Comparable efficacy of tenofovir versus entecavir and predictors of response in treatment-naïve patients with chronic hepatitis B: A multicenter real-life study

Comparable

efficacy

of

tenofovir

versus

entecavir

and

predictors

of

response

in

treatment-naı¨ve

patients

with

chronic

hepatitis

B:

a

multicenter

real-life

study

§

Ayse

Batirel

*

,

Ertugrul

Guclu

,

Ferhat

Arslan

,

Funda

Kocak

,

Oguz

Karabay

,

Serdar

Ozer

_,

_Munevver

_Turanli

_,

_Ali

_Mert

a

InfectiousDiseasesandClinicalMicrobiology,KartalDr.LutfiKirdarEducationandResearchHospital,SemsiDenizerCd.E-5KarayoluCevizliMevkii, 34890Kartal,Istanbul,Turkey

b_{InfectiousDiseasesandClinicalMicrobiology,MedicalFaculty,SakaryaUniversity,Sakarya,Turkey} c_{InfectiousDiseases,MedicalFaculty,IstanbulMedipolUniversity,Istanbul,Turkey}

d

InfectiousDiseasesandClinicalMicrobiology,BasaksehirStateHospital,Istanbul,Turkey

e

Biostatistics,IstanbulCommerceUniversity,Istanbul,Turkey

1. Introduction

Chronic hepatitis B (CHB) is a significant health problem worldwidethatmaycauseseriouscomplicationssuchascirrhosis, liver failure, and/or hepatocellular carcinoma (HCC). Nearly 400millionpeopleareestimatedtobeinfectedchronicallywith hepatitis B virus (HBV). Five-year cumulative probabilities for

developinghepaticdecompensationandcirrhosisarereportedto be 20% and 8–20%, respectively.1 _{Turkey has an intermediate}

endemicityforCHB(approximately5%).

To date, sustained virological suppression to prevent HBV-relatedmortalityhasbeentheonlyachievablegoalinthetherapy of CHB, since rates of hepatitis B surface antigen (HBsAg) seroclearance(i.e.,‘completecure’)remainverylow.2,3

Twocategoriesoftherapeuticagentsarecurrentlyavailablefor thetreatmentofCHB:(1)immunomodulatoryagents (interferon-alpha andpegylatedinterferon-alpha),and(2) oralnucleos(t)ide analogues(NAs)(lamivudine,adefovir,telbivudine,entecavir,and tenofovir).Theresponseratetointerferonsremainslow,particularly

ARTICLE INFO Articlehistory: Received7April2014

Receivedinrevisedform5August2014 Accepted15September2014 CorrespondingEditor:LarryLutwick, Kalamazoo,Michigan,USA

Keywords: Entecavir Tenofovir ChronichepatitisB HBV Treatment SUMMARY

Objective:Tocompareresponsestotenofovir(TDF)andentecavir(ETV)therapy.

Methods:Thiswasamulticenterretrospectivestudyincludingtreatment-naı¨vepatientswithchronic

hepatitisB(CHB)whoreceivedTDForETV.Theprimaryend-pointswereundetectableHBV-DNAat

48weeksandserologicalandbiochemicalresponses.

Results:Outof195CHBpatients,90(46%)receivedTDFand105(54%)receivedETV;72%weremale,

theirmeanagewas4312years,andthemeandurationoftreatmentwas30.215.7months.HepatitisB

eantigen(HBeAg)seropositivitywas32%intheTDFgroupand34%intheETVgroup.HBeAgseroconversion

ratesinHBeAg-positivepatientswere24%intheTDFgroupand39%intheETVgroup;thedifferencewasnot

significant(p=0.2). Themeantimetoalanine aminotransferase(ALT) normalizationand rates ofALT

normalizationat3,6,12,18,and24monthsweresimilarinthetwogroups(p>0.05).Themeantimeto

undetectable HBV-DNA levels in the TDF and ETV groups was 11.58.9 and 12.910.8 months,

respectively(p=0.32).AsignificantlygreaterdeclineinHBV-DNAlevelsat12and18monthswasobserved

intheTDFgroup(p=0.02andp=0.03,respectively).Seven(7%)patientsonETVtherapyhadvirological

breakthrough(p=0.01).OnlyonepatientineachgrouphadhepatitisBsurfaceantigen(HBsAg)clearance.

Noneofthepatientsdevelopeddecompensationorhepatocellularcarcinomaduringtreatment.

Conclusions: ThetwodrugsappeartohavesimilarefficacyinCHBpatients.However,7%ofpatientson

ETVtherapyhadvirologicalbreakthrough,whilenoneofthepatientsonTDFtherapydid.

ß2014TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.

ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(

http://creativecommons.org/licenses/by-nc-nd/3.0/).

§

Thisstudywaspresentedasane-posteratAPASL2014,Brisbane,Australia. * Correspondingauthor.Tel.:+902164413900ext.1951;fax:+902163520083.

E-mailaddress:aysebatirel@yahoo.com(A.Batirel).

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

j o urn a l hom e pa ge : ww w. e l s e v i e r. c om/ l o ca t e / i j i d

http://dx.doi.org/10.1016/j.ijid.2014.09.004

1201-9712/ß2014TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/3.0/).

for HBV genotype D, which is the most prevalent genotype in Turkey.4,5 Furthermore, interferon tolerability is poor due to significantadverse effects.6 _{The mechanismof action of NAs is}

theinhibitionofHBV-DNApolymeraseactivityandthereforethe suppressionofHBVreplication.Ratesofresistancetolamivudine andadefovirhavebeenreportedtobe65–70%and18–29%after4–5 yearsoftreatment.7,8_{Telbivudinecausedaresistancerateof5–25%}

inhepatitisBeantigen(HBeAg)-positivepatientsand2.3–11%in HBeAg-negativepatients.9

Entecavir (ETV; approved in 2005) and tenofovir disoproxil fumarate(TDF;approvedin2008)areNAswithhighpotencyfor profound and durable viral suppression and genetic barriers againstresistance;thesedrugsarerecommendedforthefirst-line treatmentofCHBincurrentguidelines.1,10–12_{Thelong-termuseof}

theseagentshasresultedinnoorverylowresistancetodate.13,14 Althoughtheefficacyofeachhasbeenassessedinvarious large-scalestudies,real-lifedataonthecomparativelong-termefficacy ofthesedrugs arevery limited inthe literature.Moreover, the numbers of eligible patients included in the few previously publishedstudiesdirectly comparing the two drugs havebeen quitesmall(patientsonTDFandETVtherapy,respectively:Ceylan etal.,15_{66and 51 patients;Doganet al.,}16_{65and 29patients;}

Guzelbulutetal.,17_20and24).

Theaimofthisretrospectivestudyofreal-lifepracticewasto comparethecumulativevirological,serological,andbiochemical responsestoTDFandETVinalargegroupofHBeAg-positiveand negativetreatment-naı¨ve patientswithahighviralload,overthe long-term.

2. Materialsandmethods 2.1. Studydesignanddatacollection

In thisretrospectivereal-lifestudyconductedatfourcentres (twouniversities,onetertiaryeducationandresearchcentre,and onestatehospitalinTurkey),treatment-naı¨ve CHBpatientswitha highviralload(>2106_{IU/ml),whoreceivedTDF(245mg/day)} or ETV (0.5mg/day) in a compliant manner between January 2008andOctober 2013,wereincluded.Theprimaryend-points wereundetectableserumHBV-DNAlevelsat48weeks(virological response) and serological (HBeAg seroclearance/conversion in HBeAg-positivecases)andbiochemical(alanineaminotransferase (ALT) normalization) responses; secondary end-points were persistenceofdetectableHBV-DNAandvirologicalbreakthrough. Inclusioncriteriawerethefollowing:(1)HBsAgseropositivity. (2) Pre-treatment liver biopsy consistent with CHB. (3) Pre-treatmentserumHBV-DNAlevels>2106IU/mlinboth HBeAg-positiveandHBeAg-negativepatients.(TheprescriptionofETVand TDF is restricted to these patients alone by the National Reimbursement Policy regulated by the Ministry of Health in Turkey.)(4) Positiveor negativeserologyfor HBeAg.(5) Serum HBV-DNAlevelsmeasuredat3–6-monthintervalsbyPCR.(6)No priorhistoryofreceivinganytreatmentforCHB.(7)ETV(0.5mg/ day)orTDF(245mg/day;theformavailableinTurkey)therapyfor atleast1year.

Exclusion criteria were the following: Previous use of oral antiviralsorinterferon-alphaforCHBtreatment;co-infectionwith hepatitis D virus (HDV), hepatitis C virus(HCV), or HIV; non-adherencetotreatment;cirrhosis;hepaticdecompensation;HCC oranyothermalignancy;autoimmunehepatitis;illicitdruguse; solidorgantransplantation;pregnancy;age<18years.

All of the patients were followed-up periodically, and CHB serology,biochemistry,andvirologywereinvestigatedevery3to 6months.Compliancewiththerapywasquestioned.Thefollowing datawerecollectedfromthepatientrecordsandtransferredtoan Excelfile:age,gender,Ishakscoresforpre-treatmentliverbiopsy

samples(histologicalactivityindex(HAI)andfibrosis),18_HBsAg,

HBeAg,andhepatitisBeantibody(anti-HBe)status,serumALT, aspartate aminotransferase (AST), and HBV-DNA levels before treatmentandatmonths3,6,12,18,and24oftreatment,timeto ALT normalization, undetectable HBV-DNA levels, and HBeAg seroconversion(in HBeAg-positivecases), and total duration of follow-up on therapy. The data obtained were analysed and compared for virological (undetectable HBV-DNA levels), bio-chemical(ALTnormalization),andserological(HBeAg seroconver-sioninHBeAg-positivepatients,HBsAgseroconversion)responses totreatmentwiththetwoantiviralagents.Declinesinserum HBV-DNAlevelsfrombaselinetoweeks12,24,and48werecompared forthetwogroupsofpatientstoevaluatetreatmentefficacy.For HCCscreening,allpatientsunderwentabdominalultrasonography every6months.

2.2. Definitions

Acompletevirologicalresponsewasdefinedascompleteviral suppression,shownbyserumHBV-DNAlevels<20IU/ml(<100 copies/ml)atweek48.1_{Apartialvirologicalresponsewasdefined}

as a decrease in HBV-DNA of more than 1 log10 IU/ml but detectable serum HBV-DNA levels by PCR at 12 months of therapy in compliant patients.1 _{Virological breakthrough was}

definedasa>1log10IU/mlincreaseinserumHBV-DNAlevelsfrom nadirontwoconsecutivemeasurements.1

Serological response was defined as HBeAg seroconversion (HBeAglossandanti-HBedevelopment)inHBeAg-positivecases.1 BiochemicalresponsewasdefinedasALTnormalization(declinein ALTlevelstolessthantheupperlimitofnormal)inpatientswith pre-treatmentelevatedALTlevels.1

Patientswereconsideredcompliantwiththerapyiftheytook theirdrugsoncedaily,regularly,withoutaninterruption.

With regard to adverse effects, any symptom or sign, or abnormal clinical or laboratory finding that resolved after discontinuationofthedrugwasconsideredadrug-relatedadverse effect.Anincreaseinserumcreatininelevelexceedingtheupper limitofnormalwasconsideredadrug-relatedrenaladverseeffect. 2.3. Virologicaltests

HBsAg, HBeAg, and anti-HBe were tested with an ELISA (ArchitectSystem;AbbottLaboratories,North Chicago,IL,USA). LevelsofserumHBV-DNAweretestedwithaPCRassay(TaqMan HBV Assay; Roche Diagnostics); the lower limit of HBV-DNA quantificationwas20IU/ml.

2.4. Ethicalapproval

This study was approved by the local ethics committee (Institutional Review Board of Istanbul Medipol University, Turkey).

2.5. Statisticalanalyses

SPSS17.0software(SPSSInc.,Chicago,IL,USA)wasusedforall statistical analyses. Categorical variables were defined as the proportion(%)andwerecomparedbyChi-squaretestorFisher’s exacttest.Continuous variablesweredefined as the mean standarddeviation(SD)ormedian(range)andweretestedwiththe Studentt-testorMann–WhitneyU-test,asappropriate.Afterthe ratesofperiodic(3–6-monthintervals)logdeclineinserum HBV-DNA levels of patients in the two groups were calculated, an independent samples t-test was used to test the difference. Cumulative rates of complete viral suppression were analysed byKaplan–Meier method and were comparedby log ranktest.

UnivariateandmultivariateCoxproportionalhazardsregression analysiswasusedtoidentifythevariables/factorsdeterminingthe virological response. A p-value of <0.05 was considered to be statisticallysignificant.

3. Results

Thedataofatotal210patientswithCHBwhowereprescribed eitherTDForETVwererecorded.Amongthesepatients,195(72% male,mean age4312years)were eligible forinclusioninthe study.Theywere followed-upfora meanduration of30.215.7 (range 12–72)months.Ninety(46%) patientsreceived TDF(mean treatment duration 27.215.4 months) and 105 (54%) patients receivedETV(meantreatmentduration33.015.4months).

Twenty-nine (32%) patients in the TDF group and 36 (34%) patientsintheETVgroupwereHBeAg-positive.Patientsinthetwo treatmentgroupsweresimilarin termsofbaselineparameters: age (p=0.65), gender (p=0.06), ratios of HBeAg positivity (p=0.76), pre-treatment mean ALT (p=0.55), and serum HBV-DNAlevels(p=0.42)(Table1).

Apre-treatmentliverbiopsywasperformedin92%ofpatients prescribedTDFand90%ofpatientsprescribedETV.Pre-treatment liverbiopsyscoresdifferedbetweenthetwogroups(HAI,p=0.01; fibrosis,p=0.03);meanHAIscoreswere7.62.7and8.62.8and meanfibrosisscoreswere2.51.4and2.31.0fortheTDFandETV groups,respectively.

HBeAgclearance(24%inTDFvs.44%inETV)and seroconver-sionrates(24%inTDFvs.39%inETV)inHBeAg-positivepatientsin thetwo groups didnotdiffer significantly (p=0.1 and p=0.2), althoughtherates wererelativelyhigherintheETVgroup.The meantimetoachieveundetectableserumHBV-DNAlevelsinthe TDFgroupwas11.58.9months,whileitwas12.910.8months intheETVgroup;thedifferencewasnotsignificant(p=0.32).

ThemeantimetoALTnormalization(p=0.1)andratesofALT normalizationat3,6,12,18,and24monthsweresimilarinthetwo groups(Table2).

Whenthedeclinefrompre-treatmentserumHBV-DNAlevelsat months 3, 6, 12, 18, and 24 were compared, there was no statisticallysignificantdifferencebetweentheTDFandETVgroups

atmonths6,12,18,and24(p>0.05).However, TDFinduceda significantlygreaterreductioninserumHBV-DNAlevelsatmonth 3(p=0.047).Asmostofthepatients(80%)achievedavirological responseby 24monthsof antiviraltherapy,wedidnot further comparelogdeclinesthereafter.

When the rates of cumulative complete viral suppression (undetectableserumHBV-DNAlevels)atmonths3,6,12,18,and 24 werecompared between thetwo groups, theywere signifi-cantlyhigheratmonth12 (p=0.02)andmonth18(p=0.03)in patients on TDF therapy (at months12 and 18, TDF induceda significantlyincreasedrateofundetectableserumHBV-DNAlevels comparedtoETV;p=0.02andp=0.03,respectively)(Figure1).

Seven (7%) patients who were on ETV therapy developed virologicalbreakthrough,butnoneofthepatientsintheTDFgroup did(p=0.01).Thesesevenpatientsclaimedthattheyhadadhered totherapywell,butaresistanceanalysiscouldnotbeperformedat thattime.TheywereswitchedtoTDFtherapy.ThechangesinALT and HBV-DNA levels over time in the seven patients with virologicalbreakthroughareshowninTables3and4,respectively. OnlyonepatientineachgrouphadHBsAgclearance.Noneof thepatientsinanygroupdevelopedhepaticdecompensationor HCC during the entire treatment period. On Cox regression analysis, none of the baseline parameters was found to be a significantpredictorofthevirologicalresponse(Table5). Cumu-lativerates ofvirological,biochemical, andserological response (HBeAg loss and seroconversion) over time are illustrated in

Figures2–4.

Noseriousadverseeffectssuchaslacticacidosis,severeliver problems,orincreaseinserumcreatininelevelswereseeninanyof thepatientsineithertreatmentgroup.Noadverseeffectsleading todiscontinuationoftherapyoccurredduringthewholetreatment period. Two patients on ETV therapy experienced nausea and abdominaldiscomfort.Onepatientreceiving ETVcomplainedof fatigue and dizziness that disappeared aftera few days. Three patientsreceivingTDFexperiencednausea,oneofthemalsohad diarrhoeathatresolvedwithsymptomatictherapy.Twopatients onTDFtherapydevelopedhypophosphatemia(serumphosphate level <2.5mg/dl), but they had no related symptoms such as fatigueormuscleweakness.TwopatientsreceivingETVtherapy

Table1

Comparisonofbaselinedemographicvariables,laboratoryandhistologicalparameters,andtreatmentresponsesofpatientswhoreceivedeither tenofovir(TDF)orentecavir(ETV)therapya

Characteristics TDF(n=90) ETV(n=105) p-Value

Age,years 43.312.9 42.011.2 0.7

Gender,male 59.0 82.0(78.1%) 0.06

Treatmentduration,months 27.215.4 33.015.4 0.01

HBeAgpositivity 29.0(32.2%) 36.0(34.3%) 0.8

Pre-treatmentHBV-DNA,103_{IU/ml 191613}

198.6 220199101.3 0.4

Pre-treatmentALT,IU/l 116.792.6 120.096.6 0.6

ElevatedALTbeforetherapy 80.0(89.0%) 94.0(90.0%) 0.9

Liverbiopsydone 83.0(92.0%) 94.0(90.0%) 0.8

BaselineHAI(Ishak) 7.62.7 8.62.8 0.01

Baselinefibrosis(Ishak) 2.51.4 2.31.0 0.03

HBeAgloss 7.0(24.0%) 16.0(44.0%) 0.1

HBeAgseroconversion 7.0(24.0%) 14.0(39.0%) 0.2

TimetoHBeAgseroconversion,months 12.35.6 12.35.8 0.9

ALTnormalization 88.0(97.8%) 104.0(99.0%) 0.1

TimetoALTnormalization,months 5.13.6 6.35.3 0.08

UndetectableHBV-DNA 77.0(85.6%) 90.0(85.7%) 0.9

TimetoundetectableHBV-DNA,months 11.58.9 12.910.8 0.3

Virologicalbreakthrough 0 7.0(6.7%) 0.01

HBsAgseroclearance 1.0(1.1%) 1.0(0.95%)

HCCdevelopment 0 0

Decompensation 0 0

HBeAg,hepatitisBeantigen;HBV,hepatitisBvirus;ALT,alanineaminotransferase;HAI,histologicalactivityindex;HBsAg,hepatitisBsurface antigen;HCC,hepatocellularcarcinoma.

a

decidedtodiscontinuetherapy aftera virologicalresponse had beenobtained(oneofthemattheendof2years,theotheratthe end of 30 months). One female patient in the TDF group discontinuedtherapyfor aperiodof 13monthsassheplanned apregnancyandconceivedababy.Nohepaticflarewasobserved duringtheoff-treatmentperiod.

4. Discussion

TheriskofdevelopingcirrhosisandHCCisdirectlyproportional totheviralloadinpatientswithCHB.2,3_{Sustainedsuppressionof}

serumHBV-DNAlevelsisoneofthetherapeuticgoalsinpatients with CHB and prevents the progression of liver disease and developmentofcomplications.19,20_{Thedevelopmentofresistance}

isasignificantproblemwithlamivudine,adefovir,andtelbivudine therapies.7–9 _{ETVand TDF arehighlypotentand safeNAswith}

geneticbarrierstoresistance,andthesedrugsarerecommendedin thefirst-line treatment of CHB in current guidelines.1,11 _{In the}

presentstudy, thetwo drugsinducedsimilar virological(mean time to achieve undetectable HBV-DNA levels and rates of achieving no HBV-DNA by PCR in serum), biochemical (mean timetoALTnormalizationandratesofALTnormalizationat3,6, 12, 18, and 24 months), and serological (HBeAg clearance and seroconversionratesin HBeAg-positivepatients, ratesofHBsAg clearance in the two groups) responses in patients with CHB. Cumulativecompleteviralsuppressionwassignificantlyhigherat months12and18inpatientsonTDFtherapy,butnotdifferentat othertimeintervalsduringtreatmentwitheitherdrug.While7%of thepatientsonETVtherapyhadvirologicalbreakthrough,noneof thepatientsonTDFtherapydid.

InBayesianmixedcomparisonsforthemeta-analysisofrelative efficaciesofCHB treatmentsconductedby Wooetal.,TDF was reported to be the most effective at inducing virological, biochemical,andserologicalresponsesinHBeAg-positivepatients; ETVrankedsecond.InHBeAg-negativepatients,TDFwasthemost

3 mo 6 mo 12 mo 18 mo 24 mo TDF 5.6 23.6 74.7 82.8 86.5 ETV 1.9 18.1 58.4 67.4 74.6 0 10 20 30 40 50 60 70 80 90 100 Rate of cumulave virological response (%) 0.0000 1.0000 2.0000 3.0000 4.0000 5.0000 6.0000 7.0000 0 mo 3 mo 6 mo 12 mo 18 mo 24 mo

HBV DNA log10 (IU/ml)

HBV DNA

decline

over

me

A

B

TDF ETV

Figure1.(a)CumulativeratesofvirologicalresponseovertimeinpatientswithchronichepatitisBwhoreceivedtenofovir(TDF)orentecavir(ETV).Forthecomparisonsofthe virologicalresponseat3,6,12,18,and24months,thep-valuesare0.047,0.68,0.53,0.57,and0.67,respectively.(b)DeclineinserumHBV-DNAlevelsovertime(3–24 months)inpatientswithchronichepatitisBwhoreceivedtenofovir(TDF)orentecavir(ETV).ForthecomparisonsofHBV-DNAdeclineat3,6,12,18,and24months,the p-valuesare0.07,0.65,0.43,0.58,and0.73,respectively.

Table2

ComparisonofthecumulativevirologicalresponsesandALTnormalizationat3,6, 12,18,and24monthsinpatientswithchronichepatitisBwhowereprescribed eithertenofovir(TDF)orentecavir(ETV)

TDF(n=90), n(%) ETV(n=105), n(%) Total p-Value 3months ALTnormalization 36(40.0) 29(27.6) 65(33.3) 0.07 UndetectableHBV-DNA 5(5.6) 2(1.9) 7(3.6) 0.2 6months ALTnormalization 64(71.1) 80(76.2) 144(73.8) 0.4 UndetectableHBV-DNA 21(23.6) 19(18.1) 40(20.6) 0.4 12months ALTnormalization 78(97.5) 93(93.9) 171(95.5) 0.3 UndetectableHBV-DNA 62(74.7) 59(58.4) 121(65.8) 0.02 18months ALTnormalization 61(98.4) 85(96.6) 146(97.3) 0.5 UndetectableHBV-DNA 53(82.8) 60(67.4) 113(73.9) 0.03 24months ALTnormalization 49(98.0) 69(98.6) 118(98.3) 0.8 UndetectableHBV-DNA 45(86.5) 53(74.6) 98(79.7) 0.1 ALT,alanineaminotransferase;HBV,hepatitisBvirus.

Table3

ThecourseofALTlevelsinsevenpatientsonentecavirtherapywithvirologicalbreakthrougha Patient Baseline ALT,IU/l ALT normalization, month Virological breakthrough, month ALT,IU/l

3months 6months 9months 12months 18months 24months 30months 36months

1 92 12 18b 85 60 57 32 67b 45 42 2 120 6 24b 67 48 38 NA 26 96b 40 3 69 6 24b 62 33 36 28 38 66b 37 4 89 8 36b _{NA 54 42 40 NA 39 42 87}b 5 64 6 18b _{54 43 46 42 79}b _{37 38 29} 6 108 3 18b 47 37 34 38 64b 31 7 140 6 18b 82 41 NA 42 85b 35 33 37

ALT,alanineaminotransferase;NA,notavailable.

a

ALTnormalrange:0–50IU/l.

b

effective antiviral agentat inducing a virological response and rankedsecondforbiochemical response.21_{Dakinetal.reported}

thatTDF wassignificantlysuperiortoETVregardingvirological response,butcomparabletoETVregardingHBeAgseroconversion after1yearoftherapy.22_{Bothdrugswerereportedtobeeffective}

andwelltoleratedincompensatedanddecompensatedcirrhotic patients.23

In our study, HBeAg clearance and seroconversion rates in HBeAg-positivepatientswererelativelyhigherintheETVgroup,

butdidnotdiffersignificantlyfromtheTDFgroup.Myungetal. reportedthecumulativeratesofHBeAglossat12to72weeksof ETV therapy as 10.6% to 34.5%; and 3.5% to 13.2% for HBeAg seroconversion.24_{TDFtherapy resultedinHBeAg lossin24% of}

patientsinanotherstudy.25InthestudybyCeylanetal.,HBeAg statusdidnotpredictthevirologicalresponserate,similartothe findingofourstudy.15_{Changetal.reportedalowerrateofHBeAg}

seroconversionatyear5.26HBeAgseroconversionoccurredinonly oneof29patientsintheETVgroup,butnoneof65patientsinthe TDFgroupinanotherstudy.16

The mean time to ALT normalization and rates of ALT normalizationat3,6,12,18,and24monthsweresimilarinthe twogroupsinthepresentstudy.Guzelbulutetal.reportedthata similarproportionofpatientsachievedALTnormalizationonETV orTDFtherapy.17_{Changetal.reportedthatALTnormalizationin}

patientsonETVtherapywas80%atyear5.26_{Cumulativeratesfor}

biochemicalresponseat12,24,48,and72weeksoftherapywith ETV were reported to be 40.0%, 66.2%, 84.5%, and 92.7%, respectively.24

ThemeantimetoachieveundetectableHBV-DNAlevelsand ratesofachievingnegativeHBV-DNAlevelsbyPCRinserumin bothgroupswerenotsignificantlydifferent.Thisisconsistent withtheresultsofthestudiesconductedbyGuzelbulutetal.17

and Dogan et al.16 Chang et al. reported that the rate of undetectable serum HBV-DNA levels at year 5 was 94% in ETV-treatedpatients.26

Table4

Thecourseofviremiainsevenpatientsonentecavirtherapywithvirologicalbreakthrough Patient Baseline HBV-DNA, IU/ml Undetectable HBV-DNA, month Virological breakthrough, month HBV-DNA,IU/l

3months 6months 12months 18months 24months 30months 36months

1 17106 12 18a 772103 10.3103 - 815a -2 110106 12 24a NA 2106 - - 11700a 5930 -3 487103 6 24a 48103 - - - 6850a 4 1.627106 _{6 36}a ₁₂₁ 103 _{- - - - - 480000}a 5 1.826106 _{6 18}a _{594 - - 3600}a _- -6 95106 12 18a 112103 7090 - 4200a -7 37.72106 10 18a 5930 1300 - 6577a - - NA

HBV,hepatitisBvirus;NA,notavailable.

a

Switchtotenofovirdisoproxilfumaratetherapy.

Table5

Results of the Cox regression analysis to determine independent variables predictiveofthevirologicalresponse

Characteristics HR(95%CI) p-Value

Age 1.00(0.99–1.02) 0.39 Gender 0.78(0.60–1.1) 0.53 HBeAgpositivity 1.56(0.58–4.16) 0.38 Anti-HBepositivity 2.02(0.75–5.42) 0.16 Pre-treatmentHBV-DNA 1(1–1) 0.86 Pre-treatmentALT 1.00(0.9–1.01) 0.77

BaselineHAI(Ishak) 1.00(0.95–1.07) 0.58

Baselinefibrosis(Ishak) 1.10(0.95–1.3) 0.77 TherapywithTDFvs.ETV 1.10(0.79–1.5) 0.52 HR,hazardratio;CI,confidenceinterval;HBeAg,hepatitisBeantigen;anti-HBe, hepatitisBeantibody;HBV,hepatitisBvirus;ALT,alanineaminotransferase;HAI, histologicalactivityindex;TDF,tenofovir;ETV,entecavir.

Figure2.Cumulativeprobabilitiesofavirologicalresponsetotenofovir(TDF)and entecavir(ETV)therapy(p=0.72).

Figure3.Cumulativeprobabilitiesofabiochemicalresponsetotenofovir(TDF)and entecavir(ETV)therapy(p=0.86).

Inthepresentstudy,thedeclinesfrompre-treatmentHBV-DNA levelsatmonths6,9,12,18,and24werenotsignificantlydifferent betweentheTDFandETVgroups,butTDFinducedasignificantly greaterreductioninserumHBV-DNAlevelatmonth3.Incontrast, inarecentlypublishedstudy,agreaterdeclineinserumHBV-DNA levelsatmonth3occurredwithETVtherapy;however,theratesof decline in HBV-DNA levels at other months did not differ significantly,similartoourresults.15_{Moreover,Guzelbulutetal.}

reportedsimilarrates ofdeclineinserumHBV-DNAlevelswith bothdrugsafter48monthsoftherapy.17

TDFinducedasignificantlymoreincreasedrateofundetectable HBV-DNAlevelsatmonths12and18comparedtoETV,butthe ratesofundetectableHBV-DNAlevelsatmonths3,6,12,18,and 24weresimilar.Myungetal.reportedhighercumulativeratesof virologicalresponseat3,6,12,and18monthsinpatientsonETV therapythaninpatientsonTDFtherapy.24_{Thedifferencewasdue}

to the threshold of the serum HBV-DNA level for virological response, which was set at <2000 copies/ml (approximately 400 IU/ml).In ourstudy, a ‘complete virologicalresponse’ was definedasserumHBV-DNA levels<20IU/ml (<100copies/ml). Theoverall cumulative proportion of patients achieving serum HBV-DNAlevels<400copies/mlwas79%afterameantreatment durationofnearly2yearsinanotherstudyincludingCHBpatients withpriortreatmentfailurewhoweresubsequentlyswitchedto TDFtherapy.25_{Doganetal.reportedthateitherTDForETVtherapy}

resultedinsuppressionofHBV-DNAlevelsin71.3%ofpatientsat theend of48 weeks (66%in thepresent study). There wasno statistical difference in the induction of undetectable levels of HBV-DNA between the ETV and TDF groups.16 _{Ceylan et al.}

reported that TDF-treated patients had a better virological response than ETV-treated ones. ETV was more effective in reducingserumHBV-DNAlevelsatmonth3ofantiviraltherapy.15

Seven (7%) patients onETV therapydeveloped virological breakthrough,butnoneofthepatientsintheTDFgroup did. While no viral breakthrough was observed in a study that included114naiveCHBpatientsonETVtherapy,27inanother studyinvolving258ETV-treatedpatients,onlyfivedeveloped ETVresistance,which isless thanin ourstudy.28 _Inanother

study which evaluated the long-term efficacy of TDF in 131patients,virologicalbreakthroughwasnotobserved.25_In

thestudybyChangetal.,ETVresistanceemergedinonlyone patientduring5yearsoffollow-up,thereforetheysuggested

extended long-term therapy with ETV through 5 years in HBeAg-positiveCHB.26

OnlyonepatientineachgroupdevelopedHBsAgclearance.van Bommeletal.reportedHBsAglossin3%of131TDF-treatedCHB patients withprior resistance to otherantiviral drugs.25 _Chang

etal.reportedthattherateofHBsAglosswas1.4%.26_Whilenoneof

thebaselineparametersofthepatientsweresignificantpredictors ofthevirologicalresponseinthepresentstudy,HBeAg seronega-tivityandalowserumHBV-DNAlevelatbaselinewerereportedto be significant predictors of the virological response by Myung etal.24

Themainlimitationofourstudyisitsretrospectivedesign. Pre-treatment liver biopsy scores were available for most of the patientsandtheyweredifferentinthetwogroups,asthestudy designwasretrospective.Itisverydifficulttoconvincepatientsto haveacontrolbiopsyperformedattheendoftreatment.Therefore, wecouldnotcomparethehistologicalimprovementinresponseto therapytothetwodrugs.Moreover,thepresumablyETV-resistant strainswerenotsequencedbecausethepatients’healthinsurance companieswouldnotpayforthisandwecouldnotobtainfunding forthispurpose.Nevertheless,weinvolvedquitealargenumberof patients in the study. We also looked for the predictors of a responsewith theparametersavailable, but none ofthem was significant.

Inconclusion,ratesofHBeAgseroconversioninHBeAg-positive patients,ALTnormalization,andserumHBV-DNAclearancewere notsignificantlydifferentinthetwotreatmentgroups.Moreover, themeantimetoachieveundetectableserumHBV-DNAlevelsand ALTnormalizationweresimilar.Bothdrugsresultedinsignificant viralsuppression,buttheHBsAgclearanceratewasverylowwith bothdrugs.SevenpercentofpatientsonETVtherapyexperienced virological breakthrough, while none of the patients on TDF therapy did. The two drugs induced comparable virological, biochemical,andserologicalresponsesinCHBpatients.

Funding:None.

Conflictofinterest:Nonetodeclare.

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