HCV clearance after direct-acting antivirals in patients with cirrhosis by stages of liver impairment: The ITAL-C network study

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ContentslistsavailableatScienceDirect

Digestive

and

Liver

Disease

j o u r n a l ho me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / d l d

Liver,

Pancreas

and

Biliary

Tract

HCV

clearance

after

direct-acting

antivirals

in

patients

with

cirrhosis

by

stages

of

liver

impairment:

The

ITAL-C

network

study

Antonio

Massimo

Ippolito

a,∗

_,

_Michele

_Milella

b

_,

_Vincenzo

_Messina

c

_,

_Fabio

_Conti

d

_,

Raffaele

Cozzolongo

e

_,

_Filomena

_Morisco

f

_,

_Giuseppina

_Brancaccio

g

_,

_Michele

_Barone

h

_,

Teresa

Santantonio

i

_,

_Chiara

_Masetti

j

_,

_Paolo

_Tundo

k

_,

_Antonina

_Smedile

l

_,

_Vito

_Carretta

m

_,

Pietro

Gatti

n

_,

_Antonio

_Patrizio

_Termite

o

_,

_Maria

_Rosa

_Valvano

a

_,

_Giuseppe

_Bruno

b

_,

Claudia

Fabrizio

b

_,

_Pietro

_Andreone

d

_,

_Marianna

_Zappimbulso

e

_,

_Giovanni

_Battista

_Gaeta

g

_,

Nicola

Napoli

p

_,

_Luca

_Fontanella

q

_,

_Gianfranco

_Lauletta

r

_,

_Giuseppe

_Cuccorese

s

_,

Antonio

Metrangolo

t

_,

_Ruggiero

_Francavilla

u

_,

_Emanuela

_Ciracì

n

_,

_Salvatore

_Rizzo

v

_,

Angelo

Andriulli

a

a_Division_of_{Gastroenterology,}_“Casa_Sollievo_{Sofferenza”}_Hospital,_IRCCS,_San_Giovanni_Rotondo,_Italy b_Clinics_of_Infectious_Diseases,_University_of_Bari,_Bari,_Italy

c_Infectious_and_Tropical_Diseases_Unit,_S._Anna_and_S._Sebastiano_Hospital,_Caserta,_Italy

d_Centre_for_the_Study_of_Hepatitis,_Department_of_Medical_and_Surgical_Sciences_(DIMEC),_University_of_Bologna,_Bologna,_Italy e_Division_of_{Gastroenterology,}_“De_Bellis”_Hospital,_IRCCS,_Castellana_Grotte,_Italy

f_Division_of_{Gastroenterology,}_Department_of_Clinical_Medicine_and_Surgery,_“Federico_II”_University_of_Naples,_Naples,_Italy g_Clinics_of_Infectious_Diseases,_“Federico_II”_University_of_Naples,_Naples,_Italy

h_Section_of_{Gastroenterology,}_Department_of_Emergency_and_Organ_{Transplantation,}_AOU_Policlinico,_University_of_Bari,_Bari,_Italy i_Clinics_of_Infectious_Diseases,_University_of_Foggia,_Foggia,_Italy

j_Hepatology_and_Liver_{Transplantation}_Unit,_University_of_Tor_Vergata,_Rome,_Italy k_Division_of_Infectious_Diseases,_“S._Caterina_Novella”_Hospital,_Galatina,_Italy

l_Department_of_Medical_Sciences,_University_of_Turin_and_Department_of_{Gastroenterology}_and_Hepatology,_Azienda_Ospedaliera_Città_della_Salute_e_della

Scienza,Turin,Italy

m_Liver_Unit,_Department_of_Internal_Medicine,_Hospital_of_Venosa,_Venosa,_Italy n_Internal_Medicine,_Hospital_of_Ostuni,_Ostuni,_Italy

o_Liver_Unit,_Hospital_of_{Castellaneta,}_{Castellaneta,}_Italy p_Clinica_Medica_“C._Frugoni”,_University_of_Bari,_Bari,_Italy q_Centre_for_Liver_Disease,_{Fatebenefratelli}_Hospital,_Naples,_Italy r_Clinics_of_Internal_Medicine_“G._Baccelli”,_University_of_Bari,_Bari,_Italy s_Division_of_Internal_Medicine,_“Monsignor_Di_Miccoli”_Hospital,_Barletta,_Italy t_Division_of_Internal_Medicine,_Hospital_of_Casarano,_Casarano,_Italy u_Unit_of_Infectious_Diseases,_Hospital_of_Bisceglie,_Bisceglie,_Italy

v_Division_of_Internal_Medicine,_Hospital_of_Martina_Franca,_Martina_Franca,_Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received26November2016 Accepted30March2017 Availableonline8April2017 Keywords: Antiviraltherapy Direct-actingantivirals HCV HepatitisC Livercirrhosis

a

b

s

t

r

a

c

t

Background:Sustainedvirologicalresponse(SVR12)ratesat12weeksaftertreatmentforHCV-infected patientswithdecompensatedcirrhosisareusedwhenreferringtothosewithmoderatefunctional impair-ment,whilefewdataareavailableforthosewithmoresevereimpairment.Theuseofthecirrhosisstaging systemproposedbyD’Amicomightprovidenewinsightsontimingforantiviraltherapy.

Methods:Weinvestigatedefficacy(SVR12),safety,andpost-treatmentvariationsinclinicalandlaboratory parametersin2612patientswithadvancedfibrosis(n=575)orcirrhosis(n=2037).Cirrhosiswasinthe compensatedphase(without/withvarices)orhadpreviouslybeeninthedecompensatedstage.Different direct-actingantiviral(DAA)regimenswereadministeredinaccordancewithscientificguidelines. Results:TheSVR12ratewas97.6%inpatientswithadvancedfibrosis.Forpatientswithcirrhosis,the ratewas96.5%instage1,95.1%instage2,100%instage3,95.7%instage4,and93.6%instage5. Theserateswereindependentofgender,age,HCVgenotype,andtreatmentschedule.Positivechangesin

∗ Correspondingauthorat:DivisionofGastroenterology,“CasaSollievoSofferenza”Hospital,vialeCappuccini1,71013SanGiovanniRotondo,Italy.Fax:+390882835411. E-mailaddress:antonio.ippolito@me.com(A.M.Ippolito).

http://dx.doi.org/10.1016/j.dld.2017.03.025

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biochemicalparametersandCPTclassesfollowingtherapywereevidentincompensatedandpreviously decompensatedpatients.

Conclusion:OurﬁndingssupporttheuseofDAAsinpatientswithadvancedcirrhosis(stages3–5)who areatgreatestriskandhavethemosttogainfromtherapy.

1. Introduction

Alloral,direct-actingantivirals(DAAs)totreatHCVinfection

haveadramaticimpactonlivercirrhosis,asviraleradicationhas

thepotentialtoimprovehepaticfunctionandthepatient’s

progno-sis[1–3].Patientswithcompensatedorpreviouslydecompensated

cirrhosistreatedwithDAAsshowedratesofsustainedvirological

response(SVR)comparabletothoseinpatientswithoutcirrhosis

[4–6].

TheChild–Pugh–Turcotte (CPT)classesare currentlyusedto

indicatefunctionalimpairmentoftheliver.However,theydonot

provide information onother liverdisease manifestations with

multipleoutcomeevents,eachofwhichmayaffectthetimingof

anothereventdeveloping[7].Forinstance,apatientwithcirrhosis

stagedinCPTclassBbecauseofascitesmaybere-stagedinclassA

intheeventofsuccessfultreatmentwithdiuretics,orre-stagedin

classCifacute-on-chronicliverfailureoccurs.Anewframeworkfor

classifyingcirrhosis,whichincorporateshemodynamicandclinical

signs,hasbeenproposedbyD’Amicoetal.[8].Theauthorsused

twolandmarkeventsduringlivercirrhosis(thedevelopmentof

esophagealvaricesandtheoccurrenceofdecompensatingevents)

toidentifyﬁveprognosticstageswithasigniﬁcantlyincreasedrisk

ofmortality.IntheD’Amicoetal.system[8],portalhypertension

ratherthanimpairedsyntheticliverfunctionparametersisused

todeterminepatientprognosis.Thisstratiﬁcationallowsamore

precisedeﬁnitionof‘decompensated’cirrhosisandprovidesa

prog-nosticsystemindependentofCPTclass,theModelforEnd-stage

LiverDisease(MELD),andthepresenceofco-morbidities[8].There

isapressingneedtolinkthesestagestoclinicaloutcome,suchas

long-termoutcomeafterasuccessfulcourseofantiviraltherapy.

AninitialsteptowardthisapproachhasbeenprovidedbyDiMarco

etal.[9]whofoundthatinpatientswithcompensatedcirrhosis,the

SVRratesfollowingpeg-interferonandribavirintreatmentdiffered

withstageofportalhypertension:SVRrateswere30.7%and18.1%

inpatientswithout(stage1)andwith(stage2)esophagealvarices,

respectively[10].Dataonpatientswithcirrhosisandprevious

hep-aticdecompensationwhohaveundergonetreatmentwiththenew

DAAsarefragmentaryandlimited.Guarinoetal.foundthatthe

SVRrateswerelowerthanthoseseeninpatientswith

compen-satedcirrhosis,andrangedfrom66.7%to84.7%[10].Theimpact

ofnewDAAadministrationinpatientsstratiﬁedaccordingtothe

D’Amicosystem[8]hasnotyetbeenevaluated.

Here we report theﬁndings of a prospective,observational

cohortstudyoftreatedpatientswithsevereliverdiseaseassociated

withallviralgenotypes.Wedescribetheefﬁcacyandsafetyofnew

antiviraltherapieswitheveryoralDAAregimeninpatientswith

livercirrhosis,redeﬁnedinrelationtoportalhypertensionandthe

occurrenceofpreviousepisodesofdecompensation,asindicated

bytheD’Amicostagingsystem[8].

2. Materialandmethods

2.1. Studydesign

Thisobservational,prospectivestudywasconductedbya

con-sortium of 25 community and academic Italian centers which

collectedpost-approval treatmentdata onconsecutive patients

withHCVinfectionfromMay2015toDecember2016.InMarch

2015, second generation DAAs received regulatory approval in

ItalyfromtheAgenziaItalianadelFarmaco(AIFA)andaccessto

new DAAsfor patientswith advanced ﬁbrosis or compensated

cirrhosis wasprioritized.Inthis study,theprescribingclinician

selectedtheparticulartreatmentregimenaccordingtotheviral

genotype/subtype,assuggestedbytheItalianAssociationforthe

StudyoftheLiver[11],andchosetheribavirindosage,while

treat-mentduration(12or24weeks)wasinaccordancewiththeseverity

ofliverdisease.Allpatientswhoreceivedatleastonedoseofthe

newDAAswereincluded.Approvaltotabulateandanalyzethedata

wasobtainedfromtheEthicsCommitteeoftheCoordinating

Cen-terinSanGiovanniRotondo.Thestudywasnotsupportedbyany

pharmaceuticalcompanyorotherfundingagency.

Admissioncriteriawereadultage,noevidenceofactive

hep-atocellularcarcinoma(HCC)onimaging,RNAforHCVidentiﬁed

by PCR, and noprevious similar treatmentor failure of a

pre-vious coursewith peg-interferonplus ribavirin in combination

or not withﬁrstgeneration DAAs.Patients withcirrhosis were

offeredtreatmentwhetherornottheyhadprevious

decompensa-tioncontrolledbeforestartingDAAs.Co-morbiditieswererecorded

andclassiﬁedaccordingtoHarbounandAnkri[12].Similarly,

co-administereddrugswerelistedandinteractionwiththeintended

DAAscarefullycheckedbyconsultingtheLiverpoolHEPdrug

inter-actions guidance [13]. Exclusion criteria were HIV coinfection,

majorco-morbidities, anestimatedglomerular ﬁltrationrateof

<15mL/min,andcurrenthepaticdecompensationunresponsiveto

appropriatetherapy.

Thecharacteristicsof enrolledsubjectswerecapturedeither

at baseline or at each study visit and included: gender, age,

body weight andheight, previoustreatment(whether naïveor

experiencedwithpeg-interferon/ribavirinand/orﬁrst-generation

antivirals), cirrhotic status, decompensation events (ascites,

esophagealbleeding,encephalopathy,hepatocellularcarcinoma),

listed or not for an orthotopic livertransplantation (OLT), and

co-morbidities [12].In addition,thefollowing parameters were

noted: albumin, INR, bilirubin, platelet count, creatinine, and

serum HCV RNA level and genotypes. Determination of portal

hypertension was in accordance with the Baveno VI

Consen-susWorkshop[14],andincludedesophagealvaricesdetectedat

screeningendoscopy,imagingshowingcollateralcirculation,liver

stiffnessof≥20–25kPa,oraplateletcountof<150,000inpatients

withliverstiffnessof<20kPa.

Patients were reviewed monthly during antiviral treatment

andvirologicalresponsewasassessedbyquantitativeHCVRNA

at week4, at theend of treatment, and at 4 and 12 weeks of

follow-up.Duringthestudyperiod,werecordedearly

discontin-uationoftherapyorliverdecompensationevents(ascites,hepatic

encephalopathy,jaundice,spontaneousbacterialperitonitis,and

varicealhemorrhage),HCC, OLT,ordeath(liver-related or

non-liver related). Adverse eventsdue to therapy were categorized

accordingtotheCommonTerminologyCriteriaforAdverseEvents

(version4.03)[15].

2.2. Deﬁnitionandstagingofcirrhosis

Acentralizedteamofmonitorsreviewedallrecordsobtained

fromthevariouscenters.Patientswerecategorizedashaving

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documentedhistologically at anytime beforeenrollmentor, in

patientswithouthistology,hadbeendeterminedbyFibroScan,and

(2)acombinationofclinical,laboratory,andabdominalultrasound

parametersestablishedapriori[16].Patientswereconsideredto

havecirrhosisiftheyshowedthefollowing:(1)esophagealvarices

atendoscopyorevidenceofcirrhosisand/orportalhypertension

and/orascitesatultrasound;(2)aliverstiffnessvalueonFibroScan

of>14.0kPaplusaplateletcountof≤140,000/␮L;or(3)aFibroScan

valueof10–14kPaandaplateletcountof_{≤100,000/␮L.}Patients

withaliverstiffnessvalueof<14kPa,nohepaticdecompensation,

andnoultrasoundsignsofportalhypertensionwereconsideredto

haveadvancedﬁbrosis(F3).

For patients with cirrhosis, CPT classes and MELD scores

werecentrallycalculated usingsite-derived laboratory

parame-ters.Patientswithcirrhosiswerefurtherstratiﬁedintoﬁveclasses

accordingtoD’Amicoetal.[8],asfollows:patientswith

compen-satedcirrhosiswithoutorwithportalhypertensionwereincluded

instage1or2,respectively;thosewithpreviouslydecompensated

cirrhosis(patientswithahistoryofvaricealbleeding)instage3;

thosewithaprevious,singleepisodeofascitesorencephalopathy

intheabsenceofanesophagealbleedinstage4;andthosewith

multiple,recurrentepisodesofdecompensationinstage5.

2.3. Primaryoutcomes

Theprimaryendpointwassustainedvirologicalresponseat12

weeks(SVR12)aftertherapyinpatientswithadvancedﬁbrosisand

inpatientswithcirrhosisstagedaccordingtoD’Amicoetal.[8].

Secondaryoutcomesincludedpre-andpost-treatmentvariations

in biochemical parameters and hepatic decompensationevents

duringthestudyperiod.Thecomparativeefﬁcacyofthe

differ-enttreatmentscheduleswasalsocontrolledinpatientswithHCV

genotypes(GT)1A,1B,or4.

2.3. Dataanalysis

Beforethedatabasesfromparticipatingcenterswerepooled,

twoindependentmonitors(A.I.andM.L.)systematicallyassessed

dataentriesfor completenessand consistency,anddoubts

con-cerning unlikely values were resolved withadditional queries.

SeparateanalysesforSVR12wereperformedforeachgenotype,

andforGT1bysubtypes1Aand1B.Withineachgenotype,

analy-seswereseparatedaccordingtothepresenceorabsenceofcirrhosis

andaccordingtoprevioustreatmentwithpeg-interferon/ribavirin

(withorwithoutDAAs).Sincenohead-to-headrandomized

tri-alscomparingtheefﬁcacyofthedifferentDAAsareavailable,and

therewerenosamplesizeconstraintsinourcohort,supplemental

analysesofthecomparativeefﬁcacyofadministeredDAAswere

alsoconducted;theseanalyseswererestricted topatientswith

HCVGT1A,1B,and4,asa singleregimenisconsideredoptimal

forHCVGT2and3[7,8,11].Therelapserate,treatment

comple-tion,andfrequencyofadverseeventsduringorat3monthsafter

treatmentwerecalculatedfortheentirestudypopulationandfor

subpopulations.Baselinecharacteristicswereassessedwith

stan-darddescriptive statistics.Continuousvariableswereexpressed

asmedianvaluesandcomparedusingtheMann–WhitneyUtest.

Categoricalvariableswerereportedaspercentagesandcompared

usingthe␹2_test_(or_Fisher’s_exact_test,_when_needed)._Variables

withp<0.05 were included in a multivariate stepwise logistic

regressionmodel.Inordertocomparefrequenciesatbaselineand

attheendoffollow-up,theMcNemartestwasusedforcategorical

variables,andtheWilcoxonsigned-ranktestforcontinuous

vari-ables.AnalyseswereperformedusingSPSSsoftware,version13.0

(SPSSInc.,Chicago,IL,USA).

Table1

Baselinefeaturesandsustainedviralclearancein2612HCV-infectedpatientsafter direct-actingantiviraltreatment.

Sustainedvirologicalresponse

Total N(%) pValue Overall 2612 2516(96) 0.073 Advancedﬁbrosis 575 561(98) Cirrhosis 2037 1955(96) Gender 0.407 Male 1498 1439(96) Female 1114 1077(97) Age(years) 0.654 Median(IQR) 67(58–73) <70 1581 1525(96) ≥70 1031 991(96) Genotype 0.246 1A 224 216(96) 1B 1590 1535(97) 2 494 476(96) 3 157 146(93) 4 135 132(98) Mixed 12 11(92) Albumin(g/dL) 0.139 >3.5 2137 2065(97) 2.8–3.5 436 415(95) <2.8 39 3692) INR 0.898 <1.7 2532 2439(96) 1.7–2.2 62 60(97) >2.2 18 17(94) Bilirubin(mg/dL) 0.494 <2 2431 2344(96) (2–3) 147 13995) >3 34 33(97)

Glomerularﬁltrationrate 0.002

>15–29 8 6(75) 30–59 387 368(95) 60–89 981 954(97) ≥90 1236 1188(96) Pre-therapystatus 0.555 Naïve 1383 1335(97) Treatmentexperienced 1229 1181(96) Ribavirina _0.492 Without 1004 970(97) With 1114 1070(96) Co-morbidities(n) 0.294 0 1181 1145(97) 1–2 1276 1222(96) ≥3 155 149(96)

INR,internationalnormalizedratio.

a_Genotype₂_excluded.

3. Results

Atotalof2979patientsmettheinclusioncriteria.However,367

wereexcludedfromfurtheranalysis;thesecomprised14patients

treatedwithpeg-interferonincombinationwithnewDAAs,140

patientswithHCVGT1,3, and4 treatedwiththesub-optimal

scheduleofsofosbuvir/ribavirin,and 213patientsstill on

treat-ment.Thecharacteristicsoftheremaining2612patientsareshown

in Table 1. Enrolled patients were adults with a mean age of

64.8±11.0years,39.5%wereabove70yearsofage,and57.4%were

male.ThefrequencyofHCVgenotypeswasasfollows:GT1Awas

notedin224patients(8.6%), GT1Bin1590(60.9%),GT2in 494

(18.9%),GT3in157(6.0%),GT4in135(5.2%),andmixedoruntyped

genotypesintheremaining12patients.Advancedliverﬁbrosiswas

seenin575patients(22.0%),andcirrhosisintheremaining2037

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A(86.4%),while249wereinclassB(12.2%)andtheremaining29

(1.4%)inclassC.Inaddition,96.5%hadaMELDscoreof<16.

Accord-ing tothe D’Amico staging system [8], 1758had compensated

cirrhosiswithout(stage1,n=1172)orwithportalhypertension

(stage2,n=586),whiletheremaining279patientshad

experi-encedadecompensationevent,suchasvaricealbleeding (stage

3,n=22),ascitesorencephalopathy(stage4, n=210),or

multi-pleevents(stage5,n=47).Atotalof107patientshadpreviously

beentreatedforHCC,and89%ofthesehadnothadarecurrence

foratleast6months.Regardingprevioustreatment,1383patients

werenaïvetotherapy,whiletheremaining1229(47.1%)hadbeen

exposedtopeg-interferon/ribavirintherapyeitheraloneorin

com-binationwithﬁrst-generationDAAs.Treatmentdurationwas12

weeksfor93%ofpatients,and24weeksfortherest.ExceptforGT2

patientsforwhomribavirinadministrationwasmandatoryin

con-junctionwithsofosbuvir,ribavirinusewasatthediscretionofthe

prescribingphysician,andwasgivento1114patients.

3.1. Treatmentresponse

At12-weekfollow-upaftertherapy,2516patientshadanSVR12

(96.3%)and15patientshadrelapsed.Thepatientandvirus

charac-teristicswhichmayhaveimpactedontheoutcomeoftherapyare

showninTable1:noinﬂuenceofgender,age,numberof

comor-bidities, adjunctive treatment withribavirin, or failed previous

antiviraltreatmentwasseen.Inparticular,allHCVgenotypeswere

equallyresponsivetothegiventherapy.Theoccurrenceofcirrhosis

marginallyreducedSVR12rates(p=0.073).

3.2. StagingofpatientswithcirrhosisandSVR12rates

SVR12ratesforthe2037patientswithcirrhosiswereevaluated

inrelationtoCTPclass,MELDscore,andtheD’Amico

classiﬁca-tion[8](Table2).ForCPTclassesA–C,theSVR12rateswere96.2%,

95.2%, and 89.7%, respectively; differences werenot signiﬁcant

(p=0.164).UsingtheMELDscoreforstratiﬁcation,theSVR12rates

were95.9%,97.8%,and95.8%forscoresof<12,12–15,and≥16

(p=0.672).WhentheD’Amicostagingsystem[8]wasused,the

SVR12rateswere96.5%inpatientswithoutportalhypertension

(stage1),95.1%inpatientswithcompensatedcirrhosisand

non-bleedingvarices(stage2),100%instage3patients,95.7%inpatients

withasingle,previousdecompensationevent(stage4),and93.6%

inpatientswithmultipledecompensatedevents(stage5);the

dif-ferenceamongtheﬁvestageswasnotsigniﬁcant(p=0.438).SVR12

ratesforthe2037patientswithcirrhosisinrelationtobaseline

characteristicsaregiveninSupplementaryTable1.

3.3. Comparativeeffectivenessoftheﬁvetreatmentschedules

Five DAA regimens were administered, namely

sofos-buvir/ribavirin (n=436), sofosbuvir/simeprevir±ribavirin

Table2

Sustainedvirologicalresponses after direct-actingantiviral treatmentin2037 patientswith cirrhosis,stagedaccordingtoeither theD’Amicosystem orthe Child–Pugh–Turcotte(CPT)classiﬁcation.

Stageofcirrhosis Sustainedvirologicalresponse

Total CPT N(%)

1(noportalhypertension) 1172 1131(97)

A 1093(97) B 38(88) 2(portalhypertension) 586 557(95) A 509(95) B 48(100) 3(varicealbleeding) 22 22(100) A 17(100) B 5(100)

4(singledecompensationevent) 210 201(96)

A 64(98)

B 119(94)

C 18(95)

5(multipledecompensationevents) 47 44(94)

A 9(90)

B 27(100)

C 8(80)

(n=452), sofosbuvir/daclatasvir±ribavirin (n=293), sofosbuvir/ ledipasvir±ribavirin (n=733), and dasabuvir/ombitasvir/ paritaprevir/ritonavir±ribavirin (n=686). The SVR12 rates by therapeutic schedule and the different HCV genotypes in patients with advanced ﬁbrosis or liver cirrhosis are

given in Supplementary Table 2. The recommended

reg-imens for GT2 and GT3, namely sofosbuvir/ribavirin and sofosbuvir/daclatasvir±ribavirin, were successful in most patients. The three regimens for GT1A, 1B, and 4 (i.e., sofos-buvir/daclatasvir±ribavirin,sofosbuvir/ledipasvir±ribavirin,and dasabuvir/ombitasvir/paritaprevir/ritonavir±ribavirin) produced verysimilarSVR12rates.

3.4. Treatmentsafety(Table3)

Atotal of365adverseeventsduringtreatmentwere

experi-encedby 209patients(8.0%of theentirecohort): 168patients

hadoneortwoevents,whiletheremaining41patientshad

mul-tipleevents.Themajorityofevents(320of 365,87.7%)wereof

mild/moderateseverity(grade1or2),whiletheremaining45were

severeorlife-threatening.Thetypesofadverseeventsareshown

inTable3:themostcommonadverseeventswerefatigueand

pru-ritus(especiallyinpatientsreceivingribavirin).Sixteenpatients

discontinuedtreatmentbecauseoffatigueanddiffusemyalgia(5

cases),severe anemia (3cases),itching (3cases),worsening of

liverfunction(2cases),vertigo(2cases),orpneumonia(1case).

Table3

Typesofadverseeventsseenduringantiviraltherapy.

Totalevents Mildevents(grades1–2) Seriousevents(grades3–4)

N(%) N(%) N(%) Fatigue 97(26.8) 94(29.6) 3(6.7) Dizziness/headache 42(11.5) 36(11.2) 6(13.3) Irritability 41(11.2) 39(12.2) 2(4.5) Anemia 39(10.7) 32(10.0) 7(15.6) Gastrointestinalsymptoms 53(14.5) 47(14.6) 6(13.3) Rash/pruritus 61(16.7) 51(15.9) 10(22.2) Arthralgia 18(4.9) 14(4.4) 4(8.9) Epistaxis 2(0.5) 2(0.6) – Infectiveevents 6(1.6) 1(0.3) 5(11.1)

Worseningliverfunction 4(1.1) 3(0.9) 1(2.2)

Worseningkidneyfunction 2(0.5) 1(0.3) 1(2.2)

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Table4

ChangesinbiochemicalparametersandChild–Pugh–TurcotteclassesbeforeandfollowingtherapywithDAAsindecompensatedcirrhoticpatients.

Stage(1-2-3-5) Baseline 3monthfollow-up pValue

Albumin(g/dL)(n=1881) <0.001 >3.5 1572(83.6) 1725(91.7) 2.8–3.5 286(15.2) 131(7.0) <2.8 23(1.2) 25(1.3) INR(n=1903) ≤1.7 1849(97.2) 1861(97.8) 0.001 1.7–2.2 45(2.3) 22(1.2) >2.2 9(0.5) 20(1.0) Bilirubin(mg/dL)(n=2006) <2 1866(93.0) 1899(94.7) 0.005 2–3 117(5.8) 75(3.7) ≥3 23(1.2) 32(1.6) Creatinine(n=1979) Median(IQR) 0.78(0.68–0.90) 0.80(0.70–0.90) <0.001 Platelets(n=2025) Median(IQR) 130(92–174) 137(98–184) <0.001 CPT,n(%)(n=1822) A 1644(90.2) 1733(95.1) <0.001 B 156(8.6) 79(4.3) C 22(1.2) 10(0.6) Table5A

Decompensationeventsin2612patientswithHCVinfectionduringtreatmentwithdirect-actingantiviralagents.

Liverdamage Totalpatients(N) Duringtreatment Ascites/PBS EPS Bleeding HCC

Patients Events N(%) N F3 575 – – – – – – Stageofcirrhosis 1 1172 1(0.09) 1 – – – 1 2 586 12(2.05) 13 3 2 2 6 3 22 2(9.09) 3 – – 3 – 4 210 14(6.67) 20 15 1 2 2 5 47 6(12.77) 11 3 2 4 2 CPT A 1759 15(0.85) 21 6 – 7 8 B 249 15(6.02) 20 12 3 3 2 C 29 5(17.24) 7 3 2 1 1

Adverseeventsstratiﬁedbydegreeofliverfunctionalimpairment areshowninSupplementaryTable3.Onlytwomildeventswere seeninCPTclassCpatients,whileonly11mildeventswerenoted in279patientsinstages3–5oftheD’Amicosystem.

3.5. Functionaloutcomes

BiochemicalparametersandCPTclassfollowingtherapywere not available for all patients. In patients with pairedpre- and post-treatmentdata,improvementswereevidentinpatientswith

compensated(stages1and2)andwithpreviouslydecompensated cirrhosis(stages3–5).Pre-andpost-therapydatawereavailable for 198patientsinstages 3–5(Table4):withtheexception of

bilirubinlevels,thenumbersofpatientswithnormalalbuminand

INRvaluesincreasedsigniﬁcantlycomparedtobaseline.

Circulat-ingplateletsandcreatininelevelsalsoincreasedsigniﬁcantlywith

respecttobaseline.Pre-andpost-treatmentinformationforCPT

classwasavailablefor198patientsinstages3–5:thefrequency

ofCPTclassApatientsincreasedsigniﬁcantlyfrom35.9%to80.3%

(p<0.001).

Table5B

Decompensationeventsin2601patientsa_with_HCV_infection_at_3-month_follow-up_after_treatment

Liverdamage Totalpatients(N) At3-monthfollow-up Ascites/PBS EPS Bleeding HCC

Patients Eventsno. N(%) F3 569 1(0.18) 1 – – – 1 Stageofcirrhosis 1 1165 11(0.95) 11 5 – – 6 2 586 22(3.81) 25 7 2 5 11 3 22 – – – – – – 4 212 16(7.66) 17 11 2 – 5 5 47 9(19.57) 10 5 4 1 6 CPT A 1750 33(1.89) 36 11 2 5 18 B 253 19(7.72) 20 13 3 1 4 C 29 6(21.43) 7 4 3 – 2 HCC,hepatocellularcarcinoma.

(6)

Hepaticdecompensationeventsduringandfollowingtherapy areshowninTables5Aand5B.TwoHCCs(0.35%)developedin

the575patientswithadvancedﬁbrosis,oneduringandoneafter

therapy.Thenumbersofpatientswithcirrhosiswhoexperienced

adverseeventsduringtreatmentincreasedlinearlywith

progres-sionof the staging class of both theCPT classiﬁcationand the

D’Amicostagingsystem.Thesametrendwasapparentin

follow-upaftertreatment.Atotalof111adverseeventswereseeninthe

cohortof2037patientswithcirrhosis(5.45%);ofthese,34were

HCCsandtheremaining77werehepaticdecompensationevents

(ascites,encephalopathy,andbleeding).Ofthe34HCCs,11were

diagnosedduringand23followingtreatment.ThemajorityofHCCs

(24of34,70.6%)occurredpatientswithcompensatedcirrhosis(CPT

classA,orstage1or2).Bothduringandaftertreatment,hepatic

failureeventswereseenmorefrequentlyinpatientswhohad

expe-riencedapastepisodeofdecompensation:34of48events(70.8%)

inCPTclassesBandC,and27of48events(56.3%)instages3–5.

4. Discussion

Thepresentstudyconductedbyanetworkof25Italian

cen-tersinvolvedinthemanagementofpatientswithHCV-relatedliver

disease,hasreviewedtheefﬁcacyand safetyof DAA treatment

in patientswithcompensated cirrhosis,particularly those with

previousdecompensation.Our investigation examineda cohort

ofpatientswithpreviouslydecompensatedcirrhosis(n=279)and

reportedanunexpectedlyhighrateofSVR12(95.7%),comparable

withthatofpatientswithlessadvancedliverdamage.

InformationonthetherapeuticresponseofpatientswithCPT

classCcirrhosistoDAAsisfragmentary,assafetyconcerns

regard-ingDAAusehaslimitedtheirenrollmentinregisteredtrials[4–6].

DataarenumericallymoreconsistentforCPTclassB,butthe

char-acteristicsof patientsin this subgroupare veryheterogeneous.

Indeed,CPTclassCpatientswithdecompensatedcirrhosis(ascites,

bleeding,encephalopathy,jaundice)maybereclassiﬁedintoclass

Bfollowing successful treatmentof theevent. In addition, CPT

classBcanincludebothpatientswithapastdecompensatedevent

andminimalalterationinbiochemicalparameters(INR,bilirubin,

albumin)andpatientswhohaveneverdecompensatedbuthave

largerchangesinhepaticindices.Thereisaconfusingrelationship

betweenCPT classandimpairmentofliverfunction.CPT

classi-ﬁcationconsidersﬁvevariables,ofwhichtwoareclinicalevents

consequenttoportalhypertension(ascitesandencephalopathy)

andthreearelaboratorytestslikelyreﬂectingimpairedliver

func-tion. Although the laboratory parameters are only marginally

affectedbytherapeuticinterventions,ascitesandencephalopathy

mayresolvefollowingtreatmentbutrecurduringfollow-up.This

variabilitymeansanindividualpatientmaybeclassiﬁeddifferently

overtime,withalikelytransitionfromoneclasstoanotherone

dur-ingCPTstaging.Incontrast,theD’Amicostagingsystem[8]only

considersthestatusofcirrhosisinrelationtoportalhypertension,

themostimportantconsequenceofliverﬁbrosisandaharbinger

ofepisodesofdecompensation.Adoptionofthissystemmeansa

patientwithcirrhosisandascitesremainsinthesamestageeven

aftersuccessfultreatmentoftheevent.Inourinvestigation,SVR

ratesrangedfrom96.5%intheabsenceofportalhypertension,to

95.1%inthepresenceofvarices(stage2),100%and95.7%inthe

eventofpastdecompensation(stages3and4,respectively),and

93.6%inpatientswithmultipleevents(stage5).Ourﬁndings

sug-gesttheuseofDAAsforpreviouslydecompensated(stages3–5)

patientsurgentlyneedingforacureoftheirHCVinfectioncouldbe

expanded.

As there are no head-to-head randomized controlled

tri-als comparing DAA regimes, and our data were sufﬁcient

to conduct supplemental analyses, we undertook indirect

treatment comparisons of the efﬁcacy of the different DAA

schedules. The analysis provided comparable SVR rates for all

regimens: 95.4% for sofosbuvir/simeprevir±ribavirin, 97.4%

for sofosbuvir/ledipasvir±ribavirin, and 96.4% for

dasabu-vir/ombitasvir/paritaprevir/ritonavir±ribavirin. For countries

with budget constraints, our results would allow therapeutic

choicetobegovernedonlybythecostofthedrug(s).

Ingeneral,patientswithcirrhosiswhoreceivedtreatmentwith

thenewDAAswhetherornotinregisteredtrials[10]hadlower

ratesofSVRcomparedtopatientsinthepresentcohort.Alikely

explanationmaybetheexclusion fromouranalysisofpatients

treatedwithsofosbuvir/ribavirin,aregimenconsideredoflimited

efﬁcacyforGT1andGT4patientswithcirrhosis.Afurtherreason

couldbethemeticulouscheckingforpotentialdruginteractions

betweentheDAAsandotheragentsco-administeredtothepatient

[13].

Beneﬁt from therapy in this fragile population should not

obscurethesafetyissue.Wekeretal.haverecentlydocumented

the frequency of hepatic decompensation during the courseof

DAAtreatmentforhepatitisC[17].Grayetal.havealsoreported

a 6% rate of on-treatment mortality in patients who were in

CPTclass Batbaseline,andof 21%inthoseinCPT classC[18].

Thishighfrequencyofseriousadverseeventshasbeenreported

with virtually all oral regimens [19]. However, the alternative

view that these events may be unrelated and coincidental to

therapy, representingprogression of thediseasedespite

antivi-ral therapy, has been discussed [20]. The safety proﬁle in our

real-world cohort was excellent: adverse events occurredin a

few patients but the majority of events were mild to

moder-ateand aggravated by ribavirin co-administration.It should be

remembered that a consistent proportion of our patients with

cirrhosis received off-label therapy with simeprevir-containing

schedulesandadasabuvir/ombitasvir/paritaprevir/ritonavir

com-bination, regimens that are not recommended in CPT Band C

cirrhosis[15].Despitethis,onlythreelife-threateningeventswere

seeninthe27patientsintheseclasses.

Afavorable outcomefollowingDAA administrationhasbeen

consistentlydocumentedinpreviousstudies[1,2,10]:ingeneral,

improvementsinCPTclassesand/orMELDscoreshavebeennoted

inaboutonethirdoftreatedpatients,andareusuallythoughtto

reﬂectbetterliverfunction.However,thesetwostagingsystems

donotonlyreﬂecthepaticsyntheticfunction,astwoportal

hyper-tensionadverseeventsareincludedintheCPTclassiﬁcation,and

creatininevalueintheMELDscoring.Ourdatainpreviously

decom-pensatedpatientsrevealedimprovementsintwoliversynthetic

indices,inplateletscounts,andincreatininevalues.

Inconclusion,themainﬁndingaftertreating2612HCV-infected

patientswithadvanced ﬁbrosisorcirrhosis ina real-world

set-tingisthatthetreatmentissafeandefﬁcaciousevenforpatients

with previously decompensated disease. With the

recommen-dation tocheck for druginteractions between DAAsand other

co-administeredagents,thissubgroupofpatientsmaybeneﬁtthe

mostfromDAAtreatment:followingapositivetherapeutic

out-come,parametersofliversyntheticcapabilityareimprovedand

thenumberofhepaticdecompensationeventsisreduced.

Conﬂictofinterest

Nonedeclared.

Co-authors

AngeloIacobellis:DivisionofGastroenterology,“CasaSollievo

Sofferenza”Hospital,IRCCS,SanGiovanniRotondo,Italy.

ImmacolataCarraturo:DivisionofInfectiousDiseases,“V.Fazzi”

(7)

PieraldoPaiano:DivisionofGastroenterology,Hospitalof

Scor-rano,Scorrano,Italy.

NicolaAndriulliandMartaLibrandi:DepartmentofPhysiology,

FacultyofPharmacia,“LaSapienza”University,Rome,Italy.

Silvia Martini: Department of Medical Sciences, University

of Turin and Department of Gastroenterology and Hepatology,

AziendaOspedalieraCittàdellaSaluteedellaScienza,Turin,Italy.

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound,in

theonlineversion,athttp://dx.doi.org/10.1016/j.dld.2017.03.025.

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