Treatment of chronic hepatitis C in patients with chronic kidney disease with Sofosbuvir-basead regimes

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

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Treatment

of

chronic

hepatitis

C

in

patients

with

chronic

kidney

disease

with

Sofosbuvir-basead

regimes

Giovana

Rossato

,

Cristiane

Valle

Tovo

∗

,

Paulo

Roberto

Lerias

de

Almeida

UniversidadeFederaldeCiênciasdaSaúdedePortoAlegre(UFCSPA),PortoAelgre,RS,Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received7July2019

Accepted27October2019

Availableonline21November2019

Keywords: Hemodialysis Kidneytransplantion Direct-actingantiviral Sofosbuvir Daclatasvir

a

b

s

t

r

a

c

t

Background:ToanalyzetheeffectivenessandthesafetyofSofosbuvir-basedregimensto

treatpatientswithchronichepatitis Cvirus(HCV)infectionandchronickidneydisease

(CKD).

Methods:Aretrospective,observationalstudyinpatientswithchronicHCVinfectionand

CKDtreatedwithSofosbuvir-basedregimenswasperformed.Liverﬁbrosis,comorbidities,

HCVgenotypeandsustainedvirologicalresposnse(SVR)at12thweekpost-treatmentwere

evaluated.Kidneyfunctionwasaccessedbyserumcreatinineandglomerularﬁltrationrate

(GFR).Theassumedlevelofsigniﬁcancewas5%.

Results:Thirty-ﬁve patients weretreated. The mean age was52.1±10.9 years, 19 (54.3

%) were women, 32 (91.4 %) were already kidney transplanted and3 (8.6%) were on

hemodialysis. TheSVRbyintentiontotreatwas88.6%.Themean GFRwas65.8±28.6

and63.7±28.3ml/minpre-andpost-treatmentrespectively(p>0.05).Treatmentwas

inter-ruptedin1(2.85%)patientduetoanemiaandin2(5.7%)duetolossofkidneyfunction.

Conclusion: Sofosbuvir-basedregimensareeffectivetotreatHCVinpatientswithCKD.In

patientswithmildCKDthistypeoftherapyseemstobesafe.

anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/

licenses/by-nc-nd/4.0/).

Introduction

TheprevalenceofhepatitisCvirus(HCV)infectioninpatients

withend-stagerenaldisease(ESRD)isclearlyhigherthanthe

observedinthegeneralpopulation.1_In_Brazil,_1.38_%_of_the

populationisinfectedwithHCV,2_and_in_patients_on_dialysis,

theprevalenceofthisinfectionrangesfrom4.2%–8%

depend-ingontherenalreplacementtherapycenter.3

∗ _{Corresponding}_author_at:_Rua_Sarmento_Leite_245,_Porto_Alegre_90050-170,_Brazil.

E-mailaddresses:[email protected](G.Rossato),[email protected](C.V.Tovo),[email protected]

(P.R.Almeida).

HCV infection in patients with chronic kidney disease

(CKD)isassociatedwithamorerapidprogressionofliver

dis-ease, increasedmortalityduetocomplicationsofcirrhosis,

lossofrenalgraftandglomerulonephritis,thuscontributingto

aworseprognosisinthesepatients.4_Despite_the_relationship

between HCVand the progressionofCKD, the vast

major-ity ofpatients withCKDremained untreated,becausethey

arehistoricallyadifﬁculttotreatpopulationduetothe

fre-https://doi.org/10.1016/j.bjid.2019.10.011

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quentadverse effectsassociated withmedications used to

treatHCV.5,6_In_addition_to_the_complexity_of_the_treatment,

theuseofInterferoninrenaltransplantrecipientsis

associ-atedwithahigh riskofgraft rejection(15%–100%)and has

beencontraindicatedinthisset.7

Theadventofdirect-actingantivirals(DAA)dramatically

changedthetreatmentofHCV,includingthe special

popu-lationofpatients withCKD. In2015, theuse ofSofosbuvir

(SOF)basedregimens wasapprovedinBrazil.8_Renal

trans-plantpatientsandpatientsonhemodialysishavebeentreated

withDAAsincethen,buttheimportanceofindividualizingthe

treatmentduetotheriskoflossofkidneyfunctionwasalso

emphasized.

Theobjectiveofthepresentstudywastoanalyzethe

effec-tivenessandthesafetyofSofosbuvir-basedregimenstotreat

patientswithCKD.

Material

and

methods

A retrospective, observational study was performed in all

cronically infected patients with HCV and CKDat various

stagestreatedwithSOF-basedregimensatthe

Gastroenterol-ogy/HepatologyoutpatientclinicoftheSantaCasaHospital,

PortoAlegre,atertiaryreferencehospitalfromsouthernBrazil,

fromJune2016toMarch2018.

Theage,sex,liverﬁbrosis,comorbidities,HCVgenotype

andsustainedvirologicalresponse(SVR)at12thweek

post-treatmentwereevaluated.

Kidney functionwas accessed byserum creatinine and

GFRcalculatedusingtheCockroff-Gaultformulabefore,after

treatmentand3monthsaftertheendoftreatment.5_Chronic

kidneydiseasewasclassiﬁedatdifferentstagesaccordingto

criteriaestablishedbyKidneyDiseaseImprovingGlobal

Out-ocomes(KDIGO).5_Kidney_{transplantation}_prior_to_treatment

andtheuseofimmunosuppressantswerealsoregistered.

ChronicHCVinfectionwasdeﬁnedasthepersistenceof

HCV-RNAforaperiodofatleastsixmonths.Molecular

diag-nosisHCVwereperformedbypolymerasechainreaction(PCR)

-Real-timeusingtheExtractionandAmpliﬁcationMethod:

COBAS® AmpliPrep / COBAS® TaqMan® HCVQuantitative

Test,v2.0(Roche).

Patientswereconsideredtohavecirrhosisbasedon

clin-ical, image, laboratory or histologic parameters (METAVIR

score).9

Treatment with DAA was performed according to the

BrazilianPublicHealthsystem(2015),8_which_recommended

thatpatientswithCKDandkidneytransplantpatientsshould

betreatedwithanon-interferon-alpharegimenand,if

possi-ble,withoutribavirin.

Inthestatisticalanalysis,thequantitativevariableswere

described by mean and standard deviation(if normal

dis-tribution)ormedianandinterquartile range(ifasymmetric

distribution).Thenormalityofthecontinuousvariableswas

evaluatedbytheShapiro-Wilktest.Categoricalvariableswere

describedbyabsoluteandrelativefrequencies.Tocompare

meansbeforeandaftertreatment,thepairedt-studenttest

was applied.In caseofasymmetry, the Wilcoxon testwas

used. For the categorical variables, the McNemar test was

applied. To compare means between the three moments,

Table1–ClinicalcharacteristicsofpatientswithHCV

andCKD(n=35).

Clinicalcharacteristics

Age;years;m±DP[range] 52.1±109[34–70] Sex,female;n(%) 19(54.3) HBVcoinfection;n(%) 02(5.7) Kidneytransplantrecipientes;n(%) 32(91.4) CKDstaging(Crcl;mL/min);n(%) 1(Crcl>90) 06(17.1%) 2(Crcl89–60) 13(37.1%) 3(Crcl59–30) 12(37.1%) 4(Crcl29–15) 01(2.9%) 5(Crcl<15ouhemodialysis) 03(8.6%) HCVGenotypes;n(%) 1a 16(457) 1b 06(17.1) 2 03(8.6) 3 09(25.7) 3and4 01(2.9) Comorbidities

Systemicarterialhypertersion 18(51.4) Diabetesmellitus 11(31.4) Cardiacfailure 03(8.6) Arrhythmia 04(11.4) Cirrhosis;n(%) 08(22.8) CTPA 04(11.4) CTPB 04(11.4) CTPC 00(0)

Liverﬁbrosis(elastography);n(%) 12(34.3)

F0 03(8.6)

F1 03(8.6)

F2 01(2.9)

F3 01(2.9)

F4 04(11.4)

CDK=chronickidneydisease;CTP=ChildTurcotte-Pughescore; CrCl:Creatinineclearance;HBV:HepatitisBvirus;HCV:Hepatitis Cvírus.

theanalysisofvariance(ANOVA)forrepeatedmeasureswas applied.Incaseofasymmetryorordinalvariables,the

Fried-mantestwasused.Theassociationbetweennumericaland

ordinalvariableswasevaluatedbytheSpearmancorrelation coefﬁcient. Thesigniﬁcanceleveladoptedwas5%(p<0.05)

and theanalyzeswereperformedintheSPSSprogram

ver-sion21.0.ThestudywasapprovedbytheResearchEthicsof

localCommittee(number1838479).

Results

Thirty-ﬁvepatientswereanalyzed.Therewasalight predom-inance offemales19(54.3%),themeanagewas52.1±10.1 years(34–70years),32(91.4%)werepreviouslysubmittedto renaltransplantsand3(8.6%)patientswereonhemodialysis (Table1).

ConsideringthestagesofCKD,16(45.7%)werestage3or

worse.Regardingtheetiologyofkidneyfailure,24(68.6%)had

no diagnosis,and systemiclupuserythomatous wasfound

in 3 (8.6 %) patients. Glomerulonephritis focal segmental

scleroderma (GESF), diabetes mellitus (DM), systemic

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Table2–Medicationsusedinthetreatmentofpatients

withHCVandCKD(n=35).

TreatmentofHCV N(%)

Sofosbuvir+Daclatasvir12weeks 27(77.1) Sofosbuvir+Daclatasvir+Ribavirin12weeks 03(8.6) Sofosbuvir+Daclatasvir+Ribavirin24weeks 03(8.6) Sofosbuvir+Ribavirin12weeks 02(5.7) HCV=hepatitisCvirus.

Table3–ImunosuppressantsinCKDsubmittedtorenal

transplantation(n=32).

Imunosuppressants n(%)

Prednisone,MMFandFK 15(42.9) PrednisoneandMMF 06(17.1) Prednisone,MMFandCYA 04(11.4) PrednisoneAZAandCYA 03(8.6) PrednisoneandFK 02(5.7) Prednisone+CYA+Sirolimo 02(5.7) AZA: Azathioprine; CYA: cyclosporin; FK: Tracolimus; MMF: Mycophenolatemofetil.

chronicpyelonephritisandBorsyndromewereresponsiblefor theetiologyinafewpatients(8;22.8%).HCVgenotype1was themostprevalent(22;62.8%)(Table1).

CoinfectionwithhepatitisBvirus (HBV)wasfound in2

patients(5.7%).TherewasobservedthereactivationofHBV

inoneofthese,immediatlypost-treatmentofHCV.Thiswas

arenaltransplant,genotype1patient,usingTenofovirsince

2012,with undetectable HBV viral load pre-treatment. The

patientpresentedSVR afterHCVtreatment, and afterHBV

reactivation.EntecavirwasassociatedwithTenofovir.

In the evaluation of liver ﬁbrosis, no patient

under-wentliverbiopsy.Transienthepatic elastography(THE)was

performed in 12 (34.2 %) patients, showing absence or

mild/signiﬁcantﬁbrosis(F0-F1-F2)in7(58.3%)andadvanced

ﬁbrosis(F3-F4)in5(41.7%)patients.Cirrhosiswasdiagnosed

byTHEin4(11.4%)patients,andbyclinicalpresentation

(por-talhypertensionwithascitesandesophagealvarices)in4(11.4

%).Amongthe8cirrhotics,5(14.2%)wereChild-Turcotte-Pugh

(CTP)Aand3(8.6%)CTPB(Table1).

Theprevalentcomorbiditiesweresystemichypertensionin

18(51.4)patients,diabetesmellitusin11(31.4%),heartfailure

in3(8.6%)andcardiacarrhythmiain4(11.4%)(Table1).

Ofthe35patientswhounderwentHCVtreatment,33(94.2

%)were treated withSofosbuvir and Daclatasvir, ofwhom

8 (24.2 %) received Ribavirin. The 2 (5.7 %) patients with

HCVgenotype2weretreatedwithSofosbuvirandRibavirin

(Table 2). Full dose of Sofosbuvir was used in 33 (94.2 %)

patients,andhalfdose(1tablet onalternatedays)in2(5.7

%)patients.

Thirty-two(91.4%)patientswere receiving

immunosup-pressants because they were kidney transplant recipients.

ImmunosuppressiveregimenswerenotmodiﬁedduringHCV

treatment.TherewasapredominanceofPrednisone

associ-atedwithMycophenolateMofetilandTacrolimusin15(42.9

%)patients(Table3).

Thetreatmentwassuspendedin3(8.6%)patients,being

1(2.8%)duetoanemiaand2(5.8%)duetoasigniﬁcantloss

ofkidneyfunction.Thepatientwhodiscontinuedtreatment

forsymptomaticanemia(hemoglobindrop)wascirrhoticon

hemodialysisusingSofosbuvir,DaclatasvirandRibavirin.The

twopatientsworseningkidneyfunctionwerecirrhotic

Child-Turcotte-PughB,renaltransplanted,intheadvancedstages

ofCKDstage3(GFR41mL/min)andstage4(GFR27mL/min),

worseningtoGFR29ml/minand25mLmin,respectively.

WhenthemediancreatinineandGFRwereanalyzed,there

was no statistically signiﬁcant difference before and after

treatmentwithSofosbuvir(Table4).Andalso,therewasno

statistically signiﬁcant difference when analyzed the CKD

accordingtothedifferentstages(Fig.1).

SVRwasevaluatedin32patientswhocompletedthe

treat-ment,and31(88.6%)achievedSVR12inanintentiontotreat

analysis; perprotocol96.9 %.Only1(2.8%)presentedHCV

recurrenceaftertreatment.

Discussion

Inthepresentstudy,aseriesofcasesofpatientswithCKD

andHCVweretreatedwithSofosbuvir-basedregimens,

suc-cessfullyachievingSVRandwithoutGFRdecline.Mostofthe

patientswererenaltransplantpatients,non-cirrhoticpatients

withHCVgenotype1,andthemostcommonlyusedtreatment

regimenwastheassociationofSofosbuvirandDaclatasvirfor

12weeks.

HepatitisCvirusoftenhasanegativeimpactonthe

sur-vivalofpost-renaltransplantpatientsduetotheincreased

riskofgraftlossduetorejectionanddiseaseinfection,

post-transplant diabetes, cancer and rapid progression of liver

ﬁbrosis.10

AlthougheradicationofHCVisofparamountimportance,

renaltransplantrecipientshavealwaysrepresentedaspecial

populationdifﬁculttotreat.Currently,theuseofDAAhasbeen

animportantstepinthetreatmentofHCVinfectiondueto

ratesofSVRrangingfrom60%to100%accordingtogenotype

anddegreeofhepaticdysfunction.11

Manys studies inthe literaturethat evaluatethe useof

DAA inCKD presentedwithencouraging results. Desnoyer

etal.12_observed_that_Sofosbuvir_was_well_tolerated_in₁₃

dial-ysispatients.However,SVR12was100%inpatientswhoused

Sofosbuvir fulldose and 60% inthose who receivedthree

times a week. Saxena et al., (n=19, being 5on

hemodial-ysis) observed, in the TARGET study, no difference in the

SVR regardless ofkidney function. However, patients with

GFR<30ml/minexperiencedmoreanemiaandworsened

kid-ney function after using Sofosbuvir.13 _Studies _on _kidney

transplantrecipientstreatedwithDAAsstandoutwith100

%SVR12.14–16_This_study_conﬁrms_that_{Sofosbuvir-based}

ther-apiesareeffectiveinpatientswithCKD.Inthisseriesof35

cases,theSVR12wasreachedin31(88.6%)patients.Onlyone

patient(2.8%)developedHCVrecurrenceaftertreatment;he

wasgenotype1a,underhemodialysis,presentedﬁbrosis F1

evaluatedbyTHEandwastreatedwithSofosbuvir,Daclastavir

andRibavirinfor12weeks.

TreatmentofhepatitisCwithnewDAAmay representa

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Table4–Comparisonofcreatinineandglomerularﬁltrationrate(GFR)pre,postandthreemonthsaftertreatment.

Variables Pre Post 3mafterEOT P

Creatinine(mg/dL);Median(P25–P75) 1.27(0.94–1.57) 1.23(0.92–1.70) 1.28(0.92–1.92) 0.573a

GFR(mL/min);Median±SD 65.8±28.6 63.7±28.3 64.4±29,8 0.241b

M=months;treat=treatment;GFR=Glomerularﬁltrationrate;SD=standarddeviation;EOT=endoftreatment.

a _Friedman_test.

b _Analysis_of_variance_(ANOVA)_for_repeated_measures.

0 5 10 15 20 25 30 35 40 45 50

Normal Light Moderate Severe Terminal

%

sam

p

le

Stage of CKD

Pre Post 3m/After

Fig.1–ComparationbetweenthestagesofCKDpre,postand3monthsaftertheendoftreatment.(p=0459McNemartest).

withHCV.Asystematicreviewand meta-analysisfound17

studiesinvolving1621patientsbeing242withHBVand1379

with resolved hepatitis B (HBsAg-negative and anti-

HBc-positive).Allweretreatedwithdifferentregimenscontaining

DAAagainstHCV.ThereacivationofHBVwasobservedin24

%(IC95%19–30%)inpatientswithchronicHBVinfectionand

1.4%(0.8–2.4%)inthosewithresolvedHBVinfection.17_In_the

presentstudy,2(5.7%)patientswereHBsAgpositive,andone

reactivatedHBVduringusedeDAA.

Toknow the drug interactions ofDAA is of

fundamen-talimportance,particularlytheinteractionbetweenprotease

inhibitorsandcalcineurininhibitorsormammaliantargetof

rapamycin(mTOR).Simeprevir,asecond-generationantiviral

thatinhibitstheproteasecodedbytheHCVNS3/4Aregion,

haspotentialdruginteractionwithTacrolimus,Sirolimusand

Everolimus.18

Sofosbuvir (polymerase inhibitor encoded by the HCV

NS5B region) and Daclatasvir (HCV NS5A region-encoded

polymerase inhibitor) have a low risk of interaction with

immunosuppressantsandhavepangenotypicaction.Inthis

study, the vast majority of patients were renal transplant

patients(n=33;94.3%).

AllpatientsweretreatedwithSofosbuvirbasedregimes.

Renaltransplantpatientswereusingimmunosuppressants,

8(25.0%)usedscheduleswithCiclosporin,and 17 (48.5%)

withTacrolimus.Therewasnoneedformorefrequentcontrol

ofthelevelsofimmunosuppressionduetothelackofdrug

interactionwiththeseDAA.Thisstudyshowedthattreatment

withSofosbuvirwaswelltoleratedinpatientswithmildCKD,

although3(8.6%)patientsdiscontinuedtherapy.

Apontentiallimitationofthepresentstudythefactthat

itisretrospectiveandincludedasmallnumberofpatientsin

moreadvancedstagesofCKD.

Inconclusion,thisstudysuggeststhattratamentHCVin

patientswithCKDisefetive,andinpatientswithmildCKD

thistypeoftherapyseemstobesafe.

Conﬂicts

of

interest

Thisresearchdidnotreceiveanyspeciﬁcgrantfromfunding

agenciesinthepublic,commercial,ornot-for-proﬁtsectors.

Theauthorsdeclarenoconﬂictsofinterest.

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