Effectiveness and tolerability of direct-acting antivirals for chronic hepatitis C patients in a Southern state of Brazil

w w w . e l s e v ie r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Effectiveness

and

tolerability

of

direct-acting

antivirals

for

chronic

hepatitis

C

patients

in

a

Southern

state

of

Brazil

Vinicius

Lins

Ferreira

_,

_Helena

_Hiemisch

_Lobo

_Borba

_,

_Astrid

_Wiens

_,

Maria

Lucia

Alves

Pedroso

_,

_Vanessa

_Ferreira

_de

_Camargo

_Radunz

_,

Cláudia

Alexandra

Pontes

Ivantes

_,

_Aline

_Satie

_Oba

_Kuniyoshi

_,

_Roberto

_Pontarolo

a_{UniversidadeFederaldoParaná,ProgramadePós-Graduac¸ãoemCiênciasFarmacêuticas,Curitiba,PR,Brazil} b_{UniversidadeFederaldoParaná,HospitaldeClínicas,Servic¸odeGastroenterologia,Curitiba,PR,Brazil}

c_{GastroenterologyService,CentrodeOrientac¸ãoeAconselhamentodaSecretariaMunicipaldeSaúde,Curitiba,PR,Brazil} d_{PrefeituradeMaringá,AtendimentoEspecializado,Maringá,PR,Brazil}

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Articlehistory:

Received23January2018 Accepted4April2018 Availableonline9May2018

Keywords: Brazil Direct-actingantivirals HepatitisC Observationalstudy

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Background:Thisstudyaimedtoevaluatetheclinicaleffectivenessintermsofsustained virologicalresponseandtolerabilityofavailablesecondgenerationdirect-actingantivirals inBrazilianpatients.

Methods:ThiswasaretrospectiveobservationalstudyconductedinsixcentersinSouthern Brazil.Thesamplecomprisedadultpatientswhowerechronicallyinfectedwithhepatitis Cvirus,regardlessofvirusgenotype,fibrosisstage,orpriortreatment.Statisticalanalysis wasperformedtocomparetheeffectivenessamongthetreatments,andalsotouncoverthe factorsinfluencingtheachievementofsustainedvirologicalresponse.

Results:Atotal of296patientswereincluded inthestudy,withthe majorityreceiving sofosbuvirwithdaclatasvir(59%)orsofosbuvirwithsimeprevir(26%).Overallsustained viro-logicalresponserateswereapproximately91.6%.Forgenotype1,sofosbuvirwithdaclatasvir hadansustainedvirologicalresponserateofapproximately95%,whilethesustained viro-logicalresponserateofsofosbuvirwithsimeprevirwas92%;thisdifferencewasstatistically significantonlyforsubtype1b.Theonlytreatmentusedforgenotype3patientswas sofosbu-virwithdaclatasvir,andlowerratesofsustainedvirologicalresponsewereobservedforthis group,comparedtogenotype1(84%versus95%,p<0.05).Apartfromthisdifferencebetween genotypes,andadifferencebetweenpatientswhoachievedrapidvirologicresponse com-paredwiththosewhodidnot,therewerenootherstatisticallysignificantfactorsassociated withsustainedvirologicalresponse.

∗ _{Correspondingauthor.}

E-mailaddress:pontarolo@ufpr.br(R.Pontarolo).

https://doi.org/10.1016/j.bjid.2018.04.003

1413-8670/©2018SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Conclusions:Theresultspointtotheeffectivenessofsecond-generationdirect-acting antivi-ralsinhepatitisCvirusBrazilianpatients,especiallythosewithgenotype1.Furthermore, thatpatientswithgenotype3needmoreattentionandadjustmentsinavailabletreatment options.

©2018SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Introduction

ChronichepatitisCisaserioushealth-relatedproblemthat affectsmorethan71millionpeople,causingalmost400,000 deathsworldwideeveryyear.1_{InBrazil,itisestimatedthat}

1.5–1.7millionpatientsareinfectedwiththehepatitisCvirus (HCV),which representsabout 2%ofthe population. How-ever,ahigherproportionofcasesisfromtheSouthofBrazil (about 24.2%of the total number ofcasesin the country), where Curitiba city, the capital of Paraná state, is one of citieswiththe highestnumberofcasesper 100,000 inhab-itants (36.3).2–4 _{For many years,interferon-based therapies}

weretheprimarytreatmentchoiceforchronichepatitisC, fol-lowedbythefirstgenerationofdirect-actingantivirals(DAAs), boceprevirand telapravir, whichwere usedincombination withpegylatedinterferonandribavirin(RBV).However,these treatmentswereproblematic duetolimitedefficacy,severe sideeffects,andcontraindications.5,6

Inthelastfewyears,secondgenerationDAAshavebeen developedtoprovidemoreeffective,tolerable,andsafe treat-mentsforhepatitisC.Thesecanbeusedincombinationwith other second generation DAAs, and without interferon.7–11

Since 2015 three DAA options have been available in the Brazilianpublic health system: sofosbuvir,daclatasvir, and simeprevir. The Brazilian government makes these drugs available at no cost, according to national guidelines for treating chronichepatitis C,which prioritize patients with advancedstageofthedisease.Recently,anothercombination ofdrugswasapprovedforuseinBrazil,i.e.,ombitasvirwith paritaprevir/ritonaviranddasabuvir.4

These combinations ofdrugs have shown high rates of sustainedvirologicalresponse(SVR;aprimaryefficacy out-comemeasuredatleast12weeksaftertheendoftreatment) andafavorabletolerabilityprofileinrandomizedclinical tri-als(RCTs)andprevioussystematicreviews.12–14_Itisexpected

thattheseoutcomeswouldalsobereproducedinclinical prac-tice.

Observational and regional studies are needed for evi-dence to support decisions in clinical practice. It is well establishedthat thistype ofstudy isanimportantstep in investigatingclinicaloutcomesforchronicdiseases,especially because,insomesituations,resultsfromRCTsarenotfully representative ofthegeneralpopulation.15,16 _{Hepatitis C is}

a disease which isassociated with many factors that can complicatemedicaltreatment.ThisincludesHCVgenotype, co-infectionswithotherviruses(suchasthehuman immun-odeficiencyvirus,HIV),andpatientconditions(e.g.,cirrhosis, livertransplantation,renalfailure).Geographicaldifferences

inthepopulationsstudiedcanalsoaffecttreatmentresponse duetovariedviralcharacteristicsofpatients;thismayoccur inBrazil,whichisacountrywithconsiderableextensionand regionaldiversities.

In this context, the study aimed to evaluate the clini-caleffectiveness,intermsofSVR,andtolerabilityofsecond generationDAAsinchronichepatitisCpatientsthroughan observationalcohortstudyconductedinaSouthernstateof Brazil.Wealsoaimedtocomparetheresultsobtainedfrom patientsreceivingsofosbuvirwithdaclatasvirversus sofosbu-virwithsimeprevir.

Materials

and

methods

Studydesign,eligibilitycriteria,andtreatmentoutcomes

In this retrospectiveobservationalstudy,we analyzeddata from chronic hepatitisC patients who were treated in six centersintheSouthofBrazil,locatedinfivedifferentcities of the State of Paraná: Curitiba, Londrina, Cascavel, Ponta Grossa, and Maringá. Thestudy was carried out in accor-dancewiththeethicalprinciplesoftheDeclarationofHelsinki andwasapprovedbythelocalEthicsCommitteeonHuman Research.

Data were collected from databases from each center, whichcontainalltheindividualpatientrecords.Thesample comprisedadultpatients(≥18years)diagnosedwithchronic HCV infection who concluded or discontinued any second generation DAA treatmentbefore April2017. Patientswere includedregardlessofgenotype,priortreatment,orliver fibro-sis stage. The choice, administration, and management of eachpatient’streatmentwastheresponsibilityofthecenters, accordingtothenationalguidelines.4

TheprimaryeffectivenessoutcomewasSVR12weeksor more afterthe end oftreatment (SVR12),which isdefined as undetectable HCV by polymerase chain reaction (PCR). Secondary effectiveness outcomes included rapid virologi-cal response(RVR; definedas undetectable HCV RNAafter fourweeksoftherapy)andendoftreatmentresponse(EOTr; definedasundetectableHCVRNAattreatmentcompletion), both measured using PCR tests. Patients that completed therapy but did not have any SVR results (i.e., missing data or lost to follow up) were excluded from the analy-sis.

Clinical information collected at baseline included age, sex, weight, presence/absence ofcirrhosis, priortreatment information,HCVgenotype,viralload,liverbiopsy informa-tion, intended treatment, comorbidities (hepatitis B, HIV),

Table1–Baselinedemographicandclinicalcharacteristics.

Characteristic SOF+DCV±RBV(n=176) SOF+SMV±RBV(n=79) Total(n=255)

Male,n(%) 103(58.5%) 38(48.1%)a _141(55.2%)a

Mean(SD)age,years 58.1(±10.3) 57.1(±12.4) 57.8(±10.8)

HCVgenotype 1total 102(57.9%) 79(100.0%) 198(66.8%) 1unspecified 26(14.7%) 8(10.1%) 34(13.3%) 1a 36(20.4%) 39(49.3%) 75(29.4%) 1b 40(22.7%) 31(39.2%) 71(27.8%) 3 72(41.0%) – 72(28.2%) Missingdata 2(1.1%) 1(1.2%) 3(1.1%) Viralload≥800,000IUmL−1,n(%) 89(50.5%) 37(46.8%) 126(49.4%) Missingdata 9(5.1%) 2(2.5%) 11(4.3%) Treatmentexperience,n(%) 92(52.2%) 35(44.3%) 127(49.8%) Missingdata 1(0.5%) 3(3.7%) 4(1.5%) Fibrosisstage,n(%) F0–F3 38(21.5%) 32(40.5%) 70(27.4%)b F4(cirrhotic) 77(43.7%) 22(27.8%) 99(38.8%)b Missingdata 61(34.6%) 25(31.6%) 86(33.7%) Livertransplantation 5(2.8%) 3(3.7%) 8(3.1%) Treatmentduration,n(%) 12weeks 129(73.0%)a _{77(97.4%) 206(80.7%)}a,b 24weeks 44(25.0%) 2(2.5%) 46(18.0%)b AdditionofRBV,n(%) 56(31.8%) 8(10.1%) 64(25.0%) Co-infection HepatitisBvirus(HBV) 4(2.2%) 1(1.2%) 5(1.9%)

Humanimmunodeficiencyvirus(HIV) 10(5.6%) – 10(13.9%)

a _{1patientmissingdata.}

b _{p<0.05(comparisonbetweennumberofpatientsineachgroupthatreceivedsofosbuvirwithdaclatasvirversussofosbuvirwithsimeprevir).}

Abbreviations:DAA,directactingantivirals;DCV,daclatasvir;IFN,interferon;HCV,hepatitisCvirus;LED,ledipasvir;RBV,ribavirin;SD,standard deviation;SMV,simeprevir;SOF,sofosbuvir.

otherclinicalinformation(priortransplantationor hepatocar-cinoma),andtreatmentdiscontinuationduetoadverseevents (tolerabilityoutcome).

Statisticalanalysis

Baselinecategoricalvariablesare describedasabsoluteand relativefrequencies,whilecontinuousvariablesarereported as mediansand standard deviations. Analysis was carried outusingthechi-squaretestandlogisticregressionto iden-tifyvariablessignificantlyassociatedwithSVR(e.g.,baseline parameters: treatmentoption, duration, sex,age, cirrhosis, prior treatment, and others). Bivariate logistic regression resultsarepresentedasoddsratios(OR)andtheir95% con-fidenceintervals(CI).Ap-valuelessthan0.05wasconsidered statisticallysignificantinallcases.Analysiswasperformed usingSPSSStatisticsversion24(IBMSPSS,Chicago,IL,USA) andStatSoftStatisticaversion10.

Results

Baselinecharacteristics

In the six centers, 363 patients were retrieved for this observationalstudy,although61 were excludedduetolost follow-up and another six due to missing data (e.g., no treatmentinformation).Datafrom296patientswereusedfor perprotocolanalysis.Themeanageoftheparticipantswas 57.8±10.8yearsand56%ofthesampleweremales.Interms

oftreatment, 59% ofpatientswere treated withsofosbuvir plus daclatasvir, 26% received sofosbuvir plus simeprevir, and15%receivedotherDAAtherapyoptions.Intotal,34%of patientsreceivedribavirintogetherwiththeDAAtreatment. Genotypes 1 (GT1; 66%) and 3 (GT3; 27%) were the most frequentgenotypesobserved,and48%ofthepatientswere treatment experienced. Baseline characteristics of patients that received the two most prevalent treatments (n=255), sofosbuvirwithdaclatasvir,andsofosbuvirwithsimeprevir, areshowninTable1.

Sub-cohortanalysisofpatientsreceivingsofosbuvirwith daclatasvir

SVR wasachievedby160patients(90%)ofthe176patients whoweretreatedwithsofosbuviranddaclatasvir(Fig.1Aand

Table2).Thistreatmentwasrecommendedforpatientswith GT1and 3;GT3hadlowerSVR ratescomparedtopatients infectedwithGT1(95%versus84%,p<0.05).AllGT3patients treatedfor24weeksachievedtreatmentresponse,compared to only85%ofGT3 patients treatedfor12 weeksachieved SVR(althoughinthiscasep>0.05,moredetailsin Supplemen-taryMaterial1).However,therewasnostatisticallysignificant difference (p>0.05) in SVR rates in any of the other sub-analysis,includingtheuseofsofosbuviranddaclatasvirwith orwithoutribavirin(94%versus88%),presenceorabsenceof cirrhosis(92%versus89%),priortreatment(95%versus86%, respectively fortreatmentnaïveand experiencedpatients), andtreatmentduration(95%versus89%,respectivelyfor24 and12weeksoftreatment).

Fig.1–Sustainedvirologicalresponserates(SVR)for treatmentwith(A)sofosbuviranddaclatasvir;and(B) sofosbuvirandsimeprevir:overallresults,andrates accordingtoclinicalcharacteristics.Abbreviations:GT, genotype;RBV,ribavirin.

RVRwasobtainedby74of78patients(94%),whileEOTrwas achievedby90%(64of71). Moredetailregardingsecondary outcomesisavailableinSupplementaryMaterial3.

Sub-cohortanalysisofpatientsreceivingsofosbuvirwith simeprevir

Ofthe79patientsthatreceivedsofosbuvirwithsimeprevir,73 (92%)achievedSVR(Fig.1BandTable2).ThisDAAcombination

wasonlyadministeredtoHCVGT1patients;SVRratewas94% forsubtype1a,90%forsubtype1b,and87%forunspecifiedGT 1subtype.Othersub-analysisincludedpriortreatment(97% versus 85% for treatmentnaïve and experienced patients). Useornon-useofribavirin(87%versus94%),andpresenceor absenceofcirrhosis(90%versus93%).Therewereno statis-ticallysignificantdifferences (p>0.05), exceptfortreatment duration (93%versus50%,respectivelyfor12and24weeks of treatment); however, this finding should be interpreted withcautionasonlytwopatientsreceivedtreatmentfor24 weeks.

RVRwasachievedby42of47patients(89%),whileEOTrwas obtainedby100%ofthepatientswheredatawasavailable(19 of19).Moredetailregardingsecondaryoutcomesisavailable inSupplementaryMaterial3.

Comparativeeffectivenessofsofosbuvirwithdaclatasvir versussofosbuvirwithsimeprevir

OverallSVRratesweresimilarforbothtreatments(Table2). For GT 1, sofosbuvir with daclatasvir had an SVR rate of 95%, compared to 92% for sofosbuvir with simeprevir (p>0.05), however, for GT 1b, sofosbuvir with daclatasvir was moreeffective(p<0.05). Nostatisticallysignificant dif-ferencesbetweentherapieswereobservedintermsofprior treatment, cirrhosis (Supplementary Material 2 presents more details about SVR regarding genotype and pres-ence/absence of cirrhosis), or additional use of ribavirin. Further,thesub-analysesdidnotproducestatistically signif-icant results(p>0.05inall analysis).Treatment inpatients receiving therapyfor24weekswasmoreeffectiveinthose who received sofosbuvirwithdaclatasvir;however, asonly two patients received sofosbuvir with simeprevir for 24 weeks, this result should again be interpreted with cau-tion.

PatientstreatedwithotherDAAoptions

Intotal, 41patients weretreatedwithdifferentDAAsfrom those previously described; 18 received daclatasvir with simeprevir, 12 received sofosbuvir withribavirin, twowere treated with pegylated interferon withsofosbuvir and rib-avirin,eightweretreatedwithledipasvirwithsofosbuvir,and onereceived pegylatedinterferon withdaclatasvirand rib-avirin.ThreeofthesepatientsdidnotachieveSVR(onetreated withdaclatasvirandsimeprevir,andtwowithsofosbuvirwith ribavirin). Baseline data and results for these patients are detailedinTable3.

FactorsassociatedwithSVRandtolerabilityevents

Bivariatelogisticregressionwasusedtoassesstheinfluence ofseveralbaselineparametersontreatmentresponse(Fig.2). Sex,age,cirrhosis,priortreatment,treatmentduration,use ofribavirin,baselineviralload,andtherapychoicewerenot associatedwithtreatmentsuccess(p>0.05).Theonlytwo sta-tistically significant predictors oftreatment response(both

p<0.05)weregenotype1comparedwithgenotype3(OR0.41 [CI0.17–0.98])andRVRresponse(OR0.16[CI0.03–0.72]).

Table2–Analysisofsustainedvirologicalresponse(SVR)andcomparisonofpatientstreatedwithsofosbuvirand daclatasvirversussofosbuvirandsimeprevir.

SOF+DCV±RBV,%(n=176) SOF+SMV±RBV,%(n=79) p-Valuea

OverallSVR% 90.9(160/176) 92.4(73/79) 0.69 Genotype 1unspecified 92.3(24/26) 87.5(7/8) 0.67 1a 91.6(33/36) 94.8(37/39) 0.57 1b 100(40/40) 90.3(28/31) 0.04 GT1total 95.0(97/102) 92.4(73/79) 0.45 3 84.7(61/72) – NA Cirrhosisyes 92.2(71/77) 90.9(20/22) 0.84 Cirrhosisno 89.4(34/38) 93.7(30/32) 0.52 CirrhosisNI 90.1(55/61) 92.0(23/25) 0.79 Treatmentnaïve 95.1(79/83) 97.5(40/41) 0.52 Treatmentexperienced 86.9(80/92) 85.7(30/35) 0.85 Treatment12weeks 89.1(115/129) 93.5(72/77) 0.29 Treatment24weeks 95.4(42/44) 50.0(1/2) 0.01 WithRBV 94.6(53/56) 87.5(7/8) 0.50 WithoutRBV 88.4(100/113) 94.0(63/67) 0.21 Viralload ≥800.000IUmL−1 89.8(80/89) 91.8(34/37) 0.72 <800.000IUmL−1 93.5(73/78) 92.5(37/40) 0.82

Note:Somegroupshavedifferentnumberofpatientscomparedtototalnumberofpatientsasitoccurredmissingdatainsomebaseline parameterspresentedinTable1.

a _{ComparisonbetweenSOF+DCV±RBVversusSOF+SMV±RBVpatientsforeachgroupAbbreviations:DAC,daclatasvir;GT,genotype;NA,} notapplicable;NI,notinformed;RBV,ribavirinSOF,sofosbuvir;SMV,simeprevir.

Table3–ResponseratesforpatientstreatedwithotherDAAoptions.

Treatment n Treatmentduration(weeks) GT Cirrhosis(%) Priortreatment(%) SVR(%)

Interferon+sofosbuvir+RBV 2 12(100%) 3(100%) 50% 0% 100%

Ledipasvir+sofosbuvir±RBV 8 12(87%)or24(13%) 1(62%)and3(38%) 13% 75% 100%

Sofosbuvir+RBV 12 12(91%)or24(9%) 2(100%) 66%a _{17% 83%}

Daclatasvir+simeprevir±RBV 18 12(61%)or24(39%) 1(72%),and3(28%) 88%b _{44% 94%}

Interferon+daclatasvir+RBV 1 24(100%) 4(100%) 0% 0% 100%

a _{Threepatientsmissingdata.}

b _{Ninepatientsmissingdata.Abbreviations:GT,genotype;RBV,ribavirin;SVR,sustainedvirologicalresponse.}

Fig.2–Predictorsofsustainedvirologicalresponse(SVR).Abbreviations:DAC,daclatasvir;GT,genotype;RBV,ribavirin;RVR, rapidvirologicalresponse.SOF,sofosbuvir;SMV,simeprevir;w,weeks.

Regardingtolerability,onlythreepatients(1%) discontin-uedtreatmentduetoadverseevents,butallachievedSVR.The firstwastreatedwithpegylatedinterferonwithsofosbuvirand ribavirin, and discontinued treatment due toepigastralgia.

The second received sofosbuvir with daclatasvir, and sus-pendedtreatmentduetogastrichemorrhage.Thethirdalso receivedsofosbuvirwithdaclatasvirbutthereasonfor treat-mentdiscontinuationwasnotdescribed.

Discussion

ThesecondgenerationDAAsevaluatedinthisobservational studyproducedsignificantSVRrates.Theresultsarein agree-mentwithpreviousclinicaltrialsandsystematicreviews.12–14

Assuch,it appearsthatthefindings obtainedincontrolled studiesarebeingexperiencedinclinicalpracticeinBrazil. Pre-viousobservationalstudies17–19_{conductedinotherBrazilian}

stateshaveshownoverallSVRratesof93–100%,whichisnot verydifferentfromthefindingsofthepresentstudy(91.6%).

Besides the high response rates, some points must be noted.GT3appearstobethemostdifficulttotreatandisthe secondmostcommongenotypeinBrazil(aftergenotype1). However,onlytwotreatmentoptionsareavailableinthe coun-trytodate:sofosbuvirwithdaclatasvirand sofosbuvirwith peginterferonalfaplusribavirin.Previousobservational stud-ieshavealsoshownalowerSVRrateforGT3patients.17,20–22

Other international guidelines,such as those ofthe Euro-peanAssociation fortheStudyofthe Liver(EASL)and the AmericanAssociationfortheStudyofLiverDiseases(AASLD) recommendothertreatmentoptionsforGT3,7,8_suchas

sofos-buvirwithvelpatasvir,orelbasvirwithgrazoprevir.Itisalso importanttomentionthatmanyofthesepatientsreceived treatmentofsofosbuvirwithdaclatasvirforashortduration (12weeks),whichmayhaveinfluencedtheSVRrateinthese cases.Recently,theBraziliangovernmenthasapprovedthe extensionofthesofosbuvirwithdaclatasvirtreatmentto24 weeksforcirrhoticpatients.4_{This,togetherwiththeaddition}

ofotherdrugscouldincreasethelikelihoodofcureforpatients withGT3.

GT1,whichisthemostprevalentinBrazil,usedtobethe mostdifficulttotreatgenotypeformanyyears.23,24 _Second

generationDAAsiseffectivefortreatingGT1infection,with SVRratesaround90%.Inthisstudy,patientswithGT1 pre-sentedhigherSVRratesthanthosewithGT3whentreated withsofosbuviranddaclatasvir.

Few statistically significant differences were found betweenthefactorspredictingSVR.However,patientswho achievedRVRhadagreaterlikelihoodofalsoachievingSVR. Other studies that performed similar analysis found that liverfunctionandplateletcountwerefactorsassociatedwith SVR.25–27

The stage of disease, i.e., fibrosis stage and pres-ence/absenceofcirrhosis, isrecognizedasaninfluenceon SVR. Our analysis did not show this correlation, probably duetoaconsiderableamountofmissingdataforthis vari-able,and the difference inthenumber ofpatients ineach treatmentgroup.Nevertheless,patientswithseverefibrosis shouldalwaysbecarefullymonitored.Apreviousstudyhas alsosuggestedthat liverfibrosis andHIVcoinfection influ-encestreatmentoutcome.28

PatientswithGT1treatedwithsofosbuviranddaclatasvir hadsimilarSVRratesthanthosetreatedwithsofosbuvirand simeprevir.Apharmacoeconomicstudyanalyzingthesetwo treatmentoptions,aswellasothertreatmentoptions,could helphealthprofessionalstomakeclinicaldecisionsregarding therapeuticchoice.

Some limitations of our study should be noted. Cau-tionshouldbetakenwhengeneralizingtheresultstoother

Brazilianregions and othercountries, due toregional vari-ations.Further,theabsenceofsomeinformation,especially fibrosis stage, may have compromised some ofthe analy-sis.

Conclusions

Theresultsofthisobservationalstudy confirmthatsecond generation DAAs are effectivefor thetreatment ofchronic hepatitisCpatientsinSouthernBrazil,particularlyfor geno-type1.Genotype3appearstobethemostdifficulttotreat,but evenso,currentSVRrateswithsecondgenerationDAAswere higherthanwithprevioustherapies.

Funding

Thisresearchdidnotreceiveanyspecificgrantfromfunding agenciesinthepublic,commercial,ornot-for-profitsectors.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgments

WewouldliketoexpressourthankstotheBrazilian Hepa-tologySociety(SociedadeBrasileiradeHepatologia;SBH)for sharingthedatacollectiontableandforallresearchsupport.

Appendix

A.

Supplementary

data

Supplementary data associated with this article can be found,intheonlineversion,athttps://doi.org/10.1016/j.bjid. 2018.04.003.

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