Lamivudine 44±14 55 55 44±14 Lamivudine 117 29 18 6.5±1.1 1 NR 105.7±128.2 44.9±10.03 18 0 10 Lamivudine 9.4±1.3 104 40±11.1 12 Lamivudine 102.3±78.4 8 181 272 6.9± 1 179 12 31.6±9.7 143±119.4 Lamivudine 4 9±1.3 272 146.3±132.3 44±11 271 351 Lamivudine 35±13 313 55 Lamivudine 355 51.9±10 Lamivudine 114 2 Etcvr 41 3 4±1. 6911 2 5 12 6.9±1.1 141±114.7 3 44±11 Entecavir 325 114 Telbivudine 49.6±10.9 61 61 49.6±10.9 Telbivudine 114 53 Entecavir 48 (40-56) 18 18 (40-56) 48 Entecavir 53 2 dfvr 16 N N N N 100 NR NR NR NR 31-62 Adefovir 32 0 ebvdn 5.±07 0 R .±. 1 100 12 5.8±0.6 NR 20 51.8±10.7 Telbivudine 40 0 aiuie 56 N N N N 100 NR NR NR NR 25-69 Lamivudine 30 11 41.03±11.5 13 Control 39.4±10.6 37 Lamivudine 34 73 Lamivudine 46 (37-58) 17 17 (37-58) 46 Lamivudine 73 50 53±1.1 Adefovir 91 33 Entecavir 38.4±10.8 10 10 38.4±10.8 Entecavir 33 36 Entecavir 51±13 13 13 51±13 Entecavir 36 Peg-IFN plus Peg-IFN plus Peg-IFN plus Peg-IFN plus Lamivudine Lamivudine This article isprotected by copyright. All rights reserved. Placebo Placebo al antiviralal agents: 31.7±10.3 271 114.9±94.1 9.4 ±1.2 9.4 114.9±94.1 271 31.7±10.3 2596 7 114.6±114.3 271 32.5±9.6 01. 0 40±11.7 11. 0 41±10.8 (4-85) 48 48
Hepatology Hepatology 151 72.76 72.76 ± 61.8 (22–2314) (17–2535) (47–2861) 94.4±85.9 1151±724 1499±841 72.6±46.4 75.1±54.4 90.8±76.2 (68-1530) 84 ± ± 84 87.8 100± 8.6100± (53-190) (68-244) (78-879) (5-3410) 226.5 101 128 467 287 391 364 26 26
. ±12 4 100 24 6.9 ± 1.2 (1.6-9.2) . . 2 100 24 ± 1.26.2 . . 2 100 24 ± 1.16.1 . . 2 100 24 ± 1.26.9 .±.1 4 100 24 7.5±0.01 7.1±1.6 7.5±1.2 6.4±1.1 6.6±1.4 18. ±12 14 14 ±12 18. 6.6±1.4 6.8±0.9 6.5±1.1 5.1±0.6 5.2±0.8 9.2±1.4 5± 0.9 0.2-41.5 NR NR 0.2-41.5 0.95± 3.1 . 1 45.3 12 6.1 6.3 12 48 48 12 6.3
(26.4-51.6) (37.2-240) (78-138) 0.2-41.5 0.2-41.5 164.4 79± 79± 6 104.4 37.2 18 18 18 18 18 18 18 18
53.6 NR NR NR NR 1 91 48 48 15 15 21 21 31 31 22 22 18 18 7 Cohort Cohort Cohort Cohort Cohort RCT RCT RCT RCT RCT RCT RCT RCT
QuestionEffectiveness2. of antiviral therapyin p QuestionSafety5. ofcompared entecavir tenofovto DiscontinuingQuestion3: vscontinuing antiviral t ol,21(6 Turkey Koklu,2013(66) Liaw,(71) 2011 ol,21(6 Turkey Koklu,2013(66) Fung, 2009Fung, (70) Chen, Chen, 2014(62) Chan, Chan, 2014(67) Tsai, Tsai, 2014(65) Tsai, 2014(64) Chaung, Chaung, 2012 u 056) China Lu,2015(68) Dogan, Dogan, 2012 2014(63) Zhang, Zhang, (72) (69)
0 aiuie 2485 8 R .±06 2 0 100 12 5.7± 0.6 NR 18 52.4±8.5 Lamivudine 40
national Taiwan Taiwan Taiwan national Turkey 65 Tenofovir NR 29 29 NR Tenofovir 65 Turkey Multi- China Multi- Kong Hong USA
Accepted Article
1 Lmvdn 4.±44 0 294917 5.8±1 1239.4±941.7 60 49.5±14.4 Lamivudine 215 114 Lamivudine 43±15 47 1629± 1011 7.5±6.9 4 NR NR 4 7.5±6.9 1629± 1011 47 43±15 5.8±1.2 Lamivudine 1045.3±782.8 114 35 48.6±14.1 Entecavir 107 65 Entecavir 42.8±13.1 21 352.5± 77.2 352.5± 21 42.8±13.1 Entecavir 65 88 Telbivudine 55.7±11.4 20 20 55.7±11.4 15 Telbivudine 49±13 88 Entecavir 53 8 neai 5.±. 1 158 7 5304 31 10 53.1 10 5.3±0.4 17 56.8±11.4 179 125.8± 54.2±11.2 Lamivudine 17 Entecavir 74 56.1±9.8 76 Entecavir 88 23 45.6±11.4 Lamivudine 54 2 eooi 5.±05 9 54.2±10.5 Tenofovir 72 30 30 38 Control 26.8 ± 3.1 30 30 ± 26.8 3.1 Control 38 62 64 64 22 22 39 79 79 49 49 4 eooi 5.±02 9 54.2±10.2 Tenofovir 54 2 Entecavir 22 17 45 52.4±11.2 Entecavir 60 5 Tenofovir 45 Varietyof oral antiviral antiviral alone Tenofovir and Tenofovir and Tenofovir and Emtricitabine Emtricitabine Discontinued Discontinued Peg-IFN and combination Lamivudine Continued This article isprotected by copyright. All rights reserved. Adefovir atientswith immune-tolerant chronicHBV infection Placebo therapy therapy therapy herapyHBeAgin positivewho patients seroconverted or in orin ir:
32 (21 – 55) NR NR (21 32 – 55) 26.8 ± 3.1 30 30 ± 26.8 3.1 33 ±11.2 62 62 ±11.2 33 (42-58) (47-58) (48-57) 33±9.5 63 63 33±9.5 34±10 NR NR 34±10 39±12 NR NR 39±12 50 50 54 54 52 52 Hepatology Hepatology 18 18 14 14 7 102.5± 137.5102.5± 115.2±217.1 26.9 ±14.0526.9 115.2±217.1 86.2± 86.2± 115.6 89.5345.2± (21 – (21 2069) (46 – (46 1670) 26.2 ±9.8826.2 86.2±115.6 1287± 1287± 788 53.2±44.5 (16-1281) (37-576) 114±181 (34-98) (41-66) (31-73) 4 >5 <40 158 139 176 87 87 54 54 52 52 48 48
from anti-HBe:HBeAgto (6.4 –10.2) (6.4 (3 –10.3) (3 8.4 ± 0.4 48 NR NR 48 ± 0.48.4 6.3 ± 0.76.3 (3.8-6.6) (3.5-6.7) (4.2-5.9) .±05 76 100 27.6 5.1± 0.5 6.5± 6.5± 0.9 .±12 2 100 12 4.9± 1.2 8.2± 6.8 4 NR NR 4 8.2± 6.8 8.4 ±0.4 48 NR NR 48 ±0.4 8.4 .±. 2.±. 100 21.4±9.7 4.9±1.2 . 1 100 12 ± 1.3 4 ±12 2 100 12 1.25± 7±1.2 12 NR NR 12 7±1.2 7±1.3 12 NR NR 12 7±1.3 ±. 1 N Cohort NR 12 7±6.9 ±. 2.±33 100 24.0±13.3 5±1.2 7.9 8.7 5.6 5.2 5
(6.5-71.3) (6.5-71.3) 45 NR NR 45 12 NR NR 12 20 20 20 20 12 NR NR 12 45 NR NR 45 12 NR NR 12 12 12 NR NR 12 6 NR NR 6 6 NR NR 6
42.8 49.5 NR 0
Page 32of61 Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort RCT RCT
Page 33of61 differentused that un studies DNA in HBV *Baseline con RCT=randomized reported, NR=not IFN=interferon, Mauss France 2014(77)Mallet, ug 057) Taiwan Hung,2015(76) ih 028) USA 2012(80)Gish, in 047) USA 2014(79)Tien, Cholongitas, Cholongitas, 2015(75) 2015 2014(73) Batirel, Huang, Huang, ,2011(78)
(74) Germany Turkey Greece China
Accepted Article 4 Etcvr 061. NR 50.6±14.7 Entecavir 148 36 42.0±11.2 Entecavir 105 80 80 90 Tenofovir 43.3±12.9 29 29 43.3±12.9 Tenofovir 90 31 Tenofovir 60±10 NR NR 60±10 Tenofovir 31 4 neai 5 9 NR NR ±12 55.1 8 Entecavir ±9 51 80 Entecavir 44 Entecavir 32 Entecavir 61 NR Entecavir 58±9 65 Entecavir 10 21 NR Entecavir 29 0 Tenofovir 70 3 Tenofovir 33 7 Tenofovir 37 1 eooi 4.±31 NR 49.8±13.1 Tenofovir 41 2 eooi 4 1 1 NR 11 ±12 49 Tenofovir 42
This article isprotected by copyright. All rights reserved. Tenofovir
its were converted using the formulas: 1 copythe0.2 =formulas: 1 using were its converted trolled trial, ULN=upper limitofnormal ULN=upper trial, trolled (37.8-56) (37.8-56) 451 NR 54.5±13 (20-73) (20-67) (26-61) (19-75) 43 43 47 39 47 47 35 35 43 43 Hepatology Hepatology NR NR NR NR NR NR 16 16 11 11
157.6±216.8 194.1±128.5 73 (21-528) 73 116.7±92.6 1084 ±830 1084 ±918 1104 (18-2230) 120±96.6 (32–107) (32–107) 57±40 75±34 84±69 NR NR 52 52 52 72 72
(3.49- (3.49- >8.04) (2.41- (2.41- >8.04) 6.15 ± ± 6.15 1.36 6.50 ± ± 6.50 0.69 (2.9–6.6) (2.9–6.6) (>0-5.6) (>0-7.4) .±43 02 57 NR 30.2± 15.7 7.6± 4.3 7.2±7.6 12 NR NR 12 7.2±7.6 5.8±1.2 6 34 34 20 6 6 5.8±1.2 6.3±1.2 .±. 3.±1. NR 30.2± 15.7 7.6±4.6 (0-8.7) (0-8.8) IU and 1 pg = 283,000 copies or 56,000 IU IU copies56,000 IUor 283,000 = 1 pg and 7.36 6.99 6.38 5.58 NR NR 3.8 4.6 4.4 4.4
(6.2-28.0) (6.0-27.0) (1 –55) (1 32 ± 24 10 10 20 ± 32 24 ± 26 13 (2 –45) (2 (6-66) (7-68) (6-48) (6-36) 13.4 2 NR NR 22 22 25 25 18 18 29 29 20 16 16 24 24 12 12
100 100 NR NR NR NR NR NR NR
Retrosp Cohort Cohort Cohort Cohort Cohort Cohort Cohort cohort cohort ective study
NR=not reported NR=not QuestionSafety5. ofcompared entecavir tenofovto QuestionEffectiveness2. of antiviral therapyin p QuestionHead1. to studieshead comparing individu EffectivenessQuestion1: of antiviral therapycomp Risk 2: Table bias of assessmentthe included R in
Chan, 2014(67) Randomization NR NR Randomization Chan, 2014(67) Chan, 2007(24) Liaw,2011(57) Liaw,2004(33) Eun, (25) Eun, 2007 Lau, 2005 (53)Lau, 2005 name,Author a,20 5) admzd R e N Ys R NR NR Yes NR Yes NR Randomized Lai,(52) 2006 Wang, 2013 Wang,2013 Krogsgaard, Yang, Yang, 2009 Chan, Chan, 2012 Liaw, 2011 Garg, 2011 Garg,2011 Anderson , Marcellin, Marcellin, 1998 (23) 1998 Dienstag, 2006(51) 1999(29) 2004(54) 1987 (8) 1987 Chang, year (56) (71) (55) (46) (50)
Centralized, stratifying Centralized, onbased screening centralized andcentralizedstratified accordingto the according according geographicto region ALT and according according geographicto region ALT and Randomizationwas done with random a Randomized/Centralized andstratified Randomized/Centralized andstratified Randomized / Randomizationwas not Randomized/Randomization was CPTscoreALT and level. SequenceGeneration geographicalregions. blocked or stratifiedblocked
Randomization NR NR Randomization Randomized/ Accepted Articletable.number Randomized/ Randomized Randomized Randomized NR NR NR NR NR NR NR NR NR NR Randomized Randomized NR NR NR NR No NR NR No NR NR NR NR Randomized Randomized Randomized
levels. levels. NR NR Yes Yes Yes NR NR NR NR Yes Yes Yes NR NR NR NR Yes Yes Yes NR NR NR NR Yes Yes Yes NR NR
This article isprotected by copyright. All rights reserved. atientswith immune-tolerant chronicHBV infection ared to ared controlpatientsin with immune active chr ir: al antiviralal agents: concealment Allocation CTs: Yes Yes Yes NR NR Yes Yes Yes e Ys e Ys No Yes Yes Yes Yes e Ys e N N 10-15%, No NR Yes Yes Yes R e Ys e No Yes Yes Yes NR NR Yes NR Yes NR NR NR NR Yes NR Yes NR NR Yes Yes Yes NR NR NR NR Yes Yes Yes NR NR Yes Yes Yes NR NR NR NR Yes Yes Yes NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR Hepatology Hepatology atcpns Providers Participants Yes Yes No
onic HBVonic infection (Antiviral vscontrol): Blinding Yes Yes o o No No No
Outcome assessors R None NR R None NR imbalance Baseline Baseline No
AttritionBias or lost to uplost follow More than More15%than Less10% than Less10% than Less10% than Less10% than Less10% than Less10% than Page 34of61
Page 35of61 Question 1: EffectivenessQuestion1: of antiviral therapycomp Manolakopoulos,2004 Matsumoto, (34) 2005 Papatheodoridis, 2001 Mahmood, 2005 (20) Selected group of Selectedgroup users Mahmood,2005 (20) evgu 98(6 N ecito N ecito N Nodescription Nodescription Benvegnu, (16) 1998 iMro 99(8 N ecito N ecito N Nodescription Nodescription Marco, Di (18) 1999 Tangkijvanich,2001 Niederau, 1996 (14) Selected group of Selectedgroup users (14)Niederau, 1996 Author name,Author year Fattovich, 1997(22) Selected group of Selectedgroup users Fattovich,1997(22) rnto 02(9 N ecito N ecito N Nodescription Nodescription (19)Brunetto, 2002 Truong, 2005 (11)Truong, 2005 IIHCSG, 1998 (9) Selected group of Selectedgroup users (9)IIHCSG, 1998 Ikeda, 1998 (21) Selected group of Selectedgroup users 1998Ikeda, (21) Yuen, (36)Yuen, 2007 Tong, 2009 (26) Selected group of Selectedgroup users Tong,(26) 2009 Node Nodescription Nodescription Tong,(17) 2006 Chan, 2002(30) Selected group of Selectedgroup users Chan, 2002(30) Table Risk 3: Table bias of assessmentthe for included n Lok, 2003 (31) Lok,2003 Das, (27)Das, 2010 Cui, (28) Cui, 2010 Lin, 2004 (15)Lin, 2004 of Selectedgroup users (10)Lin, 2007 a 07(5 Nodescription 2007 Ma, (35) (13) (32) (12)
Selected group ofSelectedgroup users Selected group ofSelectedgroup users Selected group ofSelectedgroup users Trulyofrepresentative Trulyofrepresentative Trulyofrepresentative representativeof the representativeof the representativeof the the community the or the community the or the community the or Exposed Exposed cohort Nodescription communityor communityor communityor population population population population population population Somewhat Somewhat Somewhat
Accepted Article Selectionof Cohort patients / ared to ared controlpatientsin with immune active chr This article isprotected by copyright. All rights reserved. derivation ofderivation the non- Drawnfromsame the derivation ofderivation the non- derivation ofderivation the non- derivation ofderivation the non- derivation ofderivation the non- derivation ofderivation the non- derivation ofderivation the non- Drawnfromsame the derivation ofderivation the non- Drawnfromsame the Drawnfromsame the derivation ofderivation the non- derivation ofderivation the non- derivation ofderivation the non- Drawnfromsame the Noofdescription the Noofdescription the Noofdescription the Noofdescription the Noofdescription the Noofdescription the Noofdescription the Noofdescription the Noofdescription the Noofdescription the Noofdescription the different communitydifferent different communitydifferent different communitydifferent oras population the oras population the oras population the communitythe as communitythe as communitythe as communitythe as communitythe as cohort/control exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort Drawnfrom a Drawnfrom a Drawnfrom a Non-exposed on-randomized studies: Hepatology Hepatology Ascertainment of No description No description NR NR NR NR Nodescription Nodescription odsrpin odsrpin NR Nodescription Nodescription odsrpin odsrpin NR Nodescription Nodescription odsrpin odsrpin NR Nodescription Nodescription odsrpin odsrpin NR Nodescription Nodescription odsrpin odsrpin NR Nodescription Nodescription odsrpin odsrpin NR Nodescription Nodescription No description No description NR NR NR NR Nodescription Nodescription odsrpin odsrpin NR Nodescription Nodescription No description No description NR NR NR NR Nodescription Nodescription Secure records Record linkage NR NR NR NR linkage Record Securerecords Secure records Record linkage Record Securerecords euercrs eodlnae opeeflo-p NR Completefollow-up linkage Record Securerecords euercrs eodlnae A Reported NA linkage Record Securerecords euercrs eodlnae opeeflo-p NR Completefollow-up linkage Record Securerecords euercrs eodlnae opeeflo-p Re Completefollow-up linkage Record Securerecords Secure records Record linkage Record Securerecords euercrs eodlnae A NR NA linkage Record Securerecords euercr Rcr ikg NR linkage Record Securerecord ecito N ecito NR Nodescription odescription ecito N ecito NR Nodescription odescription o description No description NR NR NR NR Nodescription odescription exposure cito N ecito N NR NR Nodescription scription onic HBVonic infection (Antiviral vscontrol): clear ascertainmentclear Assessment and of outcome of Adequacy of follow reasonsfor loss to reasonsfor loss to description ofdescription the description ofdescription the Follow-up Reported Funding Funding sources ported NR NR NR NR NR NR NR NR NR NR NR NR QuestionHead1. to studieshead comparing individu Kumada, 2013Kumada, (49) Hosaka, 2013Hosaka, (41) Gordon, 2014(48) Zhang, (63)Zhang, 2014 Wong,(60) 2011 Wong,(40) 2013 in,20 6) Nodescription (61)Liang, 2009 Chen, Chen, (62) 2014 Xiao, (43)Xiao, 2009 Chen, Chen, 2009(45) Kim, 2012 (38)Kim, 2012 Tsai, 2014 (64) Selected group of Selectedgroup users Tsai, (64) 2014 Eun, (39) Eun, 2010 Sun, (37)Sun, 2010 si 046) rl ersnaieo Drawnfrom t Trulyofrepresentative Tsai, 2014(65) Cui, (28) Cui, 2010 (47) 2014 Wu, Lim,2014 (58) Selected group of Selectedgroup users (58) Lim,2014 Lin, 2013 (42)Lin, 2013 Hsu, Hsu, 2012(59) Xu, (44) Xu, 2009 derivation ofderivation the cohort derivation ofderivation the cohort Trulyofrepresentative Trulyofrepresentative Trulyofrepresentative Trulyofrepresentative Trulyofrepresentative Trulyofrepresentative Trulyofrepresentative Trulyofrepresentative Trulyofrepresentative Trulyofrepresentative Noofdescription the Noofdescription the representativeof the representativeof the representativeof the representativeof the representativeof the the community the or the community the or the community the or the community the or the community the or the community the or the community the or the community the or the community the or community the or communityor communityor communityor communityor communityor population population population population population population population population population population population population population population population Somewhat Somewhat Somewhat Somewhat Accepted ArticleSomewhat al antiviralal agents: This article isprotected by copyright. All rights reserved. Drawnfromsame the derivation ofderivation the non- Drawnfromsame the Drawnfromsame the derivation ofderivation the non- Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Noofdescription the Noofdescription the different communitydifferent different communitydifferent oras population the oras population the communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort Drawnfrom a Drawnfrom a esm Scr eod Rcr ikg Follow-uprat linkage Record Securerecords samehe Hepatology Hepatology euercrs Rcr ikg N Reported NR linkage Record Securerecords. odsrpin odsrpin NR Nodescription Nodescription odsrpin odsrpin NR Nodescription Nodescription odsrpin odsrpin NR Nodescription Nodescription No description Record linkage Record Nodescription odsrpin odsrpin NR Nodescription Nodescription Securerecords Secure records No description Not reported NR NR reported Not Nodescription Securerecords euercrs eodlnae opeeflo-p Re Completefollow-up linkage Record Securerecords euercrs eodlnae opeeflo-p Re Completefollow-up linkage Record Securerecords Securerecords euercrs eodlnae R Reported NR linkage Record Securerecords Secure records Record linkage Record Securerecords euercrs eodlnae opeeflo-p NR Completefollow-up linkage Record Securerecords Secure records Record linkage Record Securerecords euercrs eodlnae NR linkage Record Securerecords euercrs eodlnae opeeflo-p NR Completefollow-up linkage Record Securerecords NR linkage Record Securerecords euercrs odsrpin R Reported NR Nodescription Securerecords euercrs eodlnae opeeflo-p Re Completefollow-up linkage Record Securerecords Independentblind Independentblind assessment assessment follow-upunlikely to Completefollow-up, introducebias,small reasonsfor loss to reasonsfor loss to description ofdescription the description ofdescription the Follow-up Reported e< Page 36of61 Reported Reported Reported Reported ported ported ported NR NR NR NR NR NR NR Page 37of61 QuestionSafety5. ofcompared entecavir tenofovto DiscontinuingQuestion3: vscontinuing antiviral t QuestionEffectiveness2. of antiviral therapyin p Cholongitas, Cholongitas, 2015 Chaung, 2012 (69) Selected group of Selectedgroup users (69)Chaung, 2012 Batirel, 2014 (73) Selected group of Selectedgroup users (73)Batirel, 2014 Huang, 2015 (75) Selected group of Selectedgroup users Huang, (75) 2015 of Selectedgroup users Dogan, (72) 2012 Mauss of Selectedgroup users 2014Mallet, (77) Koklu, 2013 (66) Selected group of Selectedgroup users Koklu,(66) 2013 Koklu,(66) 2013 Hung, 2015 (76) Selected group of Selectedgroup users (76) Hung,2015 Fung, 2009 (70) Selected group of Selectedgroup users 2009Fung, (70) Gish, 2012Gish, (80) NR=not reported NR=not of Selectedgroup users (79) 2014 Tien, Lu 2015 (68) Selected group of Selectedgroup users (68) Lu 2015 ,2011 (78) (74) Selected group of Selectedgroup users (74) Selected group of Selectedgroup users Selected group ofSelectedgroup users Trulyofrepresentative the community the or the community the or population Accepted Article population atientswith immune-tolerant chronicHBV infection herapyHBeAgin positivewho patients seroconverted ir: This article isprotected by copyright. All rights reserved. Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the Drawnfromsame the communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as communitythe as exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort exposedcohort Hepatology Hepatology euercrs eodlnae NR linkage Record Securerecords euercrs eodlnae NR linkage Record Securerecords euercrs eodlnae NR linkage Record Securerecords euercrs eodlnae NR linkage Record Securerecords euercrs eodlnae NR linkage Record Securerecords euercrs eodlnae NR linkage Record Securerecords euercrs eodlnae NR linkage Record Securerecords euercrs eodlnae NR linkage Record Securerecords euercrs eodlnae opeeflo-p NR Completefollow-up linkage Record Securerecords euercrs eodlnae NR linkage Record Securerecords Secure records Record linkage NR NR NR NR linkage Record Securerecords euercrs eodlnae NR linkage Record NRSecurerecords linkage Record Securerecords euercrs eodlnae NR linkage Record Securerecords from anti-HBeHBeAgto reasonsfor loss to description ofdescription the 90% 90% and no follow-up NR NR NR NR NR NR NR NR NR NR NR NR filtration rate rate filtration Table Outcomes 4: Table reported for Tenofovir vs. Enteca NR: not reported; NA: not available; SCr: serum cre serum SCr: available; not NA: reported; not NR: Koklu, 2013 Koklu, Hung, 2015 Hung, Liaw, 2011 Liaw, Gish, 2012 Gish, Tien, 2014Tien, Author, year Outcomes reported reported Outcomes year Author, Batirel, 2014 Batirel, Cholongitas, Cholongitas, 2015 2014 2015 2011 Huang, Huang, Mauss Mallet, Mallet, (70) (75) (74) (73) (71) , , (76) (77) (68) (72) (63) Accepted Article CK levels 2 times over the upper limit of of limit upper the over times 2 CKlevels Serum alkaline phosphatase (U/L) > 145 (U/L) 145 > phosphatase alkaline Serum Increase in Creatinine ≥ 0.5 mg/dL from from mg/dL 0.5 ≥ Creatinine in Increase Serum phosphate (mg/dL) < 2.8 mg/dL 6/42 2/44 2/44 6/42 mg/dL 2.8 (mg/dL) < phosphate Serum GFR by Cockcroft Gault < 60 mL/min 1/42 2/44 2/44 1/42 60 mL/min < Gault Cockcroft GFRby Serum creatinine (mg/dL) >1.5 mg/dL 0/42 0/44 NA NA 0/44 0/42 mg/dL >1.5 (mg/dL) creatinine Serum Phosphate threshold for renal tubular renal for threshold Phosphate Confirmed SCr increase 0.5 mg/dL 3/80 11/80 11/80 3/80 mg/dL 0.5 increase SCr Confirmed Baseline in serum creatinine of 0.5 of 0.5 creatinine serum in Baseline New Cockcroft–Gault eGFR < 60 60 eGFR < Cockcroft–Gault New Decrease in eGFR 20% (MDRD) 33/80 35/80 35/80 33/80 (MDRD) eGFR20% in Decrease Decrease of eGFR >20 ml/min 1/37 2/32 2/32 1/37 ml/min eGFR>20 of Decrease GFR by MDRD < 60 mL/min 1/42 2/44 2/44 1/42 mL/min 60 < MDRD GFRby Reduction of estimated GFR estimated of Reduction Increase of creatinine kinase 0/72 1/77 1/77 0/72 kinase creatinine of Increase Phosphorus of <2.0 mg/dL 1/45 0/22 0/22 1/45 mg/dL <2.0 of Phosphorus reabsorption < 2.8 mg/dL 2.8 < reabsorption Serum phosphate levels NR NR NA NA NR NR levels phosphate Serum Mean eGFR variation variation eGFR Mean (CKD EPI formula) formula) (CKD EPI Hypophospothamia 2/90 0/105 0/105 2/90 Hypophospothamia Hypophospothamia 1/72 0/77 0/77 1/72 Hypophospothamia eGFR <50 mL/min 3/31 2/21 2/21 3/31 mL/min eGFR<50 Renal impairment 1/72 0/77 0/77 1/72 impairment Renal Changes in eGFR in Changes This article isprotected by copyright. All rights reserved. baseline baseline mL/min mL/min normal normal mg/dL mg/dL U/L U/L Hepatology Hepatology atinine; CK: creatine kinase; eGFR: estimated glome estimated eGFR: kinase; CK:creatine atinine; vir chronic HBV in infection: 0.6 ( 0.8 to 1.94) to 1.94) ( 0.8 0.6 mL/min/1.73m Events/total Events/total Events/total Events/total Tenofovir Entecavir Entecavir Tenofovir 108 to87 108 0.92 ml/ 0.92 15/80 6/80 6/80 15/80 18/42 10/44 10/44 18/42 1/33 1/65 1/65 1/33 0/42 1/44 1/44 0/42 4/45 1/22 1/22 4/45 2/30 2/99 2/99 2/30 min min 189 189 2 0.1 ( 1.5 to1.3) ( 1.5 0.1 mL/min/1.73m 1.00 ml/min, 1.00 92 to 84 to84 92 2 rular rular (0.28 RR (95%CI) (95%CI) RR (0 (0.49 (0 (0.23, (0.13 (0.13 (0.67, (0.67, (0 (0 (0 (0 (0.05 (0.05 (1.02, 6(1.02, (0.99 (0.04, (0.19 . . . 00 . . . 13 01 01 66 08 01, 1.02 1.02 5.82 1 1 0 3.21 3.21 0 2.50 0 0 3.14 0 0 1.89 0.43 1 3 , , NA NA NA NA NA NA , , , , , , ...... 119.75) , , , , , , , 94 94 27 35 52 52 97 30 50 96 36 , 14.71) 30 22 35.40) 16.47) 77. 77. 1 0 8 5.56) 5.56) 3 4 5.57 8 ...... 35) 12) 94) 33 60) 55) . . 60) 50) 44) 44 44 ) ) Page 38of61 ) ) Page 39of61 Accepted Article This article isprotected by copyright. All rights reserved. Hepatology Hepatology Accepted Article This article isprotected by copyright. All rights reserved. 220x197mm(300 300DPI) x Hepatology Hepatology Page 40of61 Page 41of61 Accepted Article This article isprotected by copyright. All rights reserved. 220x208mm(300 300DPI) x Hepatology Hepatology Accepted Article This article isprotected by copyright. All rights reserved. 220x186mm(300 300DPI) x Hepatology Hepatology Page 42of61 Page 43of61 Accepted Article This article isprotected by copyright. All rights reserved. 220x181mm(300 300DPI) x Hepatology Hepatology 60 59 58 57 56 55 54 53 52 51 50 49 Exclusions Study design Outcomes comparisons Interventions and Population Definition of disease 1 Table Supplemental Accepted Article : Inclusion and exclusion criteriaInclusion and exclusion for RCT andRCT controlled observational studies infection HBVchronic Immunoactive such assuch hemodialysis, transplant, and treatment failure populations. Co treatment steroids with and uncontrolled studies. HBV Acute Clinical outcomes:Q7: Q3 HBeAg Intermediate outcomes (if evidence on clinical outcomes is limited or unavailable): Clinical outcomes: Cirrhosis, decompensated liver disease, HCC Q1 adultsHBVin infection Chronic Q5: Re Q5: Q6: Antiviral therapy - - 4: 2: Resistance,flare/decompensation and Q1 C nal function, hypophosphatemianal density bone and loss irrhosis, decompensat infection, This article isprotected by copyright. All rights reserved. infection HBVchronic Immunotolerant children and pregnant women, HIV C irrhosis Q2 ed liver disease, HCC , decompensated ≥ 18 y each key question key each anti to HBeAg from S therapy continuedto compared antiviralStopped therapy Hepatology Hepatology ea eroconverted r oldr (detectable HBsAg serum in >6 for months) - HBeAg loss HBeAg HBe Q3 liver disease,HCC relapse ( , relapse (+) negative HBeAg viral andclinical , HCV Q4 and death and (+) and death population HBV mono to t to Entecavir compared or HDV (+) enofovir ) and HBsAg and ) Q5 HBsAg loss, HBeAg seroconversion and - infected persons or other specialpersonsor populations loss monotherapy continued compared to antiviral drug Adding 2 treatment t entecavir or under viral load persistent withinfection HBV enofovir enofovir Q6 nd IU/ml (<2000 viremia low level cirrhosis with compensated and infection HBV therapy Antiviral Q7 ) Page 44of61 Page 45of61 6 5 4 3 2 1 Strategy: Search Reviews July 2005to 2014 Reviews August- Register Trials Controlled 2014,EBM of - and OvidMEDLINE(R)Present,Indexed Citations EBM Reviews 1946to InDatabase(s): 2014Week to 37,OvidMEDLINE(R) Embase- 1988 Strategy: Search Detailed 2: Supplemental Table # Methisazone or methisoprinol or methylcytidine metisazone or or miravirsen or libivirumab or litomeglovir or lomibuvir or mericitabine or merimepodib or la "isis or13312"iododeoxycytidine"isis or isatoribine14803" or ipilimumab or or 184" orderivative""idx imiquimod or "Inosine or Pranobex" orimexon or or "idoxuridine arabinoside"or hypericin"hypoxanthine or idoxuridine or "guanineor"gsoxide" "gene or modulator" 9256" grazoprevir expression 7 or or fosarilatefosdevirinefoscarnetfucoidin ganciclovir or or "gamma or venin" or orFilipin florenal"flucytosinearabinoside" orfomivirsen or or foravirumab or famciclovirfavipiravir or or felvizumab or fiacit orfilibuvir fialuridineabine or or or epetirimodiodide" or faldaprevir or exbivirumab eudistomin or or enviroxime "distamycin or or A"or"enisamium elbasvir edoxudine Ditiocarb droxinavir or Dideoxyadenosine Dideoxynucl or desciclovir B" or"didemnin "didemnin or detiviciclovir A"or or or deoxyaristeromycin or Deoxyglucosedeoxyribavirin or deoxypenciclovir or danoprevirordasabuvir or deitiphorin deleobuvir denotivir or or or cyclaradine"cyclosporin A" orcytarabine or or daclatasvir or damavaricin orcarrageenan or ciluprevircidofovirclevudine "cpg 10101" crofelemer or or or "antior antiviral* or "Anti or AntiRetroviral*975""antiagent" or or viral amitivir or "ammonium trichloro dioxyethyleneo tellurate" o amsacrine or or "ana rsv 01" or "adenosine"al alamifoviror "aln afovirsen dialdehyde"or or 721" alisporivir or or aciclovir or"acyclouridine or derivative"Acyclovir "adenine or or xyloside" ("1 antivirusagent/exp exp Antiviral Agents/ 1 or 2 "hepatitis typeB").mp. ("hepatitis B""serum or hepatitis" "hippie or hepatitis" or "injection hepatitis" or exp Bromodeoxyuridine or carbocyclic buciclovircarbodine or or bropirimine or or besifovir or"Br bonaphthone boceprevir or or or "behenyl or 7295" alcohol" or bavituximab orbenzimidavir balapiravir or "azd arildoneasunapreviravarone or avarol avridine astodrimer or ninamivir orninamivir larifan ledipasvir or or or levovirin or letermovir or lexithromycin - Deoxynojirimycin" or absouline or "abt 333" or"abt "abt450"Acetylcysteine absouline or or orDeoxynojirimycin" 333" or Hepatitis B/dt Accepted oramidapsone amantadineamenamevir"alvircept or or sudotox" Article - viral*" or Aphidicolin or arasangivamycin or arbidol orviral*" or or Aphidicolin arbidol arasangivamycin or This article isprotected by copyright. All rights reserved. eoside* or disoxaril or "distamycin eoside* or or disoxaril 5" Searches Hepatology Hepatology Ovid efeldin A" orefeldin brincidofovir - Retroviral*" antiretrovirus or Cochrane Database of Systematic Systematic of Database Cochrane Process & Cochrane Central Central Cochrane Other Non Other 612059 916254 178548 178548 26410 747988 Results - 3 2 1 0 9 8 7 6 5 4 3 2 1 0 rintatolimod or riodoxol oror riodoxol rintatolimod rociclo virrupintrivir or or samatasvir sangivamycin or resiquimod or"ribavirin derivative"rifabutin ribavirin or or or rimantadine molecule orrafivirumab intercellular adhesion "recombinant 1" regavirumab or or or"Pyran Copolymer" copolymer"pseudohypericin"pyran or or radavirsen or (((liver or hepatic) adj2 carcinoma*) or cirrhoses or(((liver cirrhosis or adj2 or carcinoma*) cirrhosesdeath or hepatic) or virusreactivation/exp Virus Activation/ mo.fs. Survival/ exp Death/ exp exp Mortality/ exp liver cirrhosis/exp Fibrosis/ exp carcinoma/ cell liver exp Hepatocellular/ Carcinoma, exp 8 or 9or 10 peginterferon* or peginterferron*).mp. peginterferone* or peginterferonogen* or "interleukininterferron* 28A"or"interleukin "interleukin or or or 29" or 6" leif ("clor 884"interferon*cl884 or ifninterferone* interferonogen* or interferon/exp Interferons/exp 4 or 5or 6 Zanamivir or zinviroxime).m or zanamivir or acid" "xenazoic or xanthogenate or virustatic* or repressor*" or virucidal* orvirantmycin or viroxime virucide*"virus virostatic* or or ve orvalomaciclovir or vaniprevir vapendavir or or valtorcitabine valopicitabine or valaciclovirortuvirumab or"uracil or umifenoviror arabinoside" or valganciclovir ortomeglovir trifluridine or tromantadine tunicamycin or torcitabine or arabinoside""tilorone Tilorone or or tiloronederivative"tivic or or telbivudine or"thiarubrine "Tenuazonic"thymine Acid"A""thiophene A"or or or synguanolor tebrofenor or tegobuvir tecovirimat or telaprevir taribavirin or or Streptovaricin or or suramin synadenol or orizumab suv streptovirudin or simeprevir oror streptovaricin sorivudine or sofosbuvirsovaprevir or or B" "sangivamycin oracid derivative""scopadulcicor sevirumab setrobuvir or or "pokeweedantivirus protein""Poly A or or"Phosphonoacetic pirazofurinor or or or Acid"pleconaril pirodavir pocapavir "pencicloviracid""phosphonoacetic or triphosphate" or or peramivir omaciclovir or ombitasvir or oseltamivir or palivizumab or "neominophagen C"netropsin or ornetivudinenivocasan or nesbuvir or protein""n A"or or bromoacetyldistamycin narlaprevir necepreviror moroxydine motaviz or droprevir or vidarabine or Vidarabine or viracine or "viral or Vidarabine inhibitor*"droprevir or or vidarabine viracine or Morbidity/ Accepted Article This article isprotected by copyright. All rights reserved. umab or "mycophenolic"Myxovirus acid" orresistance p. Hepatology Hepatology - U" or "Poly I "Poly or U" - C" orC" pritelivir or penciclovir or iclovir or 487873 7579 7949 448163 616331 531063 892082 612417 157245 185872 142803 142803 629423 629323 453948 453948 1210019 1 Page 46of61 Page 47of61 8 7 6 5 4 3 2 1 0 9 8 7 6 5 4 3 2 1 0 9 8 7 6 5 4 "prospective"prospective "prospective study" analysis"or or survey" or study) trial)(intervention* or "cross adj2 or "comparative"comparativestudy" or or adj2 analysis"or survey" (intervention* (trebl* adj ma adj orblind*) mask*) (tripl*adj mask*) oradj (tripl*adjor or blind*) (trebl* orortrial)adj or (doubl* (singl*blind*) adj or (singl* mask*) (doubl* adj blind*) study) trial) adj2 (randomized oradj2 (randomised adj2 or or (randomised study) guideline* study) trial)(control* or adj2 (randomized oradj2 or adj2 (control* or review*) adj3 (systematic* or analys*) adj (meta or based) adj ((evidence case exp clinical study/ exp prospectiveexp study/ study/ retrospective exp longitudinal study/exp Studies/ Cohort exp Cross exp Cross exp exp study/ comparative exp square latin exp design/ Single exp Double exp procedure/ triple blind exp Randomized Controlledexp Trial/ controlled study/exp Guideline/ Practice exp or Guideline/ exp review"/ "systematic exp Meta exp analysis/ meta exp medicine/ based evidence exp 3 andand (7 or 24 11) or/12 surviv*).mp. ormortality or or"s or myxofibrosisreactivat* myxofibroses AG" or or sAG or hepatocarcinoma* "hepatocellularcarcinoma*" or or hepatoma* morbidity or or HCC decompensat* eAGfibrosisorfatal*fibroses "e flare* AG" or or or "cross analys*" or "cross or analys*" "retrospective"retrospective or study" survey" "longitudinal"longitudinal analysis"or study" survey" or or intervention studies/ clinical trial/ - 23 - over" or "cohort study" or "cohort survey" or"cohort survey"analysis" or or"cohort over" study" or - control studies/ - - - Analysis as Topic/ as Analysis - Over Studies/ Sectional Studies/ Blind Method/ Accepted Article- Blind Method/ sk*) or "latin square""latin multivariate or orsk*) "comparative orplacebo* - secti This article isprotected by copyright. All rights reserved. onal survey*" or "cross survey*" or onal Hepatology Hepatology - sectional study" or "cross study"sectional or or "retrospective analysis" or or analysis" "retrospective or - sectional design*"crossover orsectional or - sectional sectional 51300 343004 68 723728 4517923 344743 79495 29609 134228 722657 19331 5422174 13490340 784997 53696 1729495 701582 865208 1065173 1680879 101471 307798 29818 2460744 276 6 5 4 3 2 1 0 9 8 7 6 5 4 3 2 1 0 9 to 64 years)" or "middle aged (45 plus years)"years)" 64agedto "middle (45 or orplus remove remove 63 or 64 from 62keep 3522 not animals/ humans/) (exp 62 not exp 61 and chronic*.mp. 59 or 60 57 and "middle aged").mp. (adult or"middle age" or adults or retained] In MEDLINE(R) MEDLINE(R),Ovid (adult 58to <18 years> to limit 64 Ovid years>) validin <65+ not aged [Limit or records(80 Embase,CCTR,CDSR; validin and not over)") [Limit were retained] years)"(19 44 to "youngadult (19- or adultand ("allyears)" 57to years)" adult(19limit (19 plus 24 "young to "adult or adult or 55 or 56 from 25keep 54 53 not retained] were records Process,CCTR,CDSR; Embase,OvidIn validin not MEDLINE(R),Ovid- MEDLINE(R) or portraits orindex erratum published - or video or news or article or overall patient newspaper directory or interactive tutorial or interview or lectures or legalcases legislation or comment or or dictionary or autobiography or or biography or bibliography (book 53to or booklimit series or editorial 50 or 52 retained] systematic reviews) not [Limit valid in Embase,CCTR,CDSR; records were practiceguideline or pragmaticclinical trial or randomized controlled trial or or controlled clinical trial or guideline metaanalysis or or multicenter or study clinical trial, phaseclinical iiior trial, phaseclinical iv or trial or comparative study limit 51 to (clinical trial, all or clinical trial, phasei or clinical trial, phase or ii from 25keep 13107 25 and 49 or/26 compar*)).mp. orcomparisoncontrol*) ((studyrandom*cohort* or study"and or trial or or "case or study" compeer "case or study" referent "case or study" referrent study""clinical or trial"or "case control study" "case or base study" "case or "concurrent"concurrent"concurrent study"analysis" or or"clinical survey" or - 48 duplicates from 65 Accepted Article 18831 - 3604 - - 19331 18830 This article isprotected by copyright. All rights reserved. - Process,CCTR,CDSR; were records Hepatology Hepatology or erratum or letteraddresses or erratum note or or 24 and 19- 24 audio media or webcasts)[Limit "all aged"all "aged (65 and or over)" education handout or periodical 44)" or "middle(4544)" age or 10981 1113 5724 10972 14249133 2441 3602 83 3519 3604 5510 5349 5259 9801 10673 501 10511 470 Page 48of61 Page 49of61 2 1 pirodavir OR pleconaril OR pocapavir OR "pokeweed antivirus protein" OR "Poly A protein" OR antivirus "pokeweed OR pleconaril pocapavir OR OR pirodavir OR peramivir OR "phosphonoacetic acid" OR "Pho ombitasvir OR OR ORoseltamivir palivizumab penciclovir OR OR "penciclovir triphosphate" "neominophagen ORC" nesbuvir netivudine OR netropsin OR OR nivocasan OR omaciclovir resistance protein" "nbromoacetyldistamycinOR ORmiravirsen moroxydine OR motavizumab OR "mycophenolic acid" "MyxovirusOR merimepodib OR Methisazone OR methisoprinol OR methylcytidine OR metisazone OR umablibivir ORlexithromycin litomeglovir OR OR lomibuvir OR levovirin OR OR mericitabine 13312""isis OR "isis 14803" laninamivir OR larifan OR ledipasvirOR OR letermovir OR ORimiquimod "Inosine Pranobex" iododeoxycytidine OR ipilimumab OR isatoribine OR OR "id OR idoxuridine OR arabinoside" "hypoxanthine OR OR hypericin 7 oxide" OR "guanine "gs 9256" OR grazoprevir OR modulator" expression "gene ganciclovirOR OR "gammavenin" OR fucoidinOR fosdevirine arabinoside""flucytosine OR fomivirsen OR foravirumab fosarilate OR OR foscarnet OR felvizumabOR fiacitabineOR fialuridine OR filibuvirOR Filipin OR OR florenal OR epetirimodOR eudistominOR OR exbivirumab faldaprevir OR OR famciclovir OR favipiravir DitiocarbOR OR droxinavir ed OR Dideoxyadenosine OR Dideoxynucleoside* disoxarilOR "distamycin OR 5" "distamycinOR A" deoxyribavirin desciclovirOR detiviciclovir OR OR "didemnin A" OR B""didemnin OR OR denotivir OR deoxy daclatasvir OR damavaricinOR danoprevir OR dasabuvir OR deitiphorin OR deleobuvirOR clevudine OR "cpg 10101" OR crofelemer OR cyclaradine OR "cyclosporin A" OR cytarabine carbocyc OR buciclovir OR OR bropirimine Bromodeoxyuridine OR brincidofovir OR A" "Brefeldin OR bonaphthone bavituximab OR "behenyl alcohol" OR benzimidavir OR besifovir boceprevirOR OR asunapr Aphidicolinviral*" OR OR arasangivamycin arbidolOR arildoneOR OR astodrimer OR ORagent" AntiRetroviral* - "Anti OR tr "ammonium OR 01" sudotox""alvircept amantadineOR amenamevirOR OR amidapsone OR amitivir OR "adenosine dialdehyde"OR afovirsen OR OR "al 721" alamifovir OR alisporivirOR "aln OR rsv Acetylcysteineaciclov OR or "hepatitisor type B") sangivamycin OR "sangivamycin derivative" "scopaduOR rimantadine rintatolimodOR OR riodoxolOR rociclovir rupintrivir OR OR samatasvir OR regavirumab OR resiquimod ribavirin OR OR "ribavirin derivative" OR rifabutin OR radavirsen rafivirumabOR "recombinantOR in "Poly I "Poly TITLE Accepted Article TITLE - - ABS ABS - C" OR pritelivir OR pseudohypericin OR "pyran copolymer" OR "Pyran Copolymer" OR evir ORevir avarol OR avarone OR avridine OR "azd 7295"OR balapiravir OR - - KEY("1 KEY("hepatitis B" or "serum hepatitis" or "hippie hepatitis" or "injection hepatitis" ichloro dioxyethyleneichloro o o ORtellurate" amsacrine OR "ana 975" OR "anti viral This article isprotected by copyright. All rights reserved. - Deoxynojirimycin" OR absouline OR "abt 333" OR "abt 450" OR lic OR carbodine OR carrageenan cidofovir OR ciluprevir OR aristeromycin OR Deoxyglucose OR deoxypenciclovir OR ir "acyclouridineOR derivative" OR Acyclovir OR "adenine xyloside" oxudine ORoxudine elbasvir "enisamiumOR iodide" OR enviroxime Hepatology Hepatology oxuridine derivative" OR "idx 184" OR imexon OR Retroviral*" OR antiretrovirus antiviral*OR - "anti OR Scopus tercellular adhesion molecule 1" OR sphonoacetic Acid"OR pirazofurin OR A" OR narlaprevir neceprevir OR OR lcic acid B" OR setrobuvir OR - U" OR 8 9 11 10 7 6 5 4 3 1 and (2 or 3) and 4 and 5 and 6 and 7 5 and 4 and and and 3) 6 (2 and or 1 DOCTYPE(sh) DOCTYPE(le) OR DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR OR PMID(7*) OR PMID(8*) OR PMID(9*) PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) 8 and not 9 not and 8 or control*) or and compar*)) "case compeerstudy" or control study" "caseor base study" or "case referrent study" "caseor referent study" or survey""concurrent "concurrentor analysis" "clinical or study" or trial""clinical or "case or study" "concurrent or analysis" "prospective or survey" "prospective or study" "retrospectivestudy""retrospective or survey" "retrospectiveor analysis" "prospective or "longitudinalanalysis" or study" or "longitudinal survey" "longitudinalor analysis" or TITLE design*" or crossover or "cross crossover or or design*" sectional study" "crossor "comparative analysis" or (intervention* W/2 study) or (intervention* trial)W/2 "cross or "comparativeor study" multivariate or placebo* or or square" blind*) W/1 (tripl* W/1or mask*) (trebl* or blind*)W/1 or (trebl* W/1 mask*) "latinor blind*) W/1 (doubl* W/1or mask*) (singl*or blind*) W/1 or W/1(singl* mask*) (tripl* or (randomized W/2 trial) or (randomised W/2 study) or W/2(randomised (doubl* al) or tri guideline*or or (control* study)W/2 (control* or trial)W/2 or (randomized W/2 study) or TITLE decomp mortality ORmortality myxofibroses OR ORmyxofibrosis reactivat* OR AG" "s OR sAG surviv*)OR hepatocarcinoma* OR "hepatocellular carcinoma*" OR hepatoma* OR morbidity OR TITLE TITLE peginterferon* OR peginterferone* OR peginterferonogen* OR peginterferron*) O viracine viracine "viralOR inhibitor*" OR virantmycin OR valtorcitabine OR vaniprevir OR vapendavir OR vedroprevir OR ORvidarabine Vidarabine OR OR valopicitabineOR valomaciclovir OR valganciclovir OR valaciclovir OR arabinoside" tu OR tunicamycin OR tromantadineOR trifluridine ORtilorone Tilorone OR "tilorone derivative" OR tiviciclovir OR tomeglovir OR torcitabine OR OR arabinoside" OR "thymine A" OR "thiophene A" OR "thiarubrine Acid" "Tenuazonic ORtaribavirin tebrofen OR tecovirimat OR tegobuvir O Streptovaricin streptovirudinOR suramin OR suvizumab OR OR synadenol OR synguanol OR ORsevirumab simeprevir OR sofosbuvir OR sorivudine sovaprevir OR streptovaricinOR OR zanamivir zanamivir ZanamivirOR OR zinviroxime) virucide*repressor*" OR "virus OR virustatic* OR xanthogenateOR "xenazoicacid" OR TITLE Accepted Article interferron*R OR "interleukin 28A" OR "interleukin OR 29" "interleukin 6" leifOR OR - - - - - ABS ABS ABS ABS ABS ensat* OR "e AG" eAGOR fatal* OR fibrosesOR OR fibrosis flare* OR OR HCCOR - - - - - KEY(adult or adults or "middle age" or "middle aged") KEY((evidence W/1 based) or (meta W/1 analys*) or (systematic* W/3 review*) KEY(ch KEY(((liver hepatic) W/2or carcinoma*) OR OR cirrhoses cirrhosis OR death OR KEY("cl 884" OR cl884 OR ifn OR interferon* OR interferone* OR interferonogen* This article isprotected by copyright. All rights reserved. ronic*) "case comparison study" or cohort* or ((study or trial or random* random* or trial ((study or cohort* or "caseorcomparison study" - sectional analys*" "crossor - over""coh or Hepatology Hepatology ort study" or "cohort survey" or "cohort virostatic* OR viroxime OR virucidal* OR OR virucidal* OR viroxime OR virostatic* virumab OR umifenovir OR "uracil - R telaprevir telaprevir R telbivudineOR OR sectionalsurvey*" "cross or "comparative survey" "comparative or - sectional sectional - Page 50of61 Page 51of61 0 0 and not 11 Accepted Article This article isprotected by copyright. All rights reserved. Hepatology Hepatology common HBeAg in - normal ULN) (x who stopped treatment, 35 viralhad relapse, 15 had biochemical relapse (ALT > relapse.of risk the seroconversion. A longer duration consolidationof therapy months) (>12 decreases but does not seroconversion followed by age patients of durable response patients in who stopped nucleos(t)ide analogue therapy after achieving HBeAg Despite these discrepant findings, duration of consolidation therapy the is most consistent predictor of and 71.4%and of patients who consolidationhad therapy for <12, 12- treatment after achieving HBeAg seroconversion found response that was maintained in 25.6%, 39.0%, A r recent consolidationof therapy.duration nucleos(t)idealogue an Another retrospective study included 88 Asian patients who achieved HBeAg seroconversion onvarious agewere >40 years durationand of consolidation therapy months. <12 patients who had <12 vs ≥12 mont seroconversion One retrospective study in Korea included 178patie consolidationof therapy, i.e. duration of continued treatment after achieving HBeAg seroconversion. tha HBeAg but seroreversion did not report on clinical outcomes. Theyalso did not have comparison a group published literature on this topic. studiesThese focused ondescribing relapse, viral hepatitis flares and treatment after achieving HBeAg seroconversion to those wh HBeAg An extensive review by the Evidence Practice Center at Mayo Clinic found only 2studies comparing ntiviral t PICO3: Can antiviral p ersons t continuedt treatment. Some did studies examine the durability response of relationin to the duration - positive w etrospective study from centers 3Asian included 101 patients who stopped lamivudine ho achievedho HBeAg s ( ), and), 3had HBeAg seroreversion persons receiving nucleos(t)ide analogue therapy chronic for hepatitis B who stopped Accepted1) Article . Cumulative relapse 5yearsrate after stopping treatment was 8.7% vs. 61.9% for positive s , 49 continued treatment and all maintained 39 undetectable HBV the DNA. Of herapy, s This article isprotected by copyright. All rights reserved. patients who stopped nucleos(t)ide analogue therapy achieving after HBeAg - non and Indirect eroconversion? pecifically n pecifically hs consolidationhs therapy (p<0.001). Independent predictors of relapse Supplemental File 3: File Supplemental ( 1, 3- Hepatology Hepatology ucleos(t)ide analogues be 8) ( comparative evidence . Collectively, these data indicate that viral relapse is 2 nts who received lamivudine achievedand HBeAg ) . Risk of viral relapse was not related to the o did not. There are other studies in the studies in not. are other did There o 18 and > 18 and s 18 months, respectively18 topped HBeAg in 2 times upper limit of - p ositive ositive eliminate ( 3) . 1 Page 52of61 Page 53of61 69 (range 67- normaland after ALT 4- In study third the from Greece, 33 HBeAg- week at part) 1,2,3, 4and 5 years were 43.6%, 49.7%, 52.1%, 56.1%, and 56.1%, respectively cumulative rates of viral relapse (defined as HBV DNA IU/m >2,000 - (24 IU/m 6 months apart nucleos(t)ide analogue treatment who stopped lamivudine after 2year of clinical rel reappearance HBV of DNA by 6,12, PCR) at 18 and months was 30%, 50%, and 50% respectively; and months apart year 2 in of treatment. In study, that cumulative the probability viral of relapse (defined as cirrhosis, is often limited to2 coverage ofHBV medications by government the Asian in respectively ( A subsequent study China 61 in of HBeAg- antiviral Can t 4: PICO 25 (76%) pat (76%) 25 looking specifically for titles of articles describing ca hepatitischronic B who stopped treatment compared to those who did not. We reviewed the literature treatment may be discontinued HBeAg in Of note, the A provide some guidanceon clinicallythis important question. nucleos(t)ide analogues who stopped treatment. foundWe 6retrospective studies on this that topic and HBsAgand comparing loss HBeAg- studies examining the outcomes ofcirrhosis, hepatic decompensation, HCC, relapse (viral and clini An extensive review by the Evidence Practice Center at Mayo Clinic failed findto any RCT or cohort <2000 IU/m<2000 patients (55%) who had discontinued antiviral therapy achieved sustained virologic response (HBV DNA analysis found that higher pretreatment and ofend treatment of levels ALT, noprevious treatment with p HBsAg and ersons? What is the impact on cirrhosis, hepatic 66) months66) who and had undetectable HBV DNA normal and for ALT 18 that found months l . Inmost patients, peak HBV DNA during occurred first 2months the after treatment was stopped. l loss and persistently and normal ALT). Among 13 (72%) cle these, ients ients biochemicalhad relapse defined as >1.2xALT ULN. During follow the apse (defined HBV DNAas >30,000 IU/m 72) months72) 10) sian P ( Accepted9) Article in p in . The APASLThe recommendations were mostly driven by financial considerations because . This recommendationThis was based on results of study a 27HBeAg of - acific acific atients who s atients who 5 years 5 years of adefovir treatment stopped therapy were and followed for median a of ( herapy, s 12 A This article isprotected by copyright. All rights reserved. ssociation for the for ssociation ) - . All virologic had relapse defined as increase HBVin DNA >2000 to 3 years. are at least have and undetectable HBV DNA least onat at least 3 occasions are that topped versus those who c who those versus topped pecifically n s of s negative treatment and - negative negative negative persons receiving nucleos(t)ide analogue therapy for S Hepatology Hepatology t udy of the L the of udy ucleos(t)ide patients who completed at least 2 years of non- patients who patients received lamivudine for mediana of 27 decompensation, se o series had threehad l cirrhotic patients with undetectable HBV DNA and ALT >1.5x ALT and ULN) 12%, 18% and 30%, countries, particularly for those with no iver analogues be s ontinued ontinued f HBeAg consecutive undetectable HBV DNA ≥3 (APASL) 2012(APASL) that guidelines stated l on 2 consecutive samples at least 1 HCC, relapse (viral and clinical) ared HBsAg. Multivariate - t negative herapy? topped HBeAg in persons receiving negative - up period,18 - ( n patients 11 egative ) cal), cal), . 2 be higher be in those with cirrhosis at the start of treatment necessita therapy have not been identified. Viral relapse is common but not all patients experience clinical relapse undetectable HBV DNA. Clinical factors associated with asuccessful outcome after stopping antiviral clinical relapse defined as defined relapse clinical 721 (range 395- priorwas therapy stoppingduration cirrhosis.entecavirtreatment to histologicalof evidence Median was 230 (range 79- 17 (43.6%) had clinical relapse and 1(2.6%) had decompensation. Median duration clinical to relapse treatment. Logistic regression analysis showed baselinethat HBV DNA > negative Collectively, these studies showed that cessation of nucleos(t)ide therapy possible is some in HBeAg therapy relapsed within 1year of stop ping treatment at leastat 1 year post stopped lami The fifth study also conducted in Taiwan included 263 consecutive patients with(94 cirrhosis) who predictor of clinical relapse. patients (64 cirrhosis 83and non- showed menthat more were likely to have hepatic de decompensation. Three patients with cirrhosis died of hepatic decompensation. Multivariate analysis treatment, 29.9% of patients clinical had relapse, 16.2% had hepatitis flares, and had8.2% hepatic lamivudineof was 12.1 8.6 ± months. 139patients resumed treatment. Within the year first of stop ping abstract form found 54%that HBeAg of The sixth study, conducted in presentedKorea, at the HBeAg A stud fourth y conducted in Taiwan tested the validity the of APASL recommendations. In study, this 95 clearance. interferon, and lower levels ofHBsAg the at end of treatment were significantly associated with HBsAg - negative patients who have completed 2- ting re vudine after recovering from flare a of hepatitis with hepatic decompensation - 1762) days.1762) Within 1year after stopping 43 treatment, (45.3%) patients experienced Acceptedtreatment. However, hepatic decompensation deathand can occur Article patients who met APASL criteria for stopping nucleos(t)ide analogue treatment and had - 368) days368) with74.4% clinical relapses occurring beyond 6months treatment follow ALT >2x ULN and HBV DNA >2000 IU/m DNA>2000 HBV and ULN >2x ALT This article isprotected by copyright. All rights reserved. cirrhotic) were HBeAg - up were studied - 5 years of nucleos(t)ide negative Hepatology Hepatology patients who met APASL criteria for stopping antiviral ( ( compensation. 15 AASLD Meeting Annual in 2014and published in 13) . ) - . negative . 39 (41.1%) of the patients the of 39 (41.1%) . had clinical or analogue therapy have and persistently at the start at of treatment. Mean duration l . Of the 39. Of the patients with cirrhosis, 200,000 and this andrisk appears to IU/m after stoppingafter l was the only only the was ( 14 ) . 147 - 3 Page 54of61 Page 55of61 <50 I <50 - add For tenof #6 PICO viremia (>10 therapy not did higherresult in rates of intermediate responses except in the subset patientsof with high tenofovirand vs entecavir monotherapy. Clinical outc tenofovir or entecavir monotherapy. did We identify comparing 1RCT novo de combination of entecavir monotherapy, we did not identify any RCTcomparing adding second a antiviral agent versus continuing U/ml week at 96 ( ovir) in patients with chronic HBV infection and persistent viremia? on therapy in patients : Adding a second antiviral agent compared continuing to monotherapy (entecavir or 8 Accepted Article IU/ml) higher a where proportion (79% vs of patients 62%) HBV had DNA suppression to 16 ) . This article isprotected by copyright. All rights reserved. who failed achieveto viral suppression witheither tenofoviror entecavir Hepatology Hepatology omes not were reported. De novo combination 4 were different and low level viremia but data suggest that antiviral therapy may decrease the risk ofHCC patients in with compensated cirrhosis IU/ml time the treatmentat started was and 7: Hepatitis B PICO antiviral therapy, the 5 IU/ml,<2,000 patients and who maintained undetectable HBV DNA, respectively. In patients who started patients1.4% for who experienced HBV DNA increase, patients who maintained detectable HBV DNA who not did receive antiviral therapy, 5- the therapy and longer duration ofcomplete virological response were associated with studies An extensive review by the Evidence Practice Center at Mayo Clinic failed findto any RCT or cohort and elevated ALT, respectively ( IU/ml), detectable HBV DNA IU/ml <2,000 normal and detectable and ALT, HBV DNA IU/ml <2,000 incidence rat HBV No specific titles or abstracts were found. One retrospective study 385 of treatment describing case series onpersons with cirrhosis who had lowlevel viremia and received antiviral therapy. IU/ml) compared to those who did not. We reviewed the literature looking specifically for titles of articles who r persons - related compensatedrelated cirrhosis HBVand DNA IU/ml <2,000 found 5- that examining the outcomes liver of related death, HCC hepatic and e was 2.2%, 8.0% and 14.0% for patients baselinewith undetectable HBV DNA (<12 eceived antiviral therapy HBV for compensated cirrhosis and low level viremia (<2,000 Accepted ad . In Article dition, dition, manyin who patients received treatment, HBV DNA levels were >2,000 - year cumulative HCC incidence was 5.9% rate and longer duration antiviralof characteristics of characteristics c This article isprotected by copyright. All rights reserved. ompensated c 17) . During follow up, 77patients started a . irrhosis with patients who did and those who did not start antiviral therapy year cumulative HCC incidence rates were 13.3%, 8.8% and Hepatology Hepatology l ow l ow evel viremia (<2,000IU/ml) evel decompensation comparing ntiviral therapy.In patients year cumulative HCC lower HCC risk. These - naïve patients with 5 Page 56of61 Page 57of61 15. With Chronic Hepatitis B: Quit Study. Hepatology 2014;60:1088A al. Prospective Observat 14. : the: official practice clinical journal of Americanthe Gastroenterological Association 2015;13:979 recovered from hepatitis B withflare hepatic decompensation. gastroenterology Clinical and hepatology 2013;58:1888- 11. 438. effectiveness despite stringent c negative chronic hepatitis JournalB patients. of gastroenterology and hepatology 2011;26:456 response to entecavir therapy in hepatitis B e antigen adefovir. Gastroenterology 2012;143:629 Gastroenterology adefovir. 12. loss loss HBsAgof in HBeAg 13. treatment of hepatitis B e antigen 2012;6:531- International Hepatology update. a B: 2012 hepatitis chronic of management onthe statement 10. 1. References: 7. Infectious Diseases Society Amof andprecore basal promoter core mutants. infectious Clinical diseases an : official publication theof antigen seroconversion in patients chronicwith hepatitis Bafter dipivoxiladefovir treatment: analysis of 8. 9. 6283. treatment in HBeAg positive chronic hepatitis B. World journal gastroenterologyof : WJG 2012;18:6277 year after HBeAgyear seroconversionis a factormajor for virologicsustained response in HBeAg 6. lamivudine therapy. Hepatology 2003;38:1267 H 5. 806. therapy enhances durability of lamivudine of durability enhances therapy Journal of antimicrobial chemotherapy2013;68:2332 antimicrobial of Journal Asian positive hepatitischronic B chronic hepatitis B. Hepatologychronic 2010;51:415 4. lamivudine therapy not is durable in patien 3. 2. Clinical GastroenterologyClinical 2012;46:865 a viremi recurrent after hepatitis B antigene seroconversionand consolidation therapy. Journal of epatology 2003;39:614- Seung Up Kim, et et Kim, Seung Up Kang, Wonseok Kim, Hyon Suk Chon, Eun Chung, Young sik Kyu Park, Yong Jun Chang ML, JengChang ML, WJ, Liaw YF. after events Clinical cessation lamivudineof therapy in patients Liu F, WangLiu L, XY, LiuLi YD, Wang JB, Zhang ZH, Wang PoorYZ. durability lamivudineof Hadziyannis SJ, Sevastianos I, V,Rapti Vassilopoulos D, Hadziyannis Sustaine E. Jeng WJ, Sheen IS, Chen YC, Hsu CW, Chien RN, Chu CM, Liaw Off Chu Liaw YF. CM, RN, Chien CW, Hsu YC, IS, Chen Sheen WJ, Jeng Fung SK, Wong F, Hussain M, Lok AS. Sustained response after a a 2 after response Sustained AS. Lok F,M, Hussain Wong SK, Fung Lee HW, Lee HJ, Hwang JS, Sohn JH, Jang JY, Han KJ, et al. Lamivudine maintenance beyond one beyond maintenance Lamivudine KJ, al. et Han JY, Jang JH, JS, Sohn Hwang HJ, HW, Lee Lee Wu IC, ShiffmanWu IC, ML,Tong Marcellin MJ, P, E,Mondou Frederick D, et al. Sustained he Song MJ, SongSong MJ, do S, Kim HY, Yoo SH, Bae SH, Choi JY, al. et Durability responseof viral after - off Liaw Y Liaw Chien RN, Yeh CT, Tsai SL, Chu CM, Liaw YF. Determinants for sustained HBeAg response to - Long al. Jang et MK, JW, Shin JA, Choi Kim MH, YH, Chung SH, Ryu Song BC, Suh DJ, Lee HC, Chung YH, Lee YS. Hepatitis B eantigen seroconversion after Dai CY,Dai Tseng TC, Wong GL, Huang JF,VW, Wong Liu al. CJ, et Consolidation therapy for HBeAg Chaung Ha NB, KT, Trinh HN, RT, Garcia Nguyen HA, Nguyen KK, et al. High frequency of 561. - 1896. Accepted J Kao F, Article - - H, - long B stop who hepatitis chronic with patients negative ional Study Cohort For The Dura Ofbility Antiviral Oral Treatment In Patients 619. Piratvisuth Chan H, T, Chien R This article isprotected by copyright. All rights reserved. essation criteria: aprospective clinical study in hepatitis B antigen e erica 2008;47:1305 erica patients receiving lamivudine treatment: a multicentre study. The - negative chronic hepatitis B. Journal Viral of Hepatitis 2004;11:432 - 870. - 636 e621. - induced HBeAg loss: a prospective study. Journal of of study. Journal a prospective HBeAgloss: induced ts with chronic hepatitis Bin Hepatology Korea. 2000;32:803 - 421. Hepatology Hepatology - 1273. - - 1311. - 2338. negative chronic hepatitis HepatologyB patients. - N, Liu C Liu N, - J, et al. AsianJ, et - 1128A. - term additionalterm lamivudine year - therapy durability - Pacific consensus course of lamivudine lamivudine of course term treatment with d responses and and responses d - positive positive patitis Bpatitis e - 460. of of - 986. - - - - 6 - 701. hepatitis B virus hepatitis Gastroenterology 2012;143:619 Gastroenterology 17. 16. without tenofovir disoproxil tenofovir without fumarate for nucleos(t)ide Sinn LeeJ, DH, J, Goo Kim K, Gwak GY, Paik YH, et al. Hepatocellular carcinom Lok AS, Trinh H,Lok Carosi Akarca G, US, A, Gadano Habersetzer F, et al. Efficacy of entecavir with or Accepted Article- infected compensated cirrhosis patients low with viral Hepatology load. 2015;62:694 This article isprotected by copyright. All rights reserved. - 628 e611. Hepatology Hepatology - naive patientsnaive with chronic hepatitis B. a risk in chronic - 7 Page 58of61 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 59of61 Supplemental Table 4: Table Supplemental Decompensated Decompensated (28 months for RCTs, 60months Compensated Compensated Cirrhosis Cirrhosis for observational studies AnyAntiviral vs None (mean (mean Intervention Question Question 1: Effectiveness of antiviral therapy patients in with immune active HBV chronic ollow up) follow Lamivudine vs AcceptedLamivudine vs Article Any Antiviral IFN Entecavir vs Entecavir vs None N . vs Q1.1: AntiviralQ1.1: therapy vs None one . None ) : evidence of Summary . This article isprotected by copyright. All rights reserved. . . All All All All All All All All seroconversion ** Decompensated Decompensated Decompensated Decompensated Decompensated Decompensated HBsAg loss or or HBsAg loss cause mortality -cause cause mortality -cause cause mortality -cause - -cause cause mortality -cause -cause cause mortality -cause liver disease liver disease liver disease liver liver disease liver disease liver cause mortality cause Outcome Cirrhosis Cirrhosis HCC HCC HCC HCC HCC HCC mortality mortality . no treatment,no stratified Hepatology Hepatology (23 observational (23 observational (10 observational s (3 observational (2 observational (6 observational (2 observational (1 observational (1 observational (1 observational (4 observational (1 observational (1 observational (5 observational (1 observational (4 observational tudies/ (11 RCTs) (11 (3 RCTs)(3 (4 RCTs)(4 (1 RCT)(1 RCT)(1 studies) (1RCT) studies) studies) studies) studies) studies) studies) studies) studies) (No stud study) study) stud study) stud . d y y y of of esign ) ) ) based on the status: disease the on based ) Quality ofQuality the MODERATE MODERATE MODERATE MODERATE MODERATE VERY LOW VERY VERY LOW VERY LOW VERY LOW VERY LOW VERY LOW VERY VERY LOW VERY VERY LOW VERY LOW VERY VERY LOW VERY VERY LOW VERY VERY LOW VERY ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ (GRADE) ⨁ ⨁ ⨁ ⨁ ⨁⨁⨁ ⨁⨁⨁ ⨁⨁⨁ ⨁⨁⨁ ⨁⨁ ⨁⨁ ⨁⨁ ⨁⨁ evidence ⨁⨁⨁ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ LOW LOW LOW LOW ◯◯ ◯◯ ◯◯ ◯◯ ◯ ◯ ◯ ◯ ◯ 124 124 124 124 12 12 12 14 12 1 1 4 1 1 1 1 1 infection: (0.0.35 to 0.73) to (0.0.35 Relative effect Relative (0.38 to 0.78) (0.46 to 0.81) (0.22 to 0.89) (0.28 to 1.89) (0.38 to 0.61) (0.16 to 1.29) (0.13 to 0.53) (0.19 to 0.71) (0.29 to 0.68) (0.32 to 1.11) (0.31 to 0.98) (0.25 to 0.46) (0.39 to 0.96) (0.35 to 0.58) (0.33 to 1.48) (0.43 to 0.94) (0.33 to 1.53) (0.42 to 0.77) (0.06 (95% CI) (1.2 RR 0.55 RR 0.50 RR 0.61 RR 0.45 RR 0.72 RR 0.48 RR 0.37 RR 0.44 RR 0.59 RR 0.45 RR 0.46 RR 0.55 RR 0.34 RR 0.61 RR 0.44 RR 0.14 RR 0.70 RR 0.64 RR 0.71 RR 0.57 RR 0.26 RR 2.4 - - 0.34) 4.9) 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 chronic hepatitischronic exacerbation of of exacerbation Compensated Compensated Compensated chronic liver liver chronic chronic liver liver chronic Severe acute acute Severe Cirrhosis Cirrhosis Cirrhosis C Acute on Acute on failure failure irrhosis Q1 .2 : Head to head studies comparing individual Lamivudine vs Telb Lamivudine vs Telbivudine vs AcceptedLamivudine vs Article Any Antiviral Tenofovir Entecavir vs Entecavir vs Entecavir vs Entecavir Entecavir vs Entecavir Entecavir vs Entecavir vs Entecavir Antiviral vs Adefovir vs Adefovir Lamivudine L Lamivudine Telbivudine Lamivudine Tenofovir amivudine Adefovir vs C C Control C ivu None None N None . ontrol ontrol ontrol None one dine vs vs ...... . This article isprotected by copyright. All rights reserved. . . . . . All All All All All All All All All All All All All All All All Liver transplant Liver transplant HCC (12 cause mortality -cause - - cause mortality -cause cause mortality mortality -cause cause mortality mortality -cause cause mortality -cause cause -cause cause mortality mortality -cause mortality -cause mortality -cause mortality -cause mortality -cause -cause mortality -cause cause mortality mortality -cause cause mortality mortality cause mortality cause HCC (104) HCC (221) HCC (156) HCC (48) HCC (26) (160) (120) (96) (48) (48) (96) (26) (26) (96) mortality mortality - 60) Hepatology Hepatology (1 observational (2 observational (1 observational (3 observational (1 observational (3 observational (4 observational (1 observational (1 observational (1 observational (1 observational (5 observational (1 observational (3 observational (1 observational antiviral agents (stratified based on disease status): disease on based (stratified agents antiviral (1 RCT)(1 (1 RCT)(1 (1 RCT)(1 (1 RCT)(1 (1 RCT)(1 (1 (1 (1 RCT)(1 (1 RCT)(1 (1 RCT)(1 studies) studies) stud studies) studies) study) study) study) study) study) study) study) stud study) study) study) RCT) ies y ) ) MODERATE MODERATE MODERATE MODERATE MODERATE VERY LOW VERY LOW VERY LOW VERY LOW VERY LOW VERY LOW VERY VERY LOW VERY LOW VERY LOW VERY LOW VERY VERY LOW VERY LOW VERY LOW VERY LOW VERY ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁⨁ ⨁⨁ ⨁⨁ ⨁⨁ ⨁ ⨁ ⨁ ⨁⨁⨁ ⨁⨁⨁ ⨁⨁⨁ ⨁⨁⨁ ⨁⨁⨁ ⨁⨁ ⨁⨁ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ LOW LOW LOW LOW LOW LOW ◯◯ ◯◯ ◯◯ ◯◯ ◯◯ ◯◯ ◯ ◯ ◯ ◯ ◯ 124 124 14 14 14 14 14 14 14 14 14 14 14 14 4 4 4 4 1 1 1 1 (0.07 to 16.12) (0.96 to 11.58) (0.72 to 2.39) (0.27 to 2.68) (0.68 to 0.88) (0.16 to 0.89) (0.27 to 0.99) (0.55 to 0.79) (0.64 to 0.81) (0.27 to 0.99) (0.37 to 1.25) (0.51 to 1.74) (0.07 to 1.64) (0.45 to 1.15) (0.14 to 6.24) (0.26 to 3.97) (0.01 to 4.11) (0.8to 1.27) (0.22 to 0.8) (0.47 (0.16 (0.27 (0.31 (0.31 (0.48 RR 1.31 RR 1.02 RR 0.94 RR 0.51 RR 0.85 RR 0.37 RR 0.51 RR 0.66 RR 0.72 RR 0.51 RR 0.68 RR 0.94 RR 1.03 RR 0.34 RR 0.86 RR RR 1.01 RR 0.42 RR 0.42 RR 3.34 RR 0.72 RR 0.94 RR 0.77 RR 0.2 -1.66) - - - - 0.73 - 1.88) 0.76) 1.72) 0.57) 1.5) Page 60of61 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 61of ** Footnotes: systematic review to update the U.S. Preventive Services Task F Task Services Preventive U.S. the update to review systematic eGFR: estimated glomerular filtration rate filtration glomerular estimated eGFR: Question 3: Discontinuing vs Peg IFN + Adefovir vs Adefovir + IFN Peg Stopped vs Tenofovir Chou R, Dana T, Bougatsos C, BlazinaI, Khangura J, Zakher B. Screening for hepatitis B virus infection in adolescents and ad 1. 2. 4. 3. Tenofovir vs Increased risk of bias risk Increased Inconsistency Imprecision Indirectness Tenofovir . + Question Question 2. Effectiveness of antiviral therapy patients in with C Emtricitabine ontinued therapy . AcceptedEntecavir Article . Control vs . . continuing antiviral therapy in HBeAg positive patients who seroconverted from HBeAg to anti This article isprotected by copyright. All rights reserved. Question 5. Safety of entecavir compared to tenofovir: Hypophosp Creatinine of ≥ 0.5 Decrease of eGFR eGFR of Decrease Recurrent viremia Recurrent Renal impairment Renal HBsAg clearance HBsAg kinase creatinine phosphorus <2.0 Creatinine ≥ 0.5 0.5 ≥ Creatinine seroconversion seroconversion eGFR <50 eGFR ALT Flares ALT HBeAg loss HBeAg loss suppression >20 ml/min>20 HB mg/d mg/d Increase Increase in Increase in Increase Confirmed baseline baseline HBeAg HBeAg HBeAg ml/min mg/d V l l DNA from from from from h l atemia in - 60 orce recommendation. Annals ofI Hepatology Hepatology HBe: (1 observational (2 (2 (1 observational (2 observational (3 observational (1 observational (3 (2 (2 (2 (2 o o observational observational observational (1 RCT)(1 (1 RCT)(1 (1 RCT)(1 RCT)(1 (1 RCT)(1 (1 RCT)(1 bservational bservational studies studies studies studies) studies) studies studies study) study) study) ) ) ) ) ) immune - tolerant chronic HBV infection: nternal MODERATE VERY LOW VERY LOW VERY VERY LOW VERY LOW VERY VERY LOW VERY LOW VERY VERY LOW VERY LOW VERY LOW VERY LOW VERY ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁⨁ ⨁⨁ ⨁⨁ ⨁⨁ ⨁⨁ ⨁⨁⨁ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ LOW LOW LOW LOW LOW M ◯◯ ◯◯ ◯◯ ◯◯ ◯◯ edicine 2014;16 edicine ◯ 134 134 134 134 134 134 134 134 134 134 34 34 34 34 34 3 1:31 (0.36 to 112.47) (2.62 to 666.87) (1.22 to 337.68) (0.99 to 12.40) (0.07 to 9.979) (0.23 to 16.48) (0.12 to 7.59) (0.14 to 79.9) (0.85 to 3.80) (0.65 to 1.32) (0.06 to 35.4) (13.3-670.7) (1.1to 1.8) (0.03 - (0.01 RR 41.77 RR 20.29 (0.3 45. RR 6.35 RR 94.4 RR 0.95 RR 3.51 RR 3.33 RR 0.85 RR 1.96 RR 0.14 RR 1.79 RR 0.93 RR 1.5 RR 0.3 RR 1.4 ults: a a ults: RR 1 - - -2.8) 3.9) 2.2) -