Antiviral Therapy in Chronic Hepatitis B Viral Infection During Pregnancy

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between this versionandtheVersionrecord. Pleasecitethis articleasdoi:10.1002/hep.28302. through thecopyediting, typesetting, paginationandproofreadingprocess, whichmayleadtodifferences This istheauthormanuscript acceptedforpublicationandhasundergone full peerreviewbuthasnotbeen [email protected] [email protected] Robert S. Brown, Jr., MD, MPH MD, Brown, S. Jr., Robert Authors: ZhenPhD Wang, [email protected] MD Mouchli, A. Mohamed [email protected] MBBCh Ahmed, T. Ahmed B. MD Wong, John [email protected] Lok,MD AnnaSF MD McMahon, BrianJ. [email protected]

[email protected]

Accepted Article Infe B Virus Hepatitis Therapy Chronic in Antiviral

5,6

7 5,6 A Systematic Review and Meta-Analysis Meta-Analysis and Review A Systematic

Hepatology

ction during Pregnancy: Pregnancy: during ction 1

[email protected] MPH MD, Hassan Murad, Mohammad [email protected] Larry, J MLS Prokop 8 clini InternalMayo Medicine, of Hospital 7Division USA MN, Rochester, Clinic, 6 5 4 3 AK,USA 2 USA 1 Affiliations: [email protected] MPH MBBCh, KhaledMohammed, July 20, 2015 20, July

Library Public Services, Mayo Clinic, Rochester, MN Rochester, Mayo Clinic, LibraryServices, Public AcceptedS the for Research, Center KnowledgeandEvaluation Clin Mayo Program, Research Evidence-BasedPractice Making,Medical Tufts ofDecision Clinical Division Univer andof Hepatology, Gastroenterology Division Nativ Program, Alaska Liver and Hepatitis Diseases Weill andof Hepatology, Gastroenterology Division Article 8

5,6,9 5,6,9

Hepatology Hepatology c, Rochester, Minnesota, USA USA c,Minnesota, Rochester, e Tribal Health Consortium, Anchorage, Consortium, eHealth Tribal Center, Boston, MA, USA USA MA, Boston, Center, Cornell Medical College, New York, NY, College,Medical NewCornell York, , USA USA , sity of Michigan, Ann Arbor, MI, USA Arbor, USA MI, Ann sityof Michigan, cience of Health Care Delivery, Mayo Delivery, Mayo Care Health cienceof ic, Rochester MN, USA USA RochesterMN, ic, 2 Page 2of43 Page 3of43

Corresponding author: author: Corresponding Keywords: USA 9 aeaydslsrs haveany disclosures. La Wang,Z P Mouchli, M Ahmed, A Wong, BJ McMahon, and GlaxoSmithKline Gilead, for advisory on panels Bristo from grants research Lok received AnnaS has Squibb. Meyers Bristol andGilead Gi from grants research received Brown S has Robert Interest: of Conflict (May Murad M (AASLD) to LiverDiseases of Study the Support: Financial immunode human (RCTs), trials controlled randomized B alanine aminotransferase (CHB), chronichepatitis the for American Association (HBIG), immunoglobulin trans Mother-to-child positive, (HBeAg) Be antigen Abbreviations: of List 10021. Yor College,Medical 1305 Cornell Weill Hepatology, July 20, 2015 20, July Division of Preventive, Occupational andAerospace Occupational of Preventive, Division

Phone: (646) 962-4463. Email: Email: (646) 962-4463. Phone:

Accepted Articlehepatitis B vaccine transmission, child to mother

This study was supported by a contract from the Am the from acontract by This study was supported Hepatitis B virus (HBV), Hepatitis B surface antig B surface Hepatitis B (HBV), virus Hepatitis Robert S. Brown, Jr., MD, MPH, Division of Gastroen Division MPH, MD, Brown, S. Jr., Robert This article isprotected by copyright. All rights reserved. [email protected] Hepatology Hepatology (ALT), cesarean section rate (CS), cesareansection (ALT), mission (MTCT), Hepatitis B Hepatitis (MTCT), mission l-Myers Squibb and Gilead and has served and served has and Gilead l-MyersSquibb Merck. Merck. lead and has served as a consultant for a consultant as leadand served has Medicine, Mayo Clinic, Rochester, MN, MN, Rochester, Clinic, Mayo Medicine, k Avenue, 4th Floor New York, NY NewYork, Floor 4th Avenue, k ficiency viruses (HIV). (HIV). ficiencyviruses Study of Liver Diseases (AASLD), (AASLD), LiverDiseases of Study o Clinic). Clinic). o rry, M Murad, K Mohammed do not not do KMohammed Murad, M rry, , tenofovir, telbivudine, lamivudine lamivudine telbivudine, tenofovir, ,

erican Association for Association erican en (HBsAg), Hepatitis enHepatitis (HBsAg), terology and terology 3

postpartum hemorrhage, cesarean section and elevate cesareansection hemorrhage, postpartum pregnancy. further decrease MTCT of HBV. We conducted a syste a conducted HBV. We of MTCT furtherdecrease oral antivi and vaccination, (HBIG) globulin immune infec HBV for chronic factor risk major the remains Introduction: Abstract: maternal or fetal outcome. outcome. maternalor fetal be to appear and tenofovir lamivudine telbivudine, use the to compared load high viral with infection redu and HBV suppression therapy improves Antiviral No delivery. at suppression HBV in DNA improvement weeks postpa during 4-8 and delivery at suppression or te lamivudine control, to scores. Compared APGAR congenital the in found was significantdifference DNA seropositivi HBV - (0.2 and 0.4) infant 0.3 (RR hepatiti asinfant defined by therapyMTCT, reduced reviewers. extr and data selection Study and newborns. mothers reduct were of interest therapy. Outcomes antiviral wit pregnantwomen enrolled that studies controlled committee. guideline writing (AASLD) LiverDiseases andmaterna efficacy the on evidence the synthesize July 20, 2015 20, July Results: Results: Accepted Article Methods: Perinatal or Mother-to-Child transmission (MTCT) of (MTCT) transmission or Mother-to-Child Perinatal

26 studies that enrolled 3622 pregnant women. Anti pregnantwomen. 3622 enrolled that studies 26 Hepatology Hepatology malformation rate, prematurity rate and rate rate, prematurity malformation of HBIG and vaccination alone. The use of alone.The of use ofand vaccination HBIG ion of MTCT and adverse outcomes to to outcomes and adverse of MTCT ion safe in pregnancy with no increased adverse adverse increased no with safe pregnancy in l and fetal safety of antiviral therapy during therapy during antiviral of and fetal safety l tion worldwide. In addition to hepatitis B hepatitis to Inaddition worldwide. tion h chronic HBV infection treated with treated with infection chronic h HBV rtum follow up. Tenofovir showed showed Tenofovir up. follow rtum s B surface antigen (HBsAg) seropositivity B s seropositivity (HBsAg) surface antigen action were done by pairs of independent of independent were action pairs done by d creatinine kinase rates. rates. kinase creatinine d ral therapies in highly viremic mothers can mothers viremic ralhighly therapies in ty (RR 0.3, (0.2 - 0.5) at 6-12 months. No No months. 6-12 at - (0.2 0.5) 0.3, ty(RR ces MTCT in women with chronic HBV chronic HBV with women in cesMTCT lbivudine improved maternal HBV DNA DNA maternalHBV improved lbivudine We searched multiple databases for databases searchedmultiple We matic review and meta-analysis to to andmeta-analysis review matic significant differences were found in in found were differences significant hepatitis B (HBV) virus hepatitis r the Study of of r Study the Conclusions: Conclusions: viral viral 4 Page 4of43 Page 5of43

potent, nucleos(t)ide analogues durably suppress HB suppress durably analogues nucleos(t)ide potent, patie pregnant counseling when importance paramount wit of mothers proportion high the to partiallydue 600,000 of the approximately 240 million carriers w carriers million 240 approximately of the 600,000 a remains (HBV) infection B virus hepatitis Chronic Introduction: for CHB patients show low show forCHB patients markedly advanced CHB have therapies for Antiviral offspring. their i their andespecially during pregnancy, antivirals MTCT on impact nee CHB yearsmay with child-bearing their in Women newborn. the to preventtransmission to B immunoglobu hepatitis and B vaccination hepatitis >10 w associated is (9) found as MTCT is C genotype HBV Asi in (5-8) years particularly duringreproductive (4). prophylaxis absenceof the in (HBeAg) positive B surface are who of mothers 90% hepatitis to up in of hig HBV many in ofform transmission common most o disease (1). Perinatal B (CHB)-related hepatitis July 20, 2015 20, July 6

Acceptedwome testing of prenatal IU/ml)Universal (10-13). Article

if they have immune active HBV infection. According infection. HBV active havethey if immune

(0-1%) rates of viral resistance and breakthrough a and breakthrough resistance viral ratesof (0-1%) Hepatology Hepatology mpact on potential teratogenicity, are of areof teratogenicity, potential on mpact r mother-to-child transmission (MTCT) is the the is (MTCT) transmission rmother-to-child an countries and regions of the world where where world of the regions andan countries h active replication and HBeAg positivity HBeAg and active h replication This high rate of transmission may be of hightransmission rate This antigen (HBsAg) and hepatitis B e antigen hepatitis and (HBsAg) antigen orldwide die annually due to chronic dueto annually die orldwide n important global health problem. Up to to Up problem. global health important n V viremia in most patients. Evolving data Evolving patients. most in Vviremia lin (HBIG) administration starting at birth starting at birth (HBIG) administration lin in the last decade. The newer, more Thenewer, decade. last the in nts with CHB on risks and benefits to to and benefits risks CHB on with nts d antiviral therapy independent of its of its independent therapy antiviral d ith high maternal viral load (HBV DNA DNA (HBV load viral high maternal ith h prevalence areas (2, 3) and may occur occur (2, 3) and may areas prevalence h n is therefore recommended, as are as are therefore recommended, is n ly, data on the safety of safety the data on ly, fter up to 6 years 6 fterto up 5

performed a systematic review and meta-analysis to to and meta-analysis review asystematic performed CHB with high HBV DNA levels (>10 levels DNA high HBV CHB with wom pregnant Moreover, pregnant. forCHB become may fo approved currentlyare therapies HBV Althoughno and re disease progression slowingof liver include The 15). (14, monotherapy or tenofovir ofentecavir Eligibility Criteria: Criteria: Eligibility (21). statement (PRISMA) Meta-Analyses Re Preferred the to according reported andis AASLD developed a protocol follows systematic review This Methods: bi major safety including andfetal maternal andon or tenofovir)o telbivudine entecavir, (lamivudine, gu for practice clinical a priority issue madethis Association American the Therefore, health. women’s p and other hepatologists among widelydisseminated andcontroversial knowled is pregnancy therapiesin or tenofovi of lamivudine impact adverse reportany Anti-retro the in studied mothers HIVfrom positive (10) immunoprophylaxis MT of risk the and decrease DNAlevel reduce to HBV July 20, 2015 20, July

Accepted Article

(19). Safety data on the use of anti-HBV therapies ofuse anti-HBV the on (19).data Safety This article isprotected by copyright. All rights reserved. 7 IU/mL) may want to be considered for antiviral the forantiviral beconsidered to want IU/mL) may Hepatology Hepatology ideline development and evidence synthesis. We We synthesis. evidence and development ideline n MTCT prevention, HBV DNA suppression, DNA suppression, HBV prevention, MTCT n versal of fibrosis and cirrhosis (16-18). and cirrhosis fibrosis versalof rth defect rates. defect rth rates. benefits of long-term virus suppression suppression virus of long-term benefits viral Pregnancy Registry, which do not not do which Pregnancy viral Registry, ge about the harm and benefit ratio is not not is ratio and benefit harm the geabout r use(20). However, the use of antiviral ofuse antiviral the ruse(20). However, compare the effect of oral HBV therapy therapy oralHBV effectof compare the by a guideline writing group from the the from group guidelinewriting a by roviders including those specializing in in specializing those rovidersincluding porting Items for Systematic Reviews and Reviews ItemsSystematic for porting r use in pregnancy, women being treated women pregnancy, rin use for the Study of Liver Diseases (AASLD) LiverDiseases for of Study the CT that can occur despite neonatal can despite that occur CT en in the immune tolerant phase of phase tolerant immune the enin are largely derived derived are largely rapy rapy 6 Page 6of43 Page 7of43

newborns. Both English and non-English language stu language andnon-English Both English newborns. fro outcomes and adverse efficacy, clinical ofHBV, outcome the and reported therapy antiviral received presenc the by (characterized infection chronicHBV that studies comparative or controlled included We using an online reference management system (Distil system management reference usingan online abstr and screenedtitles reviewers independent Two Studyselection: que also were AASLD from experts conducted.Content s included of the of bibliographies search Amanual search of the Details B pregnancy. in for hepatitis wa keywords with vocabulary supplemented Controlled in with (LJP) librarian experienced an conducted by 11 September to 1988 earlyfrom wasconducted Registe Cochrane Central Ovid EMBASE, Ovid MEDLINE, Othe & In-Process ofMedline search Acomprehensive Searchstrategy: p or studies studies and uncontrolled hemodialysis; tran liver chemo/immunotherapy, receivingsteroids, Dor huma C, hepatitis with co-infected of patients receive not did immunizat who infants enrolled that July 20, 2015 20, July

Accepted Article

This article isprotected by copyright. All rights reserved. Hepatology Hepatology th strategy are available in supplemental Table 1. supplemental in available are strategy 2014. The search strategy was designed and designed was strategyThe search 2014. n immunodeficiency viruses (HIV); patients patients (HIV); viruses immunodeficiency n ublished as abstracts only. as abstracts only. ublished s of interest, including prevention of MTCT of MTCT prevention including of interest, s tudies and relevant systematic reviews was reviews and relevant systematic tudies ion during the first week postpartum; studies studies postpartum; during week first ion the enrolled pregnant women diagnosed with with diagnosed women enrolled pregnant put from the principal investigator. principal the from put m antiviral therapy to both mothers and mothers both therapy to antiviral m acts for potential eligibility in duplicate duplicate in eligibility actsfor potential splant recipients and patients undergoing undergoing patients and recipients splant e of HBsAg for more than 6 months), who who months), 6 morethan for eof HBsAg lerSR, Evidence Partners, Inc.). Included Inc.). Evidence Partners, lerSR, dies were included. We excluded studies studies excluded We included. were dies r Non-Indexed Citations, Ovid Ovid Citations, r Non-Indexed s used to search for studies of antivirals of antivirals studies for search to used s ried for potential references. references. riedfor potential r of Controlled Trials, and Scopus and Scopus Trials, Controlled rof 7

For each study, data extraction was done in duplica was in done extraction data Forstudy, each DataExtraction: reviewer. aorthird by consensus reconciled by following text full in reviewed abstractsthen were and Evaluation (GRADE) approach. Criteria used to e to used Criteria approach. (GRADE) andEvaluation R of using Grading the evaluated was estimates) the respective studies, and observational (RCTs) trials Newcastle-Otta and the tool of Bias assessment Risk bi of risk the assessed independently reviewers Two assessment: of bias Risk kinase. creatine andelevated section cesarean seroconversion, HBeAg loss, HBeAg amin alanine DNAsuppression, HBV included outcomes an rate prematurity minute), score (1 APGAR months, 6- at HBsAgdefined byseropositivity transmission, infan following outcomes: the in were We interested Outcomes: and outcomes details intervention characteristics, each from following data the extracted articles.We inconsist dataand resolved reviewercompared third July 20, 2015 20, July

Accepted Article

This article isprotected by copyright. All rights reserved. Hepatology Hepatology of interest. ofinterest. the same procedure. Disagreements were were Disagreements same procedure. the ly. The quality of evidence (i.e., certainty in certaintyin (i.e., evidence quality of ly.The study: study characteristics, patient baseline baseline patient characteristics, studystudy: te using a standardized, pretested form. A pretestedform. astandardized, usingte 12 months or HBV DNA positivity at 6-12 6-12 positivityat DNA or HBV months 12 ecommendations Assessment, Development, Development, Assessment, ecommendations as (i.e., systematic error) using the Cochrane Cochrane using the error) as(i.e., systematic encies by referring to the full text of the text full the enciesreferringto by t outcomes including the risk of vertical of vertical risk the including outcomes t wa Scale (NOS) for randomized controlled controlled randomized (NOS)for waScale valuate quality of evidence were risk of risk were of evidence valuatequality d congenital malformation rate. Maternal rate. Maternal malformation congenital d rate (CS), postpartum hemorrhage ratehemorrhage rate postpartum (CS), otransferase (ALT) normalization, normalization, (ALT) otransferase 8 Page 8of43 Page 9of43

by constructing funnel plots if a if number sufficient plots funnel by constructing u bias of publication impact the explore to planned trans log the We pooled then distribution. binomial imprecisio outcomes), (surrogate indirectness bias, For dichotomized outcomes, we calculated the risk r risk the we calculated outcomes, Fordichotomized analysis: Statistical (22). bias and publication (heterogeneity) Characteristics of the included studies: studies: included the of Characteristics exclusi for and reasons process Thestudy selection weig The average studies. 26 eventually We included a and summarized Database Medicine Biological China and 3 citations 734 in resulted search Theinitial Results: (23). was low andheterogeneity (St 13 version usingSTATA, conducted analyseswere I²>50%where su I²we statistic, the used studies, measure To overa the model. Lairdand random-effect an for study each of follow-up longest the duration dif weighted calculated the we outcomes, continuous heterogene and estimated models Lairdrandom-effect July 20, 2015 20, July

Accepted Article

This article isprotected by copyright. All rights reserved. Hepatology Hepatology systematic reviews (24-26) that included the the included that (24-26) reviews systematic ggests high heterogeneity. All statistical statistical All heterogeneity. ggestshigh of studies (>20) per outcome was available was available outcome (>20) per of studies d pooled effect size using the DerSimonian DerSimonian the using effect size pooled d sing the Egger regression asymmetry test and asymmetry test regression singEgger the inconsistency intervals), (wide n confidence formed risk ratios using the DerSimonian and DerSimonian the using ratios formedrisk ons are depicted in figure 1. figure 1. are ons depictedin atio and 95% confidence intervals using using intervals confidence and 95% atio ference in means between the baseline and baseline the between ferencemeans in hted Kappa for study selection was 0.82. was 0.82. selection for study Kappa hted ity using the Mantel-Haenszel model. For model. Mantel-Haenszel the ityusing ll heterogeneity across the included included the across heterogeneity ll ataCorp LP, College Station, TX). We TX). We Station, LP, ataCorp College dditional studies published in Chinese. Chinese. publishedin studies dditional 9

Infant outcomes: outcomes: Infant assessment. bias July 20, 2015 20, July average baseline ALT level of 37.7 U/L. Inst these U/L. of 37.7 level ALT average baseline 2 the t in and none China in (92%) conducted were studies (37-52) studies and 16 RCTs (27-36) were studies 10 pr of 3622 aenrolled total that studies Twentysix 12 months (Figure 2). Use of any antiviral compared of(Figure any antiviral 2).Use months 12 I (8R HBsAg seropositivity as infant defined by MTCT in control to therapy compared antiviral Useof any 3 and data. 2 Tables up and follow measures outcome methods selection patient reported adequate studies fea and quality overall methodological the studies, out or incomplete blinding, concealment, allocation to due high of bias risk to considered were 36) 34, l have to considered were 35) 32, (28-30, FiveRCTs lamivudine. vs comparedtenofovir tenof (51)39) (38, compared studies 3 telbivudine; 2 control; vs telbivudine compared 52) 50, 49, 45, compared lamivud studies 11 Amongstudies, included of characteristics the Tablesummarizes 1 at birth. 2 =63.9%) or infant HBV DNA positivity (5 RCTs, RR 0. RR (5 RCTs, DNA positivity HBV or infant =63.9%) nd or 3

Accepted Articleo level DNA HBV an average baseline with trimester

This article isprotected by copyright. All rights reserved. Hepatology Hepatology egnant women were included in the analysis, analysis, the in included were women egnant the studies. studies. the unclear/unreported methods of randomization, of randomization, methods unclear/unreported tures were adequate/ appropriate as 60% of the as 60% appropriate adequate/ were tures studies (37) (52) compared lamivudine vs vs lamivudine (37) (52) compared studies ovir vs control and another study (38) study and another control vs ovir pregnant women reduced the likelihood of likelihood the reduced pregnantwomen udies, all infants received hepatitis B vaccine hepatitis received infants all udies, , comparable study groups, and adequate and adequate groups, comparable , study come data reporting. For non-randomized non-randomized For comedata reporting. to control reduced the risk of infant HBsAg HBsAg of infant risk the reduced control to ow risk of bias while 5 studies (27, 31, 33, 33, 31, (27, studies 5 while of bias risk ow he United States (US). Treatment started in in Treatment(US). started States heUnited were non randomized studies. Most of the Most studies. randomized non were include detailed description of the risk of risk of the description detailed include CTs, RR 0.3 (95% CI, 0.3 - 0.4) RR 0.2 CTs, ine vs control; 9 studies (27, 36, 37, 43- 37, 36, (27, studies 9 control; vs ine 3 (95% CI, 0.2 - 0.5) I (95% CI,3 - 0.5) 0.2 f 7.63 log10 IU/mL and IU/mL log10 f7.63 2 = 47.2%) at 6- at =47.2%) 10 Page 10of43 Page 11of43

Maternal outcomes: outcomes: Maternal contro vs drugs individual comparing when persisted July 20, 2015 20, July I 1 by HBsAg seropositivity infant reduced (Figure3) ris to rated due low, down to wasmoderate evidence and 13.4% by DNA positivity andHBV seropositivity normalization. normalization. I - 590) 8.5 (95% CI, 70.9, 4- and -during 921.4) 3.5 CI, 95% 57.1, RR cohort, maternal H improved lamivudine control, to Compared of bias risk rated down due to low, to wasmoderate Theq scores 6). (Figure andAPGAR rate prematurity reporti RCTs non any of the in found differencewas fo control therapy vs. anyantiviral comparing When months. 6-12 at seropositivity statistic no showed 70.08) (95% CI, 2.93 to 0.12 RR 1 (1 study, RR telbivudine lamivudine, to Compared (R up follow months 6-12 at seropositivity15.8% by tenofovir 51), 39, (38, studies Innon-randomized 3 I 0.6) CI,to 0.03 I - 0.5) 0.1 (95%CI, I 2 2 Accepted Articlesero HBsAg reduced infant also Telbivudine =47.9%). (3 21.2% positivity by DNA HBV and infant =42.4%)

2 = 62.4%) compared to the control group (Figure 4). 4). group (Figure control the to compared =62.4%)

2 = 0%) and infant HBV DNA positivity by 16.2% (2RCT 16.2% positivity by DNA HBV and infant =0%) This article isprotected by copyright. All rights reserved. 2 =12.2%) . No significant difference was found in ma in found difference was significant No . =12.2%) Hepatology Hepatology vs control (Figure 5) reduce infant HBsAg HBsAg infant 5) reduce (Figure control vs and imprecision. and imprecision. 8 weeks postpartum follow up (2 cohorts, RR RR (2 cohorts, up follow weeks 8 postpartum 1.7% (5 RCTs, RR 0.3 0.3 - 0.6) 0.2 (95%CI, RR (5 RCTs, 1.7% ng on congenital malformation rate, malformation ngcongenital on HBsAg infant in reduction allysignificant r fetal harms, no statistically significant significant statistically no rfetal harms, k of bias. This significant reduction reduction significant This of bias. k R 0.2 (95% CI, 0.1 to 0.7) I 0.7) (95% CI, 0.2 to R 0.1 l at 6-12 months after birth. Lamivudine birth. after months 6-12 at l (95% CI, 0.7 to 1.5) and tenofovir (1 study, (1 study, tenofovir and 1.5) to 0.7 (95%CI, uality of the evidence of infant outcomes outcomes of infant evidence the ualityof 18.7% respectively. The quality of of The quality respectively. 18.7% BV DNA suppression before delivery (1 beforedelivery DNA suppression BV positivity by 15.8% (4 RCTs, RR 0.2 0.2 RR (4 RCTs, 15.8% positivity by RCTs, RR 0.3 (95% CI, 0.6) 0.3 to 0.2 RR RCTs, s, RR 0.1 (95% 0.1 RR s, ternalALT 2 = 0%). =0%). 11

postpartum (2 cohorts, RR 102(95% CI, 14.4 -722.8) CI, 102(95% 14.4 RR (2 cohorts, postpartum July 20, 2015 20, July telbivudine consistently had improved maternal ALT maternal hadimproved consistently telbivudine t compared - When 1.8). 1.2 (95% CI, 1.5 RR cohort, (95% CI 52.8 RR cohorts, (3 delivery at suppression telbiv control, vs telbivudine comparing In studies outcomes. outcomes. quality the of evi summarizes 4 respectively.Table telbivudi comparing lamivudine, studies in delivery Figur and indirectness. imprecision studies, of the wa outcomes maternal in evidence the Thequality of rate, hemorrhage postpartum in found differencewas fo control therapy vs. anyantiviral comparing When (RR or seroconversion 21.5) (95% CI, 1.1 to 0.1 (RR ( 1.8 RR (1 delivery cohort, at suppression HBVDNA with treated pregnantwomen lamivudine, to Compared seroconversion. or HBeAg normalization 45.4 RR (2delivery cohorts, at suppression HBVDNA to compared Tenofovir (95% CI, 1.7 - 2.29). 1.2 RR -2 (95% CI, 1.6 1.2 RR cohort, (1 weeks postpartum (2 cohort delivery at loss HBeAg maternal increased 1. CI, 1.3(95% RR (1 cohort, weeks 28 at postpartum I - 1.8) 1.2 (95% CI, 1.5

Accepted Article 2 =0%), at 4 weeks postpartum (1 cohort, RR 1.6 (95% 1.6 RR (1 cohort, postpartum =0%),weeks 4 at This article isprotected by copyright. All rights reserved. Hepatology Hepatology es 7-9 show maternal outcomes reported at reported outcomes maternal esshow 7-9 udine showed improved maternal HBV DNA DNA maternalHBV improved showed udine dence (GRADE) for infant and maternal and maternal infant for dence(GRADE) ne and tenofovir treatment vs control group group control vs netreatment and tenofovir , 10.7 - 261.8) I - 261.8) 10.7 , r maternal harms, no statistically significant significant statistically no harms, rmaternal s, RR 1.7 (95% CI, 1.3 - 2.2) I - 2.2) (95% CI, 1.7 1.3 RR s, control showed significant improvement in in improvement significant showed control s very low due to the observational nature nature observational the to due very s low .2) and at 28 weeks postpartum (1 cohort, postpartum weeks .2)and28 at CS rate and elevated creatine kinase rate. kinase ratecreatine and elevated CS 0.6 (95% CI, 0.03 to 15.2). 15.2). (95% CI, 0.6 to 0.03 o control, pregnant women receiving women pregnant control, o 04 to 1.6). Telbivudine also significantly significantly also Telbivudine 1.6). to 04 I normalization at delivery (2 cohorts, RR RR (2deliveryat cohorts, normalization 95% CI, 1.3 to 2.6) but not HBeAg not loss but 2.6) to 1.3 CI, 95% 2 (95% CI, 9.3 - 222.5) but not ALT not but - 222.5) 9.3 (95%CI, telbivudine had significantly greater had significantly telbivudine =0%) and at 28 weeks postpartum (1 postpartum weeks 28 at and =0%) 2 =0%), at 4 weeks 4 at =0%), CI, 1.1 -and 2.3) CI, 1.1 2 =0%), at 4 4 at =0%), 12 Page 12of43 Page 13of43

prevention of MTCT of HBV does not necessarily mand necessarily not HBVdoes of of MTCT prevention of risk have highest the thesewomen phaseof CHB, bias: Publication July 20, 2015 20, July For women who are or may become pregnant, considera pregnant, become or may are who For women Discussion: due to bias publication evaluate to were We unable showed higher rates of HBV DNA suppression, ALT nor ALT suppression, DNA of HBV rates higher showed In post-partum. months 6-12 at positivity HBVDNA reduct over rates,70% with MTCT DNAreduced of HBV or telbivudine, lamivudine, therapy with antiviral B star vaccine hepatitis received who Amonginfants > HBV 10 DNA (serum highof viremia levels beunacce of HBV may MTCT against immunoprophylaxis rate failure current the However, women. formost infecti HBV successfully prevents immunoprophylaxis Add disease. liver compensated longhave as they be postpon may treatment antiviral ofCHB infection w for Even child-bearingage. of women choicesfor p andduring fetus mother for the thesemedications childbear of women many forthe unproven therapyis preg CHB during for therapy antiviral administering medic complicate mother as the as fetus well the to

Accepted Article

This article isprotected by copyright. All rights reserved. Hepatology Hepatology 6 copies/mL; ~2 x10 ~2 copies/mL; tenofovir in pregnant women with high levels with pregnantwomen in tenofovir ation treatment decisions is important, such as such important, is decisions treatment ation regnancy can help inform potential treatment treatment potential inform canregnancyhelp of post-exposure neonatal neonatal of post-exposure itionally, post-delivery neonatal combined neonatalcombined itionally, post-delivery small number of studies for outcome. each of studies number small nancy. Although the benefit for antiviral antiviral for benefit the Although nancy. omen who are in the immune active phase active phase immune the in are who omen ting at birth, this meta-analysis found that that meta-analysis found this at birth, ting as of childbearing after completion eduntil MTCT. Thus characterizing the safety of safety the of characterizing Thus MTCT. ing age who are in the immune tolerant tolerant immune the in are who age ing non-head-to-head trials, telbivudine telbivudine trials, non-head-to-head on in approximately 90% of infants. Thus, Thus, of infants. 90% approximately in on tion of the potential harms and benefits and benefits harms of potential the tion ate antiviral treatment during pregnancy during pregnancy treatment ateantiviral malization and HBeAg seroconversion and HBeAg seroconversion malization ions in the rates of infant HBsAg and HBsAg ofinfant rates the in ions ptably high (~9%) in women with with women in (~9%) high ptably 5 IU/mL) (10).

propensity to develop viral resistancelamivudin to viral develop propensityto cate pregnancy lamivudine and B, category pregnancy July 20, 2015 20, July Hepatitis B Treatment Guidelines for details). for details). Guidelines B Treatment Hepatitis 2x10 than greater for trimester women third the therapy in antiviral o in were identified outcomes or fetal formaternal insuffi were there For tenofovir, lamivudine. than 6 years of monotherapy for CHB (56). CHB (56). yearsfor 6 of monotherapy a barrier high resistance has tenofovir otherhand, rather restricted than or postpartum, pregnancy the MT of risk the and hence viremia reduce to maternal t third second or early late the usuallyin started beless may for pregnancy CHB during ortelbivudine unclea finding is ofthis significance the (54),so growt early on any impact show not did earlier data t to newbornsexposed in content lowermineral bone R or newborn(20). mother either for safetyconcerns tran preventHIV to women pregnant HIV- in infected exp substantial the However, data.sparse human in ani on FDA) primarily (US based DrugAdministration pregnancy. for in use approved are ofthesedrugs are and tenofovir telbivudine Althoughlamivudine,

Accepted Article

5 5 IU/mL to prevent MTCT seems warranted (see the acco the (see warranted seems IU/mL preventMTCT to

This article isprotected by copyright. All rights reserved. Hepatology Hepatology rimester in mothers with high HBV DNA levels levels high DNA HBV with mothers in rimester r. Additionally, initiating tenofovir, lamivudine, tenofovir, initiating Additionally, r. with no resistance identified to date after up to to up date after to resistance no identified with who are HBeAg + with a HBV DNA level level HBV DNA a + HBeAg with are who cient controlled outcome data. No safety issues issues data.safety No outcome controlled cient ur meta-analysis of these studies. Thus Thus studies. of these urmeta-analysis to the late second and third trimester. On the the On trimester. latesecond the and third to Telbivudine and tenofovir are currently rated currentlyare and tenofovir Telbivudine e or telbivudine (55) if it is used throughout used is (55) it if eor telbivudine h in infants exposed to tenofovir uteroto in exposed infants in h erience in the use tenofovir and lamivudine and lamivudine eriencetenofovir use the in licensed for CHB and HIV treatment, none HIVtreatment, and CHB for licensed ecent data in women with HIV have reported reported HIV have with ecent women data in CT of HBV. Concern remains over remains the of HBV. CT Concern enofovir throughout pregnancy (53), but but (53), pregnancy enofovirthroughout worrisome because the antiviral agents are agents antiviral the because worrisome smission has not identified any significant any identified significant not has smission gory C, by the United States Food and States goryUnited the by C, mal data with no clear evidence of harm of harm evidence clear no data with mal mpanying AASLD mpanyingAASLD 14

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July 20, 2015 20, July tenofovir (26), data on fetal safety with antiviral safety with fetal on (26), data tenofovir r increased no finding Pregnancy Registry Antiviral selection especially significant biases, to subject da of the most ofa RCTs, paucity With confidence. t is systematic review of this limitation Themajor trimester to prevent MTCT is recommended. is preventMTCT to trimester DNA> 10 andhave HBV positive HBeAg are who Int awaited. are eagerly results ongoingand these outcome maternalor fetal of adverse risk increased (>10 high loads viral with demons were These effects of MTCT. rates reducethe as level DNA lowersHBV and tenofovir, telbivudine, o the infection, chronic HBV with Inwomen pregnant Conclusion: (57). guidelines AASLD updated the infec HBV chronic of for management Recommendations

Accepted Article

This article isprotected by copyright. All rights reserved. 6 copies or copies ~2x10 Hepatology Hepatology 5 IU/mL). The limited safety data suggest no safety data IU/mL). limited The s remain limited, particularly for telbivudine. telbivudine. for particularly limited, remain s bias. Additionally, despite a report from the the areport from despite Additionally, bias. he absence of studies warranting high high warranting ofhe studies absence he meantime, the use of these agents in women women in these agents of use the hemeantime, s. Larger scale RCTs of tenofovir are are of tenofovir LargerRCTs scale s. 6 6 isk of birth defects for lamivudine or for lamivudine defects of birth isk ta are derived from cohort studies, which are which studies, cohort from derived are ta copies/mL (20,000 IU/mL) in the third IU/mL)third the in copies/mL (20,000 they do in non-pregnant women and women they non-pregnant in do ral antiviral therapies lamivudine, lamivudine, therapies ralantiviral trated in women who are HBeAg positive positive are HBeAg who women tratedin tion during pregnancy are provided in in provided are during pregnancy tion 15

Gastroenterol Hepatol Gastroenterol 2011;9:274-276. with entecavir reversalinduceswith advanced fibrosi of immunoprophylaxis inimmunoprophylaxisinfants HBsAg-positiveto born 13. Zou H, ChenH, Zou ZhangY, Z, Duan VirologicC. Pan H, f 13. 18. Schiff ER, SchiffER, SS,Chao Lee YC, S, Yoon Kew Bessone 18. hepatitis HepatologyB.chronic 2010;52:886-893. on interruption on HBVintrauterine infection. of Worl results inthe reversalresults fibrosis/cirrhosis of andc 12. Li XM, ShiXM, Yang Li Shi MF, YB, HY, Hou ZJ, ShenHM, 12. 17. Chang TT, SS, Chang Wu TT, Liaw YF, HanKH, Schiff E, Lai 17. Gastroenterology 2006;131:1743-1751. exposure is dependent is exposure on virusJmaternalInf load. Long-term Long-term therapywith adefovir dipivoxilfor HBeAg 11. Burk RD,HwangHo Burk GY, LY, Beasley ShafritzDA, 11. 6 HadziyannisSJ,Tassopoulos HeathcoteNC, EJ, C 16. transmission of hepatitis transmission B of an virus: Australianex through 5 5 through yearstherapy. of Hepatology 2009;49:1503 10. Wiseman E, Wiseman HoldenFraser MA, A, Glass S, Kidson 10. Gastroenterology 2007;133:1452-1457. term term hepatitisshows monitoring B resistance virus Clearance of hepatitis Clearance of e B antigen inpatients with 15. Tenney DJ, DJ, TenneyRE, Rose Baldick CJ, KA, Pokornowski 15. 9. Livingston SE, Simonetti SE, Livingston JP,LR, HomanBulkow CE 9. 1985;253:1740-1745. 14. Lok AS, Lok BJ.Chronic McMahon updatehepatitis B: 14. B virus virus in B transmission the States. United Preventi July 20, 2015 20, July 3. Alter SC,Hadler Alter MJ, Margolis HS,Alexander WJ, 3. 8. Stevens CE, Stevens Toy TongPT, VyasMJ, GN,Taylor PE, 8. 1984;13:385-391. Virol B virus infections virus B inpreschool childreninTaiwan. among asymptomaticamong carriers,chronic hepatitis, liv 2. Beasley RP, HwangRP, Beasley LY,Lin LeuStevens ML, CC, CE 2. S21-13. discussion of hepatitis B antigen of e andantibody inchronic he 1. Maynard JE.Hepatitis Maynard global B: importance andn 1. References: References: 7. Liaw ChuCM, Liaw YF, SheenDY, Lin YangIS, Huan CY, 7. children. HepatologyChinese 1988;8:1130-1133. 6. Lok AS, Lai CL. ALaiAS, CL. Lok longitudinal follow-upasym of 6. Gastroenterology 1987;92:1839-1843. seroconversionandreversion inChinese patients wi 5. Lok AS, LaiAS, CL, Lok Wu PC, Leung SpontanTS.EK, Lam 5. EnglJMed 1975;292:771-774. 4. Stevens CE, Stevens Beasley TsuiRP, WC. Lee J, Vertical 4. 1990;263:1218-1222. epidemiologyhepatitis BUnited of inthe States. N

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This article isprotected by copyright. All rights reserved. Hepatology Hepatology ontinuedimprovementhistological inpatients with perience.MedJAust 2009;190:489-492. JInfect Dis 1982;146:198-204. chronichepatitis B andgenotypes B,A, and C, D, on by passive-activeon immunization. JAMA patitis B infection in virus comparison Taiwan:a eedalternative for vaccination JAMA strategies. s s orcirrhosis inpatients with hepatitis B chronic dJ Gastroenterol 2004;10:3215-3217. er er cirrhosis, andhepatocellular J carcinoma. Med ectDis1994;170:1418-1423. to innucleoside-naive entecavir patients is rare th chronic hepatitis chronic th virus B infection. -negative chronic-negative hepatitis up B to years. for 5 JViral mothers. Hepat 2012;19:e18-25. -1514. CL, Safadi CL, etLong-termal. R, therapy entecavir transmission hepatitis B of antigenN inTaiwan. ptomatichepatitissurface B antigen-positive F, Wu SS,Kryczka et al. W, Long-term treatment RP.Outcome ofhepatitisperinatal virus B hangKitis G, TT, Rizzetto M, MarcellinP,et al. Eggers FangBJ, WichroskiJ, MJ, al. et Long- Hu JudsonA,FN,PY,Mares etal. changing The Teng Teng Effecthepatitis immunoglobulinBQ. B of Nair Gudavalli PV, M,et al. Perinatalhepatitis BL,Heron LG, Maley et MW,al. Perinatal g MJ. prevalence Age-specific and significance 2009.Hepatology 2009;50:661-662. eous B antigen hepatitis e antibodyto eedcontrol. Vaccinefor 1990;8 Suppl:S18-20; , ChenSzmuness W, KP.Incidence ofhepatitis actorsassociatedfailure with passive-activeto , Snowball , Cagle MM, HH,Negus etal. SE, . Clin F. 16 Page 16of43 Page 17of43

journal 2009;3:e123-130. journal by lamivudinetreatment by combined active-passiv with 34. Xiang GJ SJ,GJ XiangJiang Hu XB, AL.SQ, Qu Evaluation 34. 2008;23:1730–1731. immunization interrupting infanton mother to trans 33. Guo YZ SL,LS, Guo JH. Wang Ge Effect.lamivudi of 33. (CT): Haven Yale University 2009. July 20, 2015 20, July Y,Yang Shi Z, X,Ma L, Schreiber Li A.Lamivudi 19. HBV- a randomized,HBV-double-blind, a placebo-controlst 32. Shi ZJ LX, ShiYB,YangZJLX, Clinical Ma L. researchon t 32. transmission of chronic transmission HBV of on mothers[in50 Chine 31. YF Z. TheZ. YF clinical observationeffect ofof lami 31. HBVintrauterine infection Clin[in Chinese] Ch Med intrauterine intrauterine transmission: study.clinical a World 30. Li X-M, YangX-M, Hou Li Y-B, H-Y, Shi Z-J,ShenH-M, T 30. & Obstetrics Gynecology] 2008;43:329-331. 35. Shi MF LX, HeLX, ShiYB,YangMF J, Hou Zhuang HY, YL,She 35. ChinPrac Med 2007;2:14–16. hepatitis B B in late-pregnant hepatitis virus Chung-Hu women]. 29. Yang S, Liu Liu S, Yang [Effect high M, L. Wang viral of he 29. 20. Brown Jr.,Verna Brown RS, EC, MR,Tilson HH, Pereira 20. 159. placebo-controlledstudy. Journal ofViralHepatiti transmission of hepatitis transmission B of a systematicvirus: rev prevent perinatal prevent transmissionhepatitis B of virus 24. Shi Z, Yang Y,Yang Shi Z, X,Ma L, Schreiber Li A.Lamivudi 24. 2011;343:d4002. BMJ 28. Xu WM, CuiWM, Xu YT, L,Wang Yang ZQ,Liang H, Li XM, 28. for examining for andinterpreting asymmetr funnel plot patients]. Chung patients]. Hua Kan TsangTsa Ping Chih 2009;1 23. Sterne JA,Sutton AJ,Ioannidis Sterne Terrin J N,JP, 23. the to literature.medicalJAMA 2014;312:171-179. 27. Zhang L-j, Wang Zhang [BlockingL-j, L. infect intrauterine 27. How a read How to systematicreview and meta-analysisa meta-analysis. Clinical meta-analysis. Laboratory 2014;60:571-586. 22. Murad MH, Murad MontoriVM, Ioannidis JaeschkeR, JP, 22. andthirdtrimester pregnancy interruptsof HBVint meta-analyses: meta-analyses: the PRISMAStatement. Open medicine 21. Moher D,Liberati A, Moher TetzlaffAltmanJ, DG. Pre 21. Registry.JHepatol2012. 26. Lu YP, Liang YP, Xiao Lu XJ, HuangXM, ZW, Liu SM, Li 26. 2011;17:4321-4333. andimmunodeficiencyhuman virus drugs inpregnancy interruption interruption of mother-to-childhep transmission of 25. Han L, Zhang HW, Han L, Zhang Xie JX, HY,Wang CaoQ, G 25. 2010;116:147-159. transmission of hepatitis transmission B of a systematicvirus: rev

Accepted Article

This article isprotected by copyright. All rights reserved. Hepatology Hepatology JournalGastroenterology of 2003;9:1501-1503. iewand meta-analysis. GynecolObstet 2010;116:147- iewand meta-analysis. ObstetricsGynecology & s s 2009;16:94-103. infection: a multicentre,randomized, double-blind in 2005;21:77–78. rauterinetransmission: systematic a review and atitis B WorldJournal virus. ofGastroenterology

ones ones DR, LauCarpenterJ, etJ,Recommendationsal. mission of HBV[in mission Chinese] of Clin Focus udy.Annual Global6th Health New Conference. a a Chih [ChineseFuChan Tsa Ko Journal of se]ObstJPrat Gynecol. 2010;26:367–368. yinmeta-analyses randomised of controlledtrials. 7:561-563. nd apply the results ndthe apply patientto users'care: guides patitis B DNA virus loads on vertical transmission vudine vudine oninterrupting motherinfantto he interruption he ofmother childto transmissionof e immunization e forpregnant women[in Chinese] ne inlate ne pregnancy interruptto in utero ne inlate ne pregnancy interruptto in utero ferredreporting items forsystematic reviews and ne ne combinedtreatment active-passive with eng B-Q, Li A-M,B-Q,eng Li Interruptional. et HBV of of therapeuticeffect inHBV transmission vertical J, HocherJ, al. B, et Telbivudineduring second the ion by telbivudineinpregnant hepatitis B chronic Aguilar LeuButi CS, C, M,et Hepatitisal. B viru : Findings : fromAntiretroviral the Pregnancy : a peer-reviewed, a independent,: open-access n Study HM. inof interruption Lamivudine of Zhang SL, etZhangLamivudineal. SL, inlate pregnancy to Devereaux PJ, Neumann Prasad K, al. et I, W.meta-analysisA lamivudine of for , , s s

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Pregnancy.ClinInfect Dis2015. Newborn Bone Newborn Mineral Content Associated With Matern 53. Siberry GK, Jacobson Siberry HJ,Kalkwarf DL, JW, Wu Di 53. 2014;61:55-60. lamivudineininterrupting transmissionperinatal o 52. Yu M-M, JiangM-M, Yu Q, JiY, K-H, Wu JuX, TangL-L, 52. disoproxil fumarate ininterruptingdisoproxilfumarate mother-to-infan 51. Chen HL, HL, ChenChangCN, Lee CH, Shyu NiYH, Chen MK, 51. 41. Chen R, R, ChenZhangS-r, Liu S-y, C-j. [EfficacyTao o 41. Tsang Hua Kan Tsa Ping Chih 2012;20:888-891. JournalfurGastroenterologische und Hepatologische Reactions Drug Adverse administeredduringpregnancy highlylate to viremi 0 ZhangHH. andYF Efficacysafety oftelbivudin i 50. 0 JiangJiWangHan G-r, H-x, [Maternal-fC-m, Y. 40. Journalof Gastroenterology 2013;19:9377-9382. B viral viral J B transmission. Clin Hepatol 2011;14:259-61 disoproxil fumarate inpregnancydisoproxilfumarate forthe prevention 49. Yao ZC CM,Liao Yao WY,etal. efficacy The andsaf 49. 39. Celen MK, Celen Ay Mert MK, S,KayaM, Dal D, T, Yildirim 39. JournalHepatology virus. of 2014;61:502-507. transmission by transmission lamivudine [intreatmentChinese] C safety ofdisoproxiltenofovir safety inpregnancfumarate 48. Han ZH CY, SunLW, HanCY, ZH XW, Li ZhaoSun SuH,XS. YG, 48. 38. Greenup A-J, Tan Greenup NguyenPK, GlassV, A, Davison 38. 476. maternal to infanttomaternal transmission[inChinese] Chin H safely reduces safely perinatal transmissionofhepatitis 47. Li WF JR, WF Wei. Li Z, Y. Li Clinical andsaf effect 47. JAppl Chinese] Clin 2007;22:1019–1020.Pediatr 37. Zhang H, Pan CQ, ZhangPan H, Q, Pang Tian Yan R, X. M, Liu T 37. 6 FengHFZS.on Effect interruption ofhepatitis 46. inpregnantwomen with high load. viral Journal of and the safety andthe observation discontinuing of treatme transmission of hepatitis transmission B of infection. Journavirus July 20, 2015 20, July HJ ZY. Guo Observationthe ofroletelbivudine i 36. label study for study label the efficacy ofandtelbivud safety 45. Han G-R, CaoZhao Han G-R, M-K, W,JiangC-M,Wang B H-X, 45. Tsa Ping TsangChih 2012;20:201-205. telbivudine inpregnant telbivudine womenprevent perinatalto 44. Han G-r, Jiang Han G-r, Wang H-x, G-j, WangYue X, C-m, 44. Hepatology 2012;10:520-526. vertical transmission vertical from HBeAg-positive womenwit 43. Pan CQ,Jiang Han Pan G-R, H-X, CaoZhao W, Wan M-K, 43. Microbiology Microbiology Infectious & Diseases 2012;31:2211-221 with lamivudine with stoptothe vertical transmissiono 42. Yu M, Jiang M, Ji Yu Y, JiangQ, JuH, TangK, Wu L, 42. ChungTsangChih Hua 2012;20:703-704.Kan Tsa Ping

Accepted Article

This article isprotected by copyright. All rights reserved. Hepatology Hepatology ine inine forpregnancythe prevention ofperinatal l oflHepatology 2011;55:1215-1221. B B viruspractice. inreal-life Hepatology 2014;60:4 . fB hepatitis virus. EuropeanJournalofClinical f hepatitisf B Journal virus. of ClinicalVirology CHANGZHlMedicalCollege 2011;25:368-370. y y preventto perinatal hepatitis transmission B of epatol. 2006;11:106–107. ety oflamivudineety in interruption chronic HBV of t transmission t ofhepatitis B virus.Hepatology 201 c HBeAg+ mothers with chronic hepatitis B].Chung of vertical transmissionof vertical HBV of infection. World X, et al. X, et Theandefficacy antiviral safety ther of nt afterdelivery time on motherinfected with HBV] hinMedJIntern2005;44:378. transmissionofhepatitis B virus].Chung Hua Kan f telbivudinef inblocking the verticaltransmission Yang Y-F.Yang Comparison oftelbivudine versus 2010;12:157-159.Erkrankungen h chronic hepatitis B.hchronic Clinical Gastroenterology & 8. 8. B B virus vertical by transmission lamivudine [in ety of telbivudineinblocking intraterine hepatiti etaloutcomes lamivudine of treatment npreventing HBVmother-to-infant tranmission. N, GulsunN, al. et andS,Efficacy safety of tenofov nblocking mother-to-childtransmission HBV of Kan N-y, Kan Wu [EfficacyandM-m. safetyof elbivudine or lamivudineelbivudine or inlate use pregnancy Meglio LA, Meglio Yogev R, KnappetKM,Loweral. S, U, Chatterjee Holdaway etS, andEfficacyal. al Useal ofTenofovir DisoproxilFumarate During . andEffectsafety preventing of HBVvertical SM, al. HuJJ, et Efficacy of tenofovir maternal aiS-F, X, etprospectiveAal.Yue and open- g C-M,g Yue X, etTelbivudineal. prevents 68- apy apy 5.

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Chronic Hepatitis Chronic B. 57. Terrault NBN, Terrault Chang K-M, HwangJonas J, M, Mur 57. 2011;140:132-143. efficacy and safety efficacy of tenofovirdisoproxilfumarat 56. Heathcote Heathcote MarcellinEJ, M, P, Gane Buti E, M De 56. lamivudineintreatmentpatients chronic hepatwith 55. Lok AS, LaiAS, CL, Lok Leung GB,YaoN, CuiZY, Schiff 55. 2012;26:1151-1159. tenofovir use during use tenofovir pregnancy: earlygrowth outcom July 20, 2015 20, July GK, Williams Siberry PL, MendezSeageH, GR, 3r 54.

Accepted Article

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This article isprotected by copyright. All rights reserved. Hepatology Hepatology e treatment e forchronic hepatitis GastroenteroloB. itisGastroenterologyB. 2003;125:1714-1722. es inHIV-exposed uninfected es infants. AIDS ER,Dienstag al. JL, et Long-termsafety of an RA,an GermanidisKrastev Z, etThree-yearal. G, d, Jacobsond, HazraR,DL, Rich Safetyal. KC,et of ad Guidelines H.AASLD for Treatment of es-0 .HEPATOLOGY 2015. gy 19

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months follow up follow months for RCTs outcomes of infant Forest plots Figure 4: up follow months for RCTs outcomes of infant Forest plots Figure 3: up follow months 6-12 for RCTs outcomes of infant Forest plots Figure 2: deliveryat non- for maternaloutcomes of Forest plot Figure 9: deliveryat control non- for maternaloutcomes of Forest plot Figure 8: delivery non- for maternaloutcomes of Forest plot Figure 7: control therapy vs any antiviral comparing an malformation of congenital Forest plot Figure 6: up follow months for non-R outcomes of infant Forest plots Figure 5:

Accepted Article

This article isprotected by copyright. All rights reserved. Hepatology Hepatology CTs comparing tenofovir vs control at 6-12 6-12 at control vs comparing CTs tenofovir d prematurity rates reported for studies for studies reported rates prematurity d comparing telbuvidine vs control at 6-12 6-12 at control vs telbuvidine comparing 6-12 at control vs lamivudine comparing at control therapy vs any antiviral comparing RCTs studies comparing tenofovir vs control control vs comparing tenofovir studies RCTs vs comparing telbivudine studies RCTs at control vs comparing lamivudine RCTs 60 59 58 57 Table Characteristics1: of the included studies: uhr er Interventions Author, year 2005(34) Shi, 2007(33) Xiang, 2008(32) Guo, 2009(31) Shi, 2010(30) Zhang, Li,2003(29) 2008(28) Yang, 2009(27) Xu, 2009(26) Zhang, hn Lmvdn 7 Cia R .±. N 2-2 All 4 24-32 NR 7.7±0.5 NR China 75 Lamivudine Chen, 2012(39) Jiang, 2013(38) Celen, 2014(37) Greenup, 2014(36) Zhang, 2011(35) Guo,

oto ru 4 N 64±21 R A NA NA NA NA NR NA NA ± 6.4 2.1 NA NR NR NR NR ± 7.1 1.3 NA 20-40 NR 43 Controlgroup 20-40 NR 50 Controlgroup ± 7.5 0.5 52 43 Controlgroup 20-40 Lamivudine 20 Controlgroup 61 Controlgroup 30 Controlgroup oto ru 9 2.±. 7906 2204 A NA NA NA NA 4 NA 42.2±0.4 NA NA 4 52(19-77) NA 7.9±0.6 32 NA 26.4±3.2 25(17-31) 8.3 NA 22(18-30) 26.9±2.9 NA 28-30 NA NA ± 0.04 8 ± 7.7 0.6 28.0±5.0 NA 28.0±5.3 29.5±20.7 39.7±26.4 92 Controlgroup NA NR 6.8± 0.5 NA 6.9±0.4 28.9±4.6 24 28.4±7.1 Controlgroup NR ± 7.9 3.5 20 52 Controlgroup NR NR ± 8.9 1.1 Lamivudine NR NR ± 7.2 0.8 352 51 Controlgroup NR NR Lamivudine 26 NR Controlgroup 18 Controlgroup 18 Controlgroup 40 Controlgroup aiuie 21 Lamivudine 21 Lamivudine 70 Lamivudine 49 Lamivudine 50 Lamivudine 20 Lamivudine 89 Lamivudine 31 Telbivudine aiuie 164 AcceptedLamivudine 21 Tenofovir 58 Tenofovir 252 Telbivudine 28 Telbivudine Article Participants (Mothers) (N)

China China China China China China China China China China Turkey Australia China China Country

R . . N 2 4 4 4 28 4 28 28 4 NR 28 NR ± 8.7 0.7 NR NR ± 8.0 1.2 28 NR NR NR NR ± 7.2 1.9 NR NR ± 6.8 0.9 NR R . . N 2 4 28 NR ± 7.7 4.6 NR 04 75±05 R 8 4 28 NR ± 7.5 0.5 20-40 04 N N 2 4 28 NR NR 32-36 NR 20-40 NR 32) 26(19- ± 7.4 0.8 20-40 8241 . 5(27) 8-2 4 - 1827 39.6±26.0 56(22-71) 4 7.8±0.8 27.3±4.4 8.3 28.2±4.1 28-30 8.5 30.1±27.9 30.0± 6.9±0.4 29.8±6.3 36) 25(20- (Years) Age This article is protected by copyright. All rights reserved. 8.6 ± 8.6 0.2 . . 2(23) 2 12 32 28(22-36) ± 7.9 0.8 8.7 ± 8.7 0.2 ± 6.9 1.7 BaselineHBV (log10IU/mL) DNAlevel

R A NA NA NR xULN 0.4(0.1-5.3) xULN 0.4(0.1-6) BaselineALT Hepatology Hepatology (U/L) level A NA NA 2 4 32 24-32 (gestationalweeks) Treatmentstart

Atdelivery

(postpartumweeks) discontinuation Treatment l RCT All l RCT All RCT All l Retrospectivestudy Cohortstudy All All All l RCT RCT All RCT All RCT All RCT All All l RCT All withoutHBIG withor HBVvaccine l Cohortstudy All (Infants) HBIG+ Cohortstudy vaccine

Interventionaltrial. label, Prospective,open- RCT Studydesign Page 30of43 60 59 58 57 Page 31of43

2011(48) Yao, 2010(49) Zhang, 2005(47) Han, Li,2006(46) 2007(45) Feng, 2011(44) Han, 2012(43) Han, 2012(42) Pan, 2012(41) Yu, 2012(40) 2014(51) Yu, 2015(50) Chen,

oto ru 10 6432 .±. 3.±51 A NA NA NR NA NR 31.5±35.1 NA 44 7.3±0.6 36 Controlgroup 26.4±3.2 Lamivudine 42 45.0 Controlgroup 94 7.0±0.6Controlgroup 25.8 100 Controlgroup 35 Controlgroup 91 Controlgroup aiuie 14 6735 . . 5. 27 A N NA NA NA 56.3 ± 82.7 23.3±36.2 ± 7.7 0.7 26.7±3.5 8.2±0.4 32.4±3.1 NR 154 NRLamivudine 56 NRControlgroup 30 Controlgroup 60 Controlgroup 35 Controlgroup ebvdn 28 Telbivudine 60 Telbivudine 43 Lamivudine 48 Lamivudine 135 Telbivudine 120 7.3±0.4 Telbivudine NR 53 Telbivudine 94 Lamivudine 28 Controlgroup Accepted 233 Telbivudine 62 Tenofovir Article

China China China China China China China China China China Taiwan

NR NR NR NR NR 6035 .±. 31.0±32.2 38) 27(20- 7.3±0.5 26.0±3.5 34) 45.0 27(21- 6.9±0.4 26.4±4.2 6839 . . 5. 35 -2 Atdelivery 4 8-32 28 57.6 ± 83.5 16.6±14.4 ± 7.8 0.8 26.8±3.9 8.2±0.5 32.5±3.2 35) 26(20- 33) 27(21- This article is protected by copyright. All rights reserved.

R NR NR NR NR . . NR ± 8.3 1.2 . . NR NR ± 7.5 0.7 ± 7.5 0.6 NR NR NR 5.6 > NR± 7.2 0.9 NR5.00 > ± 6.9 0.8 ± 8.3 1.9 . . 35.7 ± 43.4 ± 7.4 0.6 60.4(41.4-422) 8.08(6.6–9.4) . . 4. 01 A NA NA NA 42.5 ± 40.1 ± 7.3 0.6 NA 63.2(42.4-262.5) (6.8–9.1) 8.1 NR

Hepatology Hepatology A NA NA NA NA NA NA NA NA NA NA A NA NA 8 4 28 8 4 4 4 28 4 28 28 28 20-32 12-30 20-32 . 24-32 4 duration afterdelivery Continuedfor variable 4 duration afterdelivery Continuedfor variable A AllNR l RCT All l RCT All RCT RCT All All l Cohortstudy All All l Cohortstudy All All l Cohortstudy All Cohortstudy All

RCT trial. randomizedcontrolled Open-labeled,non- trial randomizedopen-label Prospective,non- 60 59 58 57 Table of Risk 2: bias assessment for the includedR hn,21(0 Ucer nla Ucer nla Non Unclear Unclear Unclear Nomissing Unclear Unclear Unclear Zhang, 2010(30) Unclear Zhang, 2009(26) in,20(3 Aeut Ucer nla Nomissing Unclear Unclear Adequate Xiang,2007(33) ag 082) Random numbertable Yang, 2008(28) u,21(5 Ucer nla Noblinding Nomissing o Unclear Unclear Unclear Unclear Guo,2011(35) Adequate Guo,2008(32) h,20(4 Rno al Unclear Random table Shi,2005(34) Computerrandom numbergenerator Shi,2009(31) Author, year u 092) Unclear Xu, 2009(27) Li,2003(29) Accepted Article

Numbergenerator Computerrandom

generation Sequence

This article is protected by copyright. All rights reserved. Sequentiallynumbereddrug Sequentiallynumbereddrug Allocationconcealment Sequentiallynumbered containersof identical containersof identical identicalappearance CTs: drug containersof appearance appearance Unclear Hepatology Hepatology Adequate blinding Adequate blinding Adequate blinding influenced bylack influenced bylack Measurement not Measurement not personneland participants, Blindingof ofblinding ofblinding assessors Missingoutcomes Onearmof data haveno impact outcomedata outcomedata outcomedata outcomedata outcomedata on effecton size Incomplete Nomissing Nomissing Nomissing Nomissing missingfor ethics

outcome outcome utcome Allpre specified Allprespecified Allprespecified Allprespecified Allprespecified l rseiid o low No Allprespecified Allprespecified Allprespecified Allprespecified reporting outcomes outcomes outcomes outcomes outcomes outcomes outcomes outcomes Selective outcome reported reported reported reported reported reported reported reported Nn Unclear None e sources of Other bias o Unclear No o Low No o Unclear No o Low No o Low No o Low No No High/ High/ unclear No o Unclear No Riskbias of Page 32of43 60 59 58 57 Page 33of43 Table of Risk 3: bias assessment for the observatio Author,Year in,21(9 N ecito Drawnfrom samethe Nodescription Somewhatrepresentative of Jiang, 2012(39) Celen,2013(38) Somewhatrepresentative of Somewhatrepresentative of Greenup, 2014(37) Zhang, 2014(36) hn,21(9 N ecito N ecito Node Nodesc Nodesc Nodescr Nodescription somewhatrepresentative of Nodes Nodescription Nodescription Nodescription Somewhatrepresentative of Yu, 2014(51) Nodescription Nodescription Nodescription Chen, 2015(50) Nodescription Zhang, 2010(49) Nodescription Yao,2011(48) Drawnfrom samethe Nodescription Han,2005(47) Li,2006(46) Somewhatrepresentative of Feng,2007(45) Nodescription Han,2011(44) Somewhatrepresentative of Drawnfrom samethe Han,2012(43) Somewhatrepresentative of Pan,2012(42) Nodescription Yu, 2012(41) Chen, 2012(40) exposed cohort Representativeness the of the communitythe or population communitythe or population communitythe or population Acceptedcommunitythe or population communitythe or population communitythe or population communitythe or population communitythe or population Article

Selection

exposed cohort Selectionof the non- cohort communitythe as exposed cohort communitythe as exposed cohort communitythe as exposed cohort communitythe as exposed Drawnfrom samethe cohort communitythe as exposed Drawnfrom samethe cohort communitythe as exposed Drawnfrom samethe cohort communitythe as exposed Drawnfrom samethe cohort communitythe as exposed Drawnfrom samethe cohort communitythe as exposed Drawnfrom samethe cohort communitythe as exposed Drawnfrom samethe cohort communitythe as exposed Drawnfrom samethe This article is protected by copyright. All rights reserved. nal studies: or or analysis. the basison the designof Comparabilityof cohorts importantfactor Studycontrols for most importantfactor Studycontrols for most importantfactor Studycontrols for most importantfactor Studycontrols for most additionalfactors Studycontrols for any additionalfactors Studycontrols for any importantfactor Studycontrols for most additionalfactors Studycontrols for any importantfactor Studycontrols for most importantfactor Studycontrols for most importantfactor Studycontrols for most cito N ecito N ecito Nodescript Nodescription Nodescription scription Hepatology Hepatology rpin odsrpin odsrpin Nodescripti Nodescription Nodescription cription ito N ecito N ecito Nodescriptio Nodescriptio Nodescription Nodescription Nodescription Nodescription ription ription pin odsrpin odsrpin Nodescription Nodescription Nodescription iption Comparability odsrpin e Adequate Yes Nodescription odsrpin nla unclear Unclear Unclear Nodescription No Nodescription seseto ucm Wasfollow up long enough Assessment outcomeof eodlnae e Adequate Adequate Adequate Yes Yes Recordlinkage Yes Recordlinkage Recordlinkage eodlnae e Adequate Yes Adequate assessment Independentblind Recordlinkage Adequate Adequate Yes Recordlinkage Yes Yes Recordlinkage Recordlinkage for for outcomesoccur to e Adequate Yes Outcome cohorts Adequacy of followup of ion on n n

Ovid MEDLINE(R) to 1946 Present, Reviews EBM EBM Reviews Reviews EBM Search Strategy: 6 5 4 3 2 1 Database(s): Embase 1988to 2014 Week 36, Ovid MEDLINE(R) In Supplemental #

valganciclovir or valomaciclovir or valopicitabine or valtorcitabine or vaniprevir or vapendavir or or vapendavir or vaniprevir or valtorcitabine or valopicitabine or valomaciclovir or valganciclovir or valaciclovir or arabinoside" "uracil or umifenovir or tuvirumab or tunicamycin or tromantadine ortivic derivative" or "tilorone Tilorone "TenuazonicAcid" or "thiarubrineA" or "thiophene A" or "thymine arabinoside" or tilorone or or synguanol or taribavirin or tebrofen or tecovirimat or tegobuvir or telaprevir or telbivudine or suv or suramin or streptovirudin or Streptovaricin or streptovaricin or sovaprevir "scopadulcic acid B" or setrobuvir or sevirumab or simeprevir or sofosbuvir or sorivudineor rociclo or riodoxol or rintatolimod or rimantadine or rifabutin or derivative" "ribavirin or ribavirin or resiquimod radavirsen rafivirumab "recombinant or or intercellular regavirumabmolecule or adhesion or 1" A Acid" or pirazofurin or pirodavir or pleconaril or pocapavir or "pokeweed antivirus protein" or "Poly penciclovir or "penciclovir triphosphate" or peramivir or "phosphonoacetic acid" or "Phosphonoacetic netivudine or netropsin or nivocasan or omaciclovir or ombitasvir or oseltamivir or palivizumab or or nesbuvir or C" "neominophagen or neceprevir or narlaprevir or A" bromoacetyldistamycin moroxydinemotaviz or merimepodib or Methisazoneor methisoprinol methylcytidine or or metisazonemiravirsen or or or mericitabine or lomibuvir or litomeglovir or libivirumab or lexithromycin or levovirin or letermovir ipilimumab or isatoribine or "isis 13312" or "isis 14803" or la derivative" or "idx 184" or imexon or imiquimod or "Inosine Pranobex" or iododeoxycytidine or "idoxuridine or idoxuridine or arabinoside" "hypoxanthine or hypericin or oxide" 7 "guanine or 92 "gs or grazoprevir or modulator" expression "gene or ganciclovir or venin" "gamma or fucoidin "flucytosine arabinoside" or fomivirsen or foravirumab or fosarilate or foscarnet or fosdevirine or fiacit or felvizumab or favipiravir or famciclovir "enisamium iodide" or enviroxime or epetirimod or eudistomin or exbivirumab or faldaprevir or disoxaril or "distamycin or 5" "distamycinA" or Ditiocarb or droxinavir or edoxudine or elbasvir or or detiviciclovir or "didemnin A" or "didemnin or Dideoxyadenosine B" or Dideoxynucl denotivir or deoxyaristeromycin or Deoxyglucose or deoxypenciclovir or deoxyribavirin or desciclovir cytarabine daclatasvir or or cidofovir or ciluprevir or clevudine or "cpg 10101" or crofelemer or cyclaradine or "cyclosporin A" or or Bromodeoxyuridine or bropirimine or buciclovir or carbocyclic or carbodine or carrageenan or alcohol" or benzimidavir or besifovir or boceprevir or bonaphthone or "Br asunaprevir avarone avarol or or avridine or or 7295" balapiravir "azd or or bavituximab "behenyl or "anti antiviral* or or "Anti or AntiRetroviral* or agent" viral "anti or 975" "ana or amsacrine amenamevir or amidapsone or amitivir or "ammonium trichloro dioxyethylene otellurate" or or "al 721" or alamifovir or alisporivir or "aln rsv or 01" "acyclouridine or or derivative" Acyclovir "adenineafovirsen xyloside" "adenosine or dialdehyde" ("1 agent/ antivirus exp Agents/ Antiviral exp or 2 1 B").mp. type or "hepatitis hepatitis" or "injection hepatitis" or "hippie hepatitis" or "serum B" ("hepatitis exp - U" or U" "Poly I - Deoxynojirimycin" or absouline or "abt 333" or "abt 450" or Acetylcysteine or aciclovir or Hepatitis B/dt Hepatitis

vir or rupintrivir or samatasvir or sangivamycin or "sangivamycin derivative" or or derivative" "sangivamycin or sangivamycin or samatasvir or rupintrivir or vir table -

Accepted ArticleCochrane Database of Systematic Reviews2005 to July 2014

1: Detailed Search Detailed 1: Strategy: C" or pritelivir or pseudohypericin or "pyran copolymer" or "PyranCopolymer" or

- viral*" or Aphidicolin or arasangivamycin or arbidol or arildone or astodrimer or

umab or "mycophenolic acid" or "Myxovirus resistance protein" or "n This article isprotected by copyright. All rights reserved. damavaricin or danoprevir or dasabuvir or deitiphorin or deleobuvir or iclovir or tomeglovir or torcitabine or trifluridine or or trifluridine or torcitabine or tomeglovir or iclovir

Searches abine or fialuridine or filibuvir or Filipin or florenal or or florenal or Filipin or filibuvir or fialuridine or abine Hepatology Hepatology -

Cochrane Central Register of Controlled Trials August 2014, Ovid

"alvircept sudotox" or amantadine or

ninamivir or larifan or ledipasvir or or ledipasvir or larifan or ninamivir - Process & Process - Retroviral*" or antiretrovirus antiretrovirus or Retroviral*" efeldinor brincidofovirA"

- Non Other izumab or synadenol Indexed Citations and eoside* or 56" 56"

611278 915473 178415 178415 26394 747307 Results

Page 34of43 Page 35of43 5 4 3 2 1 0 9 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 3 2 1 0

exp experimental study/ experimental exp studies/ validation exp study/ quantitative exp exp Topic/ as Studies Evaluation exp Studies/ Evaluation exp study/ clinical trial/ clinical exp study/ observational exp exp population research/ study/ prospective exp exp retrospective study/ study/ longitudinal exp exp Cohort Studies/ Cross exp Cross exp exp comparative study/ Effect/exp Placebo exp exp latinsquare design/ Single exp exp Double exp triple blind procedure/ Trial/ Controlled Randomized exp study/ controlled exp exp or Guideline/ exp review"/ "systematic exp exp Meta metaexp analysis/ exp evidencemedicine/ based 3 and (7 or 11) and 14 12 or 13 kw, nm, kf (pregnan* or gestation* or "child bearing" or childbearing).mp. [mp=ti, ab, sh, hw, tn, ot, dm,mf, dv, Pregnancy/ exp or 10 or 9 8 peginterferonogen* or peginterferron*).mp. or leif or 6" "interleukin or 29" "interleukin or 28A" "interleukin ("cl 884" or cl884 or ifn or interferon* or interferone* or interferonogen* or interferron* or interferon/ exp exp Interferons/ or 6 or 5 4 zanamivir"xenazoicor acid" Zanamiviror zinviroxime).m or or xanthogenate or virustatic* or repressor*" "virus or virucide* or virucidal* or viroxime or ve droprevir or vidarabine or Vidarabine or viracine or "viral inhibitor*" or virantmycin or virostatic* virostatic* or virantmycin or inhibitor*" "viral or viracine or Vidarabine or vidarabine or droprevir

Twin Study/ Twin Placebos/

- - - Analysis as Topic/ as Analysis

- Over Studies/ Over Studies/ Sectional , px,ui, rx, tx, ct] Blind Method/ -

Blind Method/

Accepted Article

Practice Guideline/ Practice

Hepatology Hepatology p.

peginterferon* or peginterferone* or 29510 134011 721205 1340 1463788 1448492 1080989 628758 628658 453504 453504 1208899 14612 113515 5818 31182 1130031 208013 53598 1728711 65081 68087 701082 864314 1065024 1680397 101407 307288 2459742 7231 267995 276 51259 342895 68 723249 4512490 344377 79207

0 9 8 7 6 5 4 3 2 1 0 9 8 7 6 5 4 3 2 1 0 9 8 7 6

(correlation* study) analys*) (correlation* adj2 or adj2 "case controlbase or study" "case or study" or "feasi or " analysis or "theoretical study" or "theoretical " analysis "replication or study" "replication or analysis" "prevention or survey" "prevention or study" "prevention or analysis" "panel or study" vivo "in or analysis" "field or survey" analysis" "quasiexperimental or study" "quasiexperimental or analysis" "fieldstudy" or or "field "experimental "experimental or study" or analysis"quasi experimental " "quasi or study" experimental anal or "validation survey" "validation or study" "validation or analys*" "quantitative or study" "quantitative or analysis" "twin or survey" "twin or study" "twin or analysis" "evaluation study" or "clinical studies" survey" or "observational or study" analysis" "case or "case series" or "clinical series"or "case "follow or study" "concurrent or analysis" "incidence study" "incidence or survey" or "in or survey" "concurrent or study" "concurrent or analysis" "population or survey" "population or study" study "prospective "retrospective study" "retrospective or "retrospective retrospectiv* survey" or or analysis" or or longitudinal* or analysis" "longitudinal or survey" "longitudinal or study" "longitudinal sur frequency "disease or analys*" frequency study" or "prevalence or analys*" "prevalence survey*" "disease or frequencyor study" "disease "cross or compar* or (intervention* study) adj2 or (intervention* trial) adj2 or "cross control*or multivariate or "comparative or or study" "comparative"comparative survey" or analysis" (tripl*mask*) adj (trebl* or adj blind*) or (doubl* mask*) adj or (singl* blind*) adj or (singl* mask*) adj or (tripl* blind*) adj or ((evidence based) adj or (meta adj analys*) or (systematic* review*) adj3 or guideline* or (doubl* adj "limitmedline embase. ratioaboveto maps odds odds ratio/ "limit study case only. embase aboveto medlinemaps case to report".ti. exp case study/ exp follow up studies/ medline to studies up follow "limit multivariateexp analysis/ exp proportional hazardsmodel/ analysis/ regression exp exp confidence interval/ exp case exp study/ trend exp exp Theoretical/ Models, Studies/ Feasibility exp exp theoretical study/ study/ replication exp study/ prevention exp study/ pilot exp Pilot exp study/ panel exp study/ vivo in study/ field exp study/ experimental quasi exp correlational study/ correlational bility study" or "feasibility analysis " or "trend study" or "trend survey" or "trend analysis" or or analysis" or "trend survey" or"trend study" or "trend " analysis "feasibility or study" bility - sectional analys*" or "cross - control studies/ control Projects/

Accepted Article

- up survey" or "follow or survey" up

" or "prospective" survey" or "prospective analysis" or prospectiv* or "population

blind*) or (trebl* mask*) adj or "latin square" or placebo or random*

- sectional survey*" or "cross or survey*" sectional only. embasemaps to followup".ti. - up analysis" or "observational study" or "observational "observational or study" "observational or analysis" up vey*" or crossover or "cross or "in vivo analysis" or "panel study" or "panel survey" survey" "panel or study" "panel or analysis" vivo "in or Hepatology Hepatology to risk".ti. to

- sectional "prevalence or design*" cidence analysis" or "follow cidence or analysis"

- over" or cohort* or - sec tional study" or or study" tional ysis" or or ysis" - up up 94889 570654 122062 784804 11312 11365 1387826 99507 1368248 949 2120 171018 171018 373 189705 1531 2028 22128887 0 383358 0 1738225 1343640 0 343014

Page 36of43 Page 37of43 7 6 5 4 3 2 1 0 9 8 7 6 5 4 3 2 1

remove duplicates from 86 84 or 85 from 83keep 896 83 not (exp 81 or 82 from 15keep 1301 79 not 80 retained] not valid in Embase,Ovid MEDLINE(R),Ovid MEDLINE(R) In handout or periodical index or port lecturesor legal or cases legislation or newsarticle overall or or newspaper or or patient education or bibliography or biographyor comment or dictionary or directory or interactive tutorial or interview limit 79 to (book or book series or editorial or erratum or letter or note or addresses or 76 or 78 were retained] records in valid Embase,CCTR,CDSR; not [Limit studies) validation randomi or trial pragmatic clinical or studiesmeta guideline or multicenter or or analysis observational study study or practiceguideline or evaluation or trial clinical controlled or study comparative or trial clinical or iv phase trial, clinical or phase trial, clinical iior phase trial, clinical ior phase trial, clinical or all trial, (clinical to limit 77 from 15keep 962 15 and 75 or/70 or/16 from 68keep 1 from 66keep from 65keep 793339 analysis").mp. "change or model" or "hazards analysis" or "regression interval" or "confidence ratio" or "odds pilot or trial study or referrent"case study" "case or referent or study" " - - 74 63

animals/ not exp humans/)

Accepted Article1 - - 318765 25622

- - 916 1300 - 1340 - 1301733

raits or published erratum or video- zed controlled trial or systematic reviews or twin study or or study twin or reviews systematic or trial controlled zed

Hepatology Hepatology case study" compeer or comparison "case or study" - Process,CCTR,CDSR; records were were records Process,CCTR,CDSR; audio mediawebcasts)audio or [Limit

autobiography iii 41 934 83 339 934 23255184 12606394 318765 25622 508395 735 906 21 885 916 40 893

2 1

inhibitor*" OR virantmycin OR virostatic* OR viroxime OR virucidal* OR virucide* OR "virus OR "virus virucide* OR virucidal* OR viroxime OR virostatic* OR OR virantmycin inhibitor*" vap OR vaniprevir OR valtorcitabine OR valopicitabine OR valomaciclovir OR valganciclovir OR OR valaciclovir arabinoside" OR "uracil OR umifenovir OR tuvirumab OR tunicamycin tromantadine OR trifluridine OR OR torcitabine OR tomeglovir OR tiviciclovir ive" derivat "tilorone OR OR Tilorone OR tilorone arabinoside" "thymine OR A" "thiophene OR A" "thiarubrine OR Acid" "Tenuazonic OR telbivudine OR telaprevir OR tegobuvir OR tecovirimat OR tebrofen OR taribavirin OR synguanol OR synadenol s OR streptovirudin OR OR Streptovaricin streptovaricin OR sovaprevir "scopadulcic acid B" OR setrobuvir OR sevirumab OR simeprevir OR sofosbuvir OR sorivudine OR OR derivative" "sangivamycin OR sangivamycin OR samatasvir OR rupintrivir OR rociclovir riodox OR rintatolimod OR rimantadine OR OR rifabutin derivative" OR "ribavirin OR ribavirin OR rafivirumab "recombinantmolecule OR OR intercellular adhesion resiquimod regavirumab 1" OR I OR pirodavir OR pleconaril OR pocapavir OR "pokeweed antivirus protein" OR "PolyA triphosphate" OR peramivir OR "phosphonoacetic acid" OR "PhosphonoaceticAcid" OR pirazofurin OR p oseltamivir OR ombitasvir OR omaciclovir OR nivocasan OR netropsin OR netivudine OR nesbuvir OR C" "neominophagen OR neceprevir OR acid" "Myxovirus OR resistanceprotein" bromoacetyldistamycin"n A" OR narlaprevirOR methylcytidinemetisazone OR ORmiravirsen ORmoroxydi OR methisoprinol OR OR Methisazone merimepodib OR mericitabine OR lomibuvir OR litomeglovir OR libivirumab OR lexithromycin OR levovirin OR letermovir OR ledipasvir OR OR larifan iododeoxycytidine OR ipilimumab OR isatoribine OR "isis 13312" OR "isis 13312" OR "isis OR isatoribine ipilimumab OR iododeoxycytidine OR Pranobex" "Inosine OR imiquimod OR imexon OR 184" "idx OR derivative" "idoxuridine "gs 9256" OR "guanine 7oxide" OR hypericin OR "hypoxanthine arabinoside" OR idoxuridine OR grazopre OR modulator" expression "gene OR ganciclovir OR venin" "gamma OR fucoidin OR "flucytosine OR fomivirsen arabinoside" foravirumab OR OR fosarilatefoscarnetfosdevirine OR OR felvizu OR favipiravir OR famciclovir OR OR faldaprevir OR exbivirumab eudistomin OR OR epetirimod enviroxime "distamycinA" OR Ditiocarb OR droxinavir OR edoxudineOR elbasvir OR "enisamiumiodide" OR "didemnin OR B" Dideoxyadenosine O OR A" OR "didemnin detiviciclovir OR desciclovir OR OR deoxyribavirin deoxypenciclovir deitiphorin OR deleobuvir OR denotivir OR deoxyaristeromycinOR Deoxyglucose OR "cyclosporinA" OR cytarabine OR da cidofovir OR ciluprevir OR clevudinecrofelemer 10101" OR "cpg OR cyclaradine OR Bromodeoxyuridine OR bropirimine OR buciclovir OR OR OR carbodine OR carbocyclic carrageenan OR benzimidavir brincidofovir OR A" OR besifovir OR boceprevir "Brefeldin OR OR bonaphthone OR OR avarone7295" balapiravir avridine OR OR OR OR bavituximab "azd OR alcohol" "behenyl Aphidicolin arasangivamycin OR OR OR astodrimer arildone arbidol OR OR OR avarol asunaprevir AntiRetroviral* OR "Anti OR AntiRetroviral* OR agent" ORviral "anti 975" "ana OR OR amsacrine tellurate" o o dioxyethylene trichloro "ammonium OR amitivir OR amidapsone OR amenamevir OR amantadine OR sudotox" "alvircept "adenosine OR OR dialdehyde" alamifovir afovirsen 721" "al OR alisporivir OR "al OR AcetylcysteineOR aciclovir OR "acyclouridineAcyclovir OR derivative" OR xyloside" OR "adenine "hepatitis type B") type "hepatitis TITLE TITLE -

Accepted pse OR OR pritelivir C" Article

- - ABS ABS - - KEY("1 KEY("hepatitis B" or "serum hepatitis" or "hippie hepatitis" or "injection hepatitis" or or hepatitis" or "injection hepatitis" or "hippie hepatitis" or "serum B" KEY("hepatitis This article isprotected by copyright. All rights reserved.

endavir OR vedroprevir ORendavir vidarabine Vidarabineviracine OR "viral OR OR - mab OR fiacitabine OR fialuridine OR filibuvir OR Filipin OR florenal OR florenal OR Filipin OR filibuvir OR fialuridine OR fiacitabine mab OR Deoxynojirimycin" OR absouline"abt OR 333" OR "abt 450" OR udohypericin OR "pyran copolymer" OR udohypericin OR OR copolymer" "Pyran "pyran radavirsen Copolymer" - Retroviral*" OR antiretrovirus OR antivir OR OR antiretrovirus Retroviral*" Hepatology Hepatology clatasvir OR OR damavaricin OR dasabuvir danoprevir OR R Dideoxynucleoside* OR disoxaril OR "distamycin OR 5" Scopus

alivizumab OR penciclovir OR "penciclovir OR "penciclovir OR penciclovir alivizumab ne ORmotavizumab OR "mycophenolic al* OR "anti OR al* uramin OR suvizumab OR OR suvizumab OR uramin

14803" OR laninamivir laninamivir OR 14803" - viral*" OR OR viral*" n rsv 01" OR OR 01" n rsv - U" OR "Poly U" vir OR OR vir ol OR OR ol Page 38of43 Page 39of43

9 8 7 10 6 5 4 3

OR PMID(7*) OR PMID(8*) OR PMID(9*) PMID(0*) OR PMID(1*) PMID(2*) OR OR PMID(3*) PMID(4*) OR OR PMID(5*) PMID(6*) OR 6 and not 7 DOCTYPE(sh) OR OR DOCTYPE(no) OR DOCTYPE(er) OR DOCTYPE(bk) OR DOCTYPE(ed) DOCTYPE(le) 8 and not 9 1 a W/2 analys*)W/2 ORcontrol study" "case OR " (correlation* study)OR W/2 OR (correlation* analysis" OR "trend survey" OR "trend study" "trend OR " analysis OR "feasibility study" OR "feasibility " analysis OR "theoretical study" "theoretical "replicat OR study" "replication OR analysis" "prevention OR survey" "prevention OR study" "prevention OR analysis" "panel OR survey" "panel OR study" "panel OR analysis" analysis" study" analysis" OR "quasiexperimental OR "quasiexperimental OR study" "quasiexperimental "validation OR analysis" "experimental OR study" "experimental"quasi Or analysis " experimental analysis") ratio"OR"odds "confidencemodel" OR OR interval" OR "change "regression "hazards analysis" referent study" OR comparison OR compeer "case study" OR "case study" OR study trial pilot OR OR OR "quantitative study" OR "quantitative study" OR "quantitative analysis" "twin OR survey" "twin OR study" "twin OR analysis" "evaluation OR survey" "evaluation OR study" OR "evaluation trial" OR "clinical study" OR "clinical studies" OR "case series" "observational survey" OR "observational analysis" OR "case study" OR study" "case OR analysis" "observational OR survey" "observational "disease frequency"disease OR survey*" crossover "cross OR analys*" OR "prevalenceOR survey*" "disease "follow "concurrent OR analysis" "incidence OR study" "incidence survey"OR OR analysis" "incidence OR survey" "concurrent OR study" "concurrent OR analysis" "population OR survey" "population "prospective survey" OR "prospective analysis" OR prospectiv*OR "population study" OR "retrospective OR study" "retrospective OR longitudinal* OR analysis" "longitudinal OR survey" "longitudinal "cross study) OR (intervention* W/2 trial) OR "cross trial) W/2 (intervention* study) OR W/2 study" OR "comparative survey" OR (intervention* OR "comparative analysis" compa r* OR ORmask*) OR random* placebo multivariate "latin OR square" OR control*OR "comparative OR W/1 OR (trebl* blind*) W/1 OR (trebl* mask*) W/1 (tripl* OR blind*) W/1 OR mask*) (tripl* W/1 (guideline*) OR (doubl* W/1 blind*) OR (doubl*mask*) W/1 OR (singl* W/1 blind*) (s OR TITLE OR peginterferone* OR peginterferonogen* OR peginterf OR peginterferonogen* OR peginterferone* OR peginterferon* OR leif OR 6" OR "interleukin 29" OR "interleukin 28A" "interleukin OR interferron* TITLE z OR Zanamivir OR zanamivir OR acid" "xenazoic OR xanthogenate OR virustatic* OR repressor*" TITLE inviroxime)

Acceptednd 2and 3and 4and 5 Article - sectional survey*" OR "cross OR survey*" sectional - - -

- ABS ABS ABS up study" OR "follow OR study" up OR "field study" OR "field survey" OR "field analysis" OR "in vivo study" OR "in vivo vivo "in OR study" vivo "in OR analysis" "field OR survey" "field OR study" "field OR

- - -

KEY((evidence W/1 based) OR based) (metaW/1 analys*)KEY((evidence OR W/1 review*) (systematic* W/3 OR KEY(pregnan* gestation* or or "child bearing" or childbearing) KEY("cl 884" OR cl884 OR ifn OR interferon* OR interferone* OR interferonogen* OR survey" OR OR analysis" "retrospective retrospectiv* OR study" "prospective OR

- up survey" OR "follow OR survey" up - sectional design*" OR "prevalencesectional OR OR design*" study" "prevalence Hepatology Hepatology

analys*" OR "validation study" OR "validation survey" OR OR survey" "validation OR study" "validation OR analys*" caseOR referrent base study" "case OR study"

- - "cross OR study" sectional frequency study" OR "disease frequency analys*" OR OR analys*" frequency "disease OR study" frequency - - over" OR cohort* OR "longitudinal study" OR OR study" "longitudinal OR cohort* OR over" up analysis" OR "observational study" OR erron*)

"case series" OR"case "clinical sectional OR analys*"

ion analysis " OR OR " analysis ion ingl* ingl* 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 Supplemental Any antiviral vs Telb Lamivudine vs Intervention control ivu None none dine

vs vs

Table

AcceptedCongenital malformation rate ArticleCongenital malformation rate Infant HBsAg seropositivity Infant HBsAg seropositivity Infant HBsAg seropositivity Infant HBsAg seropositivity Infant HBsAg seropositivity Infant HBsAg seropositivity Infant DNA HBV positivity Infant DNA HBV positivity DNAInfant HBV positivity Infant DNA HBV positivity

2: Quality ofevidence summary: Infant HBV DNA HBV Infant Prematurity rate Prematurity rate Prematurity rate APGAR score APGAR score APGAR seropositivity (Follow up) (Follow Outcome (6 (6 (6 (6 (6 (6 (6 (6 (6 (6 (6 12 m) -12 m) -12 m) -12 12 m) -12 - 12 m) -12 m) -12 m) -12 12 m) -12 12 m) -12 12 m) -12 12 m) 12 This article isprotected by copyright. All rights reserved.

(1 observational study) No. Infant outcomes: (5 observational (4 observational (1 observational (9 observational (3 observational (2 observational (3 observational (2 observational (2 observational (5 observational (1observational (Study design) (Study Hepatology Hepatology

6 6 6 6 6 6 6 of participants ------(8 RCTs)(8 (5 RCTs)(5 (2 RCTs)(2 RCTs)(4 RCTs)(3 RCTs)(5 12 months 12 months 12 months 12 months 12 months 12 months 12 months studies) studies) studies) studies) studies) studies) studies) studies) studies) studies) studies) 1154 1190 737 444 812 496 220 815 174 309 293 514 493 289 322 662 90 90

Quality ofQuality the MODERATE MODERATE MODERATE VERY LOW VERY LOW VERY VERY LOW VERY LOW VERY VERY LOW VERY LOW VERY VERY LOW VERY LOW VERY VERY LOW VERY LOW VERY LOW VERY LOW VERY ⨁ ⨁ ⨁ ⨁ ⨁⨁ ⨁⨁ ⨁⨁ (GRADE) ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁⨁⨁ ⨁⨁⨁ ⨁⨁⨁ ⨁ ⨁ evidence ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ LOW LOW LOW ◯◯◯ ◯◯◯ ◯◯ ◯◯ ◯◯ ◯ ◯ ◯

13 13 13 14 13 13 13 1 1 1 4 1 4 4 1 1

Means differences differences Means Means difference difference Means ( Relative effect Relative ( - (0.03 to 0.55) (0.21 to 0.56) (0.35 to 1.65) (0.01 to 6.76) (0.15 to 0.56) (0.16 to 0.44) (0.10 to 0.52) (0.20 to 0.49) (0.21 to 3.62) (0.17 to 0.84) (0.17 to 0.84) (0.35 (0.12 to 0.38) (0.01 to 0.49) (0.03 to - (0.09 to 7.4) 0.048to 0.03) 0.75 to 0.47) (95% CI) RR 0.29 RR 0.26 RR 0.23 RR 0.31 RR 0.88 RR 0.38 RR 0.38 RR 0.73 RR 0.21 RR 0.06 RR 0.12 RR 0.13 RR 0.34 RR 0.76 RR 0.84 RR 0.28 -0.009 0.012

to 1.53) to 0.45)

Page 40of43 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 41of43 Telb Lamivudine vs Telb Tenofovir vs Tenofovir vs Lamivudine lamivudine control control control ivu ivu dine dine

vs vs vs vs

rate kinase Creatinine Elevated

Accepted ArticleCongenital malformation rate Congenital malformation rate Postpartum hemorrhage rate Postpartum hemorrhage rate Infant HBsAg seropositivity Infant Infant HBsAg seropositivity

(4 (28 weeks postpartum) (4 weeks postpartum) rate section Cesarean rate section Cesarean

Maternal HBV DNA HBV Maternal DNA HBV Maternal Maternal HBN DNA HBN Maternal DNA HBN Maternal Maternal HBN DNA HBN Maternal -8 weeks postpartum) ALT normalization ALT normalization Prematurity rate Prematurity rate Prematurity rate HBsAg seropositivity (at delivery) (at (at delivery) (at delivery) (at (at delivery) (at Suppression Suppression Suppression suppression suppression (at birth) (at birth) (6 - 12 m) 12 This article isprotected by copyright. All rights reserved.

(1 observational study) (1 observational study) (1 observational study) (1 observational study) (1 (2 observational study) (1 observational study) (1 observational study) (1 observational study) Maternal Outcomes: Maternal

observational study) (2 observational (2 observational (2 observational (2 observational (3 observational (3 observational (3 observational (2 observational (2 observational Hepatology Hepatology studies) studies) (1 RCT)(1 RCT)(1 studies) studies) studies) studies) studies) studies) 111 111 387 684 122 219 581 185 161 685 537 185 514 115 514 115 349 87 78 88

VERY LOW VERY LOW VERY LOW VERY VERY LOW VERY VERY LOW VERY VERY LOW VERY VERY LOW VERY VERY LOW VERY LOW VERY VERY LOW VERY VERY LOW VERY LOW VERY LOW VERY LOW VERY VERY LOW VERY ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁⨁ ⨁⨁ ⨁ ⨁⨁ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ LOW ◯◯◯ LOW LOW ◯◯ ◯◯ ◯◯ LOW

134 14 14 14 34 34 34 34 34 3 14 14 4 4 4 4 4 4

3 4

(10.66to 261.82) (8.53 to 589.96) (3.54 to 921.41) (2.65 to 664.73) (14.4 to 722.83) (0.12 to 70.08) (0.05 to 25.21) (0.12 to 72.03) (0.65 to 1.48) (0.03 to 2.84) (0.55 to 7.21) (0.07 to 0.70) (0.01 to 28.8) (0.89 to 1.31) (0.78 to 1.26) (0.74 to 2.31) (0.04 to 4.9) (0.71 to 1.3) (0.7to 1.31) 102.94 RR RR 70.93 RR 52.83 RR 57.14 RR 2.93 RR 0.22 RR 0.46 RR 1.89 RR 1.07 RR 0.98 RR 1.08 RR 0.99 RR 0.96 RR 0.96 RR 1.46 RR 0.3 RR 1.7 RR 1.3 RR 2.9 RR 42

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 Telb Tenof Lamivudine control ivu o dine vir vir

vs vs vs vs

rate kinase Creatinine Elevated rate kinase Creatinine Elevated Accepted Article

Postpartum hemorrhage Postpartum hemorrhage (28 weeks postpartum) (28 weeks postpartum) (28 weeks postpartum) Maternal HBeAg loss HBeAg Maternal loss HBeAg Maternal loss HBeAg Maternal (4 weeks postpartum) (4 weeks postpartum) (4 weeks postpartum)

rate section Cesarean rate section Cesarean Maternal HBV DNA HBV Maternal DNA HBV Maternal Maternal HBN DNA HBN Maternal ALT normalization ALT normalization ALT normalization Maternal HBeAg HBeAg Maternal HBeAg Maternal Maternal HBeAg Maternal (before delivery) (before seroconversion seroconversion seroconversion seroconversion (at delivery) (at ( delivery) (at delivery) (at (at delivery) (at Suppression suppression suppression at

(1 observational study) (1 observational study) (1 observational study) (1 observational study) (1 observational study) (1 observational study) (1 observational study) (1 observational study) (1 observational study) (1 observational study) (1 observational study) (2 observational study) (1 observational study) (2 observational (2 observational (2 observational Hepatology Hepatology 1(observational 2(observational studies) studies) studies) studies) studies) studies) 708 708 303 387 637 308 318 88 88 88 88 88 45 78 78 45 88

VERY LOW VERY VERY LOW VERY VERY LOW VERY LOW VERY LOW VERY LOW VERY LOW VERY LOW VERY VERY LOW VERY LOW VERY LOW VERY LOW VERY LOW VERY LOW VERY LOW VERY LOW VERY VERY LOW VERY VERY LOW VERY LOW VERY ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ⨁ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ 34 34 34 34 34 34 34 34 34 3 3 3 3 3 3 4 4 4 4

(0.33 to 119.97) (9.26 to 222.48) (0.69 to 236.44) (0.67 to 190.29) (0.31 to 27.58) (0.16 to 67.42) (0.15 to 79.47) (1.25 to 2.24) (0.94 to 1.45) (1.22 to 2.29) (1.24 to 2.15) (1.04 to 1.62) (1.28 to 2.61) (0.15 to 2.19) (0.41 to 7.21) (0.89 to 1.88) (0.64 to 1.25) (1.1to 2.31) (1.18 to 1.8) RR 12.78 RR 11.33 RR 1.67 RR 1.17 RR 6.33 RR 45.4 RR 1.24 RR 3.33 RR 1.67 RR RR 1.29 RR 1.59 RR 1.83 RR 3.41 RR 0.57 RR 1.72 RR 2.9 RR 1.3 RR 0.9

1.64

Page 42of43 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 43of Footnotes: Tenofovir vs Lamivudine 1. 2. 4. 3.

Increased risk of bias risk Increased Inconsistency Imprecision Indirectness

Accepted Article rate kinase Creatinine Elevated

Maternal HBeAg loss HBeAg Maternal (4 weeks postpartum)

rate section Cesarean rate section Cesarean Maternal HBeAg Maternal seroconversion (at (

(1 observational study) (1 observational study) (1 observational study) (1 observational study) (1 observational study) (1 observational study) Hepatology Hepatology 318 387 310 310 111

VERY LOW VERY LOW VERY VERY LOW VERY LOW VERY LOW VERY LOW VERY ⨁ ⨁ ⨁ ⨁ ⨁ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ ◯◯◯ 34 34 34 4 4

(0.03 to 15.21) (0.05 to 21.49) (0.36 to 1.62) (0.1to 34.96) (0.78 to 1.97) (0.86 to 1.3) RR 0.76 RR 1.05 RR 1.91 RR 0.63 RR 1.05