HCV mono-infected and HIV/HCV co-infected individuals treated with direct-acting antivirals: to what extent do they differ?

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HCV

mono-infected

and

HIV/HCV

co-infected

individuals

treated

with

direct-acting

antivirals:

to

what

extent

do

they

differ?

Giuseppe

Bruno

a,

*

,

Annalisa

Saracino

a

,

Luigia

Scudeller

b

,

Claudia

Fabrizio

a

,

Raffaele

Dell

’Acqua

a

,

Eugenio

Milano

a

,

Michele

Milella

a

,

Nicoletta

Ladisa

a

,

Laura

Monno

a

,

Gioacchino

Angarano

a

ClinicofInfectiousDiseases,UniversityofBari,Bari,Italy

b_Scientiﬁc

Direction,ClinicalEpidemiologyUnit,IRCCSPoliclinicSanMatteoFoundation,Pavia,Italy

ARTICLE INFO

Articlehistory:

Received28February2017 Receivedinrevisedform3July2017 Accepted4July2017

CorrespondingEditor:EskildPetersen, Aar-hus,Denmark Keywords: Direct-actingantivirals DAAs SVR Safety HIV/HCVco-infection Realworld ABSTRACT

Background:Direct-actingantiviral(DAA)-basedtreatmentofhepatitisCvirus(HCV)hasbeenassociated withhighsustainedvirologicalresponse(SVR)ratesandgoodtolerabilityinrandomizedclinicaltrials. ThisstudywasperformedtoassessthesafetyandeffectivenessofDAAsinbothHCVmono-infectedand HIV/HCVco-infectedpatients.

Methods:AllconsecutiveHCV-infectedpatients,includingHIV/HCVco-infectedpatients,receiving DAA-basedtreatmentfromFebruary2015toSeptember2016atthestudyclinicwereincluded.Clinical, virological, andbiochemicaldata wereretrieved.Theprimaryend-point wastheSVR12(HCVRNA undetectable12weeksaftertheendoftreatment)iscommonlyusedworldwide.Thesecondary end-pointwasthesafetyproﬁleofDAAsduringthetreatmentperiod.

Results:Atotalof382patientswereincluded;62wereHIV/HCVco-infected.Cirrhosiswasfoundin256 patients(67.4%).SVR12wasachievedin365/382(95.5%)individuals(58/62HIV/HCVco-infected,93.5%) intheintention-to-treat(ITT)analysis.Aplateletcount<90109_/l_(odds_ratio_(OR)_4.12,_95%_conﬁdence

interval(CI)1.5–11.3,p=0.006),HCVgenotype3infection(OR5.49,95%CI1.9–15.7,p=0.002),liver stiffness>20kPa(OR3.05,95%CI1.03–8.96,p=0.04),andModelforEnd-StageLiverDisease(MELD) score>10(OR5.27,95%CI1.16–23.8,p=0.03)wereassociatedwithlowerSVRrates.Onmultivariate analysis,onlygenotype3infectionremainedanegativepredictorofSVR(OR21.6,95%CI3.81–123, p=0.001).Treatmentdiscontinuationwasobservedin10subjects.Severeadverseevents(SAEs)occurred in17patients(4.5%).

Conclusions:HighSVR12rateswereobservedinbothHCVmono-infectedandHIV/HCVco-infected individuals.Overall,DAA-basedtreatmentwassafeandtherewerenodifferencesintermsofSAEsand treatmentdiscontinuationbetweenthetwogroups.

http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Globally,anestimated130–170millionpeopleareinfectedwith thehepatitisCvirus(HCV),andthevirusisfoundin10–30%ofall peoplelivingwithanHIVinfection(Hajarizadehetal.,2013;Wyles etal.,2016).Furthermore,chronicHCVinfectionisstilla major cause of liver disease worldwide (Hajarizadeh et al., 2013). In addition,HCV-relatedliverdiseasehasemergedasaleading

non-HIVcauseofdeathinHIV/HCVco-infectedsubjectsasaresultofan acceleratedliverﬁbrosisprocess(Wylesetal.,2016).

Fornearlytwodecades,interferon(IFN)-basedtreatmentwas theonlytherapeuticoptionagainstHCVinfection.Thistreatment ischaracterizedbyverylowsustainedvirologicalresponse(SVR) rates,particularlyinHIV/HCVco-infectedindividuals(Wylesetal., 2016;Sulkowsky,2016).Therecentintroductionofdirect-acting antivirals (DAAs) has widely changed the anti-HCV treatment scenario,improvingSVRratesandpromisingadramaticreduction inHCV-relatedmorbidityandmortality(Flisiaketal.,2017;EASL RecommendationsonTreatmentofHepatitisC,2016).Moreover, the favourable safety proﬁle of DAAs reported in randomized clinicaltrialshasrenderedtheDAA-basedregimensveryattractive (Wyles et al., 2016; Flisiak et al., 2017). However, ‘IFN-free’

*Correspondingauthorat:ClinicofInfectiousDiseases,UniversityofBari,Piazza G.Cesare,11,70124Bari,Italy.Tel.:+390805592473;Fax:+390805716333.

E-mailaddress:giusbruno85@gmail.com(G.Bruno).

http://dx.doi.org/10.1016/j.ijid.2017.07.001

1201-9712/©2017TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

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

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regimensstillhavehighcosts,thereforeaccesstotreatmentwith DAAs is limited by current reimbursement criteria in different countries(Craxìetal.,2016).

OnlyafewpublishedstudiesontheefﬁcacyandsafetyofDAAsin thereal-worldclinicalsettingareavailable,withparticularlyfew related to HIV/HCVco-infected individuals (Milazzo et al., 2016; Bruno et al., 2017; Hawkins et al., 2016; Del Bello et al., 2016; Rockstroh etal.,2016;Younossietal.,2016;Sognietal.,2016).Therefore,theaim ofthisstudywastoassessthesafetyandeffectivenessofDAA-based antiviral therapy in both HCV mono-infected and HIV/HCV co-infectedpatientsinaclinicalpracticesetting.

Materialsandmethods

AllconsecutiveHCV-infectedpatients(18yearsold),withor withoutHIVinfection,whohadreceivedatleastonedoseof DAA-basedanti-HCV therapybetweenFebruary2015and September 2016intheClinicofInfectiousDiseasesofBari,wereincludedin thisretrospectiveobservationalstudy.

Demographic,clinical(medicalhistory,concomitant co-med-ications, failure with previous anti-HCV therapy, and adverse events), chemical, and virological data were collected for all subjects during the treatment period and after the end of treatment (EOT). Biochemical data collected included levels of serumcreatinine,albumin,totalbilirubin,alanine aminotransfer-ase(ALT),aspartateaminotransferase(AST),haemoglobin,andthe plateletcount(PLT).DataregardingthehistoryofHIVinfection, CD4cellcount,andantiretroviraltherapy(ART)werealsoretrieved forallHIV/HCVco-infectedpatients.

The primary end-point was the SVR12 rate (undetectability lastingfor12consecutiveweeksafterthecessationoftreatment) usinganintention-to-treat(ITT)analysis;allpatientswhoreceived atleast onedoseof anti-HCV medicationwereincludedin the analysis.Thesecondaryend-pointwasthesafetyproﬁleofDAAs duringthetreatmentperiod.

DAA-basedanti-HCVtreatment

Thefollowingregimenswereadministeredbasedoncurrent guideline recommendations (EASL Recommendations on Treat-mentof Hepatitis C, 2016;Sogniet al.,2016):sofosbuvir (SOF; nucleosideNS5Bpolymeraseinhibitor)+ribavirin(RBV)in geno-types2and3;SOFandledipasvir(LDV;NS5Ainhibitor)RBVin genotypes1and4;SOFanddaclatasvir(DCV;NS5Ainhibitor) RBV in genotypes 1, 2, and 3; SOFand simeprevir (SMV; NS3 proteaseinhibitor)RBVingenotypes1and4;ombitasvir(OMB; NS5A inhibitor), paritaprevir/ritonavir (PTV/r; ritonavir-boosted protease inhibitor), and dasabuvir (DSV; non-nucleoside NS5B polymeraseinhibitor)RBVingenotype1;andOMB,PTV/r,and RBVingenotype4.

RBV(weight-basedRBVdose:_<65kg,800mgperday;₆₅and <75kg,1000mg perday;75kg,1200mg per day)was added according to the clinician’s judgement and based on the international recommendations (EASL Recommendations on Treatment of HepatitisC, 2016; Europeanassociation for study ofliver,2015).

Assessmentofliverﬁbrosisatbaseline

Baselineliverﬁbrosiswasassessedinallpatientsbymeansof surrogatebiomarkers(ﬁbrosis-4score(FIB-4)andAST-to-PLTratio index(APRI))andbyliverstiffness.

APRIwascalculatedaccordingtotheformulaproposedbyWai (Wai et al., 2003) and FIB-4 was calculated using the Sterling formula(Sterlingetal.,2006).AnAPRIscore>1andFIB-4score 3.25signiﬁesadvancedliverﬁbrosisorcirrhosis.

Liverstiffnesswasevaluatedbycertiﬁedoperators(trainedby the manufacturer) using transient elastography (FibroScan; EchoSens, Paris, France). Liver cirrhosis was deﬁned as a liver stiffness12.5kPa(Casteraetal.,2008),orinthepresenceofa clinicaldiagnosis.

HCVRNAmeasurementandHCVgenotypeassessment

Plasma HCV RNA levels were measured for all patients at baseline,atweek4,atEOT,and3and6monthsafterEOT,usingthe Siemens Real TimePCR assay(SiemensHealthcare Diagnostics, Tarrytown,NY,USA),withalowerlimitofdetectionof15IU/ml. HCVgenotypeandsubtypeweredeterminedusingtheSiemens VersantHCVLiPAV2assay(Siemens,Munich,Germany). Deﬁnitions

Rapidvirologicalresponse(RVR)wasdefinedasan undetect-ableserumHCVRNAlevelatweek4andSVRasanundetectable HCVRNAlevelatweek12afterEOT.Virologicalbreakthroughwas definedasanundetectableHCVRNAduringtreatmentfollowedby adetectableHCVRNA,despitecontinuedtreatment.Relapsewas definedasundetectableHCVRNAatEOTbutdetectableHCVRNA duringfollow-up.

TwoconsecutiveHIVRNAmeasurements>200copies/mlafter virological suppression (Panel on Antiretroviral Guidelines for AdultsandAdolescents,2017)signiﬁedvirologicalfailureto anti-HIV treatment. A virological blip was de_ﬁned as an isolated detectableHIVRNAlevelaftersuppression,followedbyareturnto HIVRNAsuppression.

Severeadverseevents(SAEs)

Serious adverseevents wereclassiﬁedaccording toa recent deﬁnition (Common Terminology Criteria for adverse events (CTCAE),2017).

Ethics

Thisresearchdidnotrequireformalapprovalfromtheethics committeeaccordingtoItalianlaw,sinceitwasperformedasan observationalretrospectivestudyinthecontextofnormalclinical routines.However,thestudywasconductedinaccordancewith theDeclarationofHelsinkiandnationalandinstitutional stand-ards.Allpatientsprovidedinformedconsentfortheuseoftheir dataforresearchpurposes.

Statisticalanalysis

Descriptivestatisticswerecalculatedfordemographic,clinical, and laboratory characteristics of cases. Mean and standard deviation (SD) values were recorded for normally distributed variables, and the median and interquartile range (IQR) were recordedfornon-normallydistributedvariables.Thenumberand percentage wererecorded for categorical variables. Differences betweengroupswereanalysedusingtheChi-squaretest,t-test,or Mann–Whitneytest,asappropriate.Univariableandmultivariable logisticregressionmodelswereappliedtoassessfactorsassociated withaSVRandwiththeoccurrenceofSAEs.Ap-valueof<0.05was consideredtoindicatesigniﬁcance.

Results

Atotalof382patients(320HCVmono-infectedand62HIV/ HCV co-infected) were included in this study. The clinical

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characteristicsofthesepatientsatbaseline,whetherHCV mono-infectedorHCV/HIVco-infected,aresummarizedinTable1.

AllsubjectswereCaucasian.ComparedwithHCVmono-infected patients,HIV/HCVco-infectedindividualswere younger(median age 52.5 vs.68 years,p<0.001), mostly male (91.9% vs. 58.8%, p<0.001),andmorefrequentlyinfectedwithgenotype1a(51.6%vs. 6.3%,p<0.001),genotype3(22.6%vs.7.8%,p<0.001),andgenotype 4 (16.1% vs. 2.8%, p<0.001). Failure to a previous anti-HCV treatmentwasreportedin208patients(54.4%).AmongtheHCV treatment-experiencedsubjects,ﬁvehadexperiencedfailure witha previousIFN-freeregimen.Interleukin28(IL-28)genotypeswere availablefor61patients:14(22.9%)hadaCCgenotype,29(47.5%) hadaCTgenotype,and18(29.5%)hadaTTgenotype.

Cirrhosis was foundin 256 (67%) patients (37HIV/HCV co-infected).Mostpatientshadcompensatedliverdiseaseexcepttwo HCVmono-infectedpatientswithChild–PughclassC.

HIV/HCVco-infectedsubjectsshowedahigherModelfor End-StageLiverDisease(MELD)scoreandalowerPLTcountatbaseline compared with HCV mono-infected subjects.No differences in

liverstiffness,APRIscore,orFIB-4scoreatbaselinewereobserved betweenthetwogroups.

HCVmono-infectedindividualsweremorelikelytohavetwoor more comorbidities than HIV/HCV co-infected patients before starting DAAtreatment.Arterialhypertension(33%) and type2 diabetesmellitus(16.8%)werethemostcommoncomorbidities.

HIV/HCV co-infected patients were more frequently treated withaDAA-basedregimenwithoutRBVcomparedtoHCV mono-infectedpatients(66.2%vs.46.7%,p=0.003).

SafetyproﬁleofDAAsandfactorsassociatedwiththeoccurrenceof SAEs

Overall, DAA-basedtreatmentwas safeandwell-tolerated inboth HCVmono-infectedandHIV/HCVco-infectedpatients.Thesafety proﬁleisdescribedinTable2.Themostcommonadverseevents wererash(16.5%),fatigue(12%),andanaemia(11.5%).HIV/HCV co-infectedpatientsweremorelikelytoshowjaundiceandaPLTcount <70109_/l_during_treatment_than_HCV_{mono-infected}_patients._No

Table1

Clinicalcharacteristicsatbaselineofthe382patients.a

Total HCV HIV/HCV p-Value

Number n=382 n=320 n=62 Age,years 65(53–73) 68(58–75) 52.5(51–55) <0.001 Male,n 247(64.6) 190(59.3) 57(91.9) <0.001 BMI 25.9(23.5–28.4) 26.1(23.7–28.6) 25.6(23–27.4) 0.02 HBsAg-positive 4(1) 3(0.9) 1(1.6) 0.5 HCVgenotypes 1a 52(13.6) 20(6.3) 32(51.6) <0.001 1b 207(54.2) 202(63.1) 5(8.1) <0.001 2 65(17) 64(20) 1(1.6) <0.001 3a 39(10.2) 25(7.8) 14(22.6) <0.001 4 19(5) 9(2.8) 10(16.1) <0.001 HCVRNA,IU/ml 1 307000(390400–3080000) 1150000(377050–3043769) 1845000(680925–3879500) 0.49 Treatment-experienced 208(54.4) 171(53.4) 37(59.6) 0.22

Liverstiffness,kPa 13.6(11.1–20.3) 13.5(11.3–19) 13.9(9.5–22.35) 0.98 FIB-4score 3.36(2.02–5.64) 3.43(2.11–5.71) 2.77(1.94–4.9) 0.1 APRIscore 1.25(0.68–2.28) 1.23(0.68–2.15) 1.49(0.77–2.78) 0.28 Cirrhosis,n(%) 256(67) 219(68.4) 37(59.7) 0.18 Child–Pughclass A 244(95.3) 209(95.4) 35(94.5) 0.18 B 10(3.9) 8(3.6) 2(5.5) 0.74 C 2(0.8) 2(1) 0 0.53 MELDscore 7(7–8) 7(7–8) 8(7–9.7) <0.001 Plateletcount,n109 /l 141(106–186.5) 143(108–187) 137(98.7–184.5) 0.33 Plateletcount<90109 /l 60(15.7) 47(14.7) 13(21) 0.25 Albumin,g/dl 3.9(3.7–4.2) 3.9(3.7–4.2) 3.9(3.7–4.2) 0.84 AST,IU/ml 66(44.5–96.5) 66(44–94) 65.5(48.7–101.5) 0.91 ALT,IU/ml 77(51–130) 74(50–125) 93.5(57–141.5) 0.04 2comorbidities 99(25.9) 91(28.4) 8(12.9) 0.01 TypeofHCVtherapy SOF+RBV 75(19.6) 63(19.7) 12(19.4) 0.95 SOF+SMVRBV 57(14.9) 40(12.5) 17(27.4) 0.002 SOF+LDVRBV 64(16.8) 42(13.1) 12(19.4) 0.19 SOF+DCVRBV 37(9.7) 31(9.7) 6(9.6) 0.81 OMB+PTV/r+DASRBV 141(36.9) 129(40.3) 12(19.4) 0.001 OMB+PTV/r+RBV 8(2.1) 5(1.6) 3(4.8) 0.1 DurationofHCVtherapy 12weeks 254(66.5) 216(67.5) 38(61.3) 0.34 16weeks 15(3.9) 15(4.7) 0 0.08 24weeks 108(28.3) 85(26.6) 23(37.1) 0.09 Other 5(1.3) 4(1.3) 1(1.6) 0.81 AdditionofRBV 241(63) 212(66.2) 29(46.7) 0.003 PatientsonART 60(96.8) CD4nadir,cells/mm3 124.5(68.25–223.25) ChangeofART 23(37.1)

UndetectableHIVRNA 61(98.4)

CD4count,cells/mm3 ₆₁₁_{(414–843.5)}

ALT,alanineaminotransferase;ART,antiretroviraltherapy;AST,aspartateaminotransferase;BMI,bodymassindex;DAS,dasabuvir;DCV,daclatasvir;HBsAg,hepatitisB surfaceantigen;HCV,hepatitisCvirus;LDV,ledipasvir;MELD,ModelforEnd-StageLiverDisease;OMB,ombitasvir;PTV/r,paritaprevir/ritonavir;RBV,ribavirin;SMV, simeprevir;SOF,sofosbuvir.

a

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othersigniﬁcantdifferencesintermsoftheoccurrenceofadverse eventswereobservedbetweenthetwogroups.Inaddition,patients receivingRBVmorefrequentlyshowedadverseeventsinthecourse oftreatmentincomparisonwithsubjectstreatedwithRBV-sparing regimens. Erythropoietin use and a RBV dose reduction were reported in 16 (4.2%) and 26 (6.8%) patients, respectively. Five patients(1.3%)neededbloodtransfusions.

SAEsoccurredin17 patients(4.5%) anda discontinuationof anti-HCVtreatmentwasobservedin10(2.6%)individualsoverall. One HCVmono-infected patient, who achieveda SVR, stopped therapybecauseoflivertransplantation.OneHIV/HCVco-infected patient withHCV genotype 4 who was treated with SOF+LDV experienced a virological breakthrough at week 8 and discon-tinuedanti-HCVtherapy.Ofthe17patientswithSAEs,14required hospitalization.ThemostcommonSAEsweresevereanaemiain ﬁvepatients(1.3%)andgastrointestinalbleedinginfour(1%).Two patientsdevelopednewlydiagnosedatrialﬁbrillation.

A baseline PLT count <90109_/l _(odds _ratio _(OR) _5.34, _95%

conﬁdenceinterval(CI)1.97–14.49,p=0.001),abaseline albumin <3.5g/dl(OR4.3,95%CI1.5–12.27,p=0.006),andaMELDscore>10 (OR 7.4, 95% 1.82–30.3, p=0.005) were associated with the occurrenceofSAEsonunivariateanalysis.However,on multivari-able analysis adjusting for a MELD score >10 and PLT count <90109_/l, _a _baseline _MELD _score _>10 _was _the _only _factor

signiﬁcantlyassociated with SAEs (OR 4.78, 95% CI 1.02–22.53, p=0.04).

Twodeaths(0.5%)werereportedduringanti-HCVtherapy(due tobleedingoesophagealvaricesandnon-Hodgkinlymphoma). EffectivenessofDAAsandfactorsassociatedwithSVR12

Overall,SVR12wasachievedin365/382(95.5%)patientsinthe ITTanalysis.SVRratesaccordingtotheuseofRBV,diagnosisof

cirrhosis, failure on a prior HCV treatment, concomitant HIV infection,andHCVgenotype3infectionareshowninFigure1.

FactorsassociatedwithSVRaredescribedinTable3.Patients withabaseline PLTcount<90109_/l_(OR_4.12, _95%_CI_1.5_–11.3,

p=0.006), a liver stiffness >20kPa (OR 3.05, 95% CI 1.03–8.96, p=0.04),aMELDscore>10(OR5.26,95%CI1.16–23.89,p=0.03), and agenotype 3infection(OR5.48,95% CI1.9–15.7,p=0.002) werelesslikelytoachieveSVR.Femalesex(OR0.1,95%CI0.01– 0.82, p=0.03) was associated with higher rates of SVR. On multivariableanalysis, adjusting for sex,liverstiffness >20kPa, PLTcount<90109_/l,_MELD_score_>10,_and_genotype₃_infection,

onlygenotype3infectionremainedindependentlyassociatedwith alowerrateofSVR(OR21.64,95%CI3.81–123,p=0.001).

SVR12 ratesaccording totheDAAregimenwereas follows: 89.3% (67/75) forSOF+RBV,94.7% (54/57)for SOF+SMVRBV, 93.7%(60/64)forSOF+LDVRBV,97.3%(36/37)forSOF+DCV RBV,99.3%(140/141)forOMB+PTV/r+DASRBV,and100%(8/8) forOMB+PTV/r+RBV.

SVR12ratesaccordingtotheHCVgenotypewereasfollows: 98%(51/52)forgenotype1a,98%(203/207)forgenotype1b,93.8% (61/65)forgenotype2,84.6%(33/39)forgenotype3,and89.4%(17/ 19)forgenotype4.

SVR12ratesaccordingtotheDAAregimenforthe39patients infectedwithgenotype3wereasfollows:78.9%(15/19)fora 24-week course of SOF+RBV, 75% (3/4) for a 24-week course of SOF+DCV,100%(4/4)fora12-weekcourseofSOF+DCV+RBV,and 100%(8/8)fora24-weekcourseofSOF+DCV+RBV.

An additional patient, wrongly classiﬁed as infected with genotype1b,receiveda 12-weekcourseofSOF+SMV+RBV and relapsed, because afterrepeatHCV genotypingthepatientwas actuallyfoundtohaveagenotype3infection.

Allpatientswhohadexperiencedpreviousfailurewithan IFN-sparingregimenachievedSVR12.

Table2

SafetyoftreatmentwithDAAs.

Total,n=382 HCV,n=320 HIV/HCV,n=62 p-Value

RBV NoRBV RBV NoRBV

NumberaccordingtoRBVuse 212 108 29 33

Mostcommonadverseevents

Headache 29(7.6) 16(7.5) 7(6.4) 2(6.9) 4(12.1) 0.75 Insomnia 12(3.1) 8(3.7) 2(1.8) 1(3.4) 1(3) 0.83 Fatigue 46(12) 30(14.1) 5(4.6) 8(27.5) 3(9) 0.003 Dizziness 14(2.7) 8(3.7) 5(4.6) 0 1(3) 0.69 Mooddisorders 27(7.1) 18(8.5) 3(2.7) 3(10.3) 3(9) 0.22 Gastrointestinaldisorders 41(10.7) 31(14.6) 6(5.5) 2(6.9) 2(6) 0.05 Rash,pruritus,orphotosensitivityreaction 63(16.5) 38(17.9) 16(14.1) 3(10.3) 6(18.1) 0.7

Jaundice 10(2.6) 4(1.8) 0 6(20.6) 0 <0.0001

Other 62(16.2) 32(15.1) 25(23.1) 1(3.4) 4(12.1) 0.05

Haematologicalabnormalities

Anygradeofanaemia 44(11.5) 36(16.9) 2(1.8) 6(20.6) 0 <0.0001 Anaemia<10g/dl 30(7.9) 22(10.3) 2(1.8) 6(20.6) 0 <0.0001 Anaemia<8g/dl 6(1.6) 5(2.3) 1(0.9) 0 0 0.54 Useoferythropoietin 16(4.2) 12(5.6) 1(0.9) 3(10.3) 0 0.04 RBVdosereduction 26(6.8) 25(11.7) 0 1(3.4) 0 <0.0001 Bloodtransfusions 5(1.3) 4(1.8) 1(0.9) 0 0 0.02 Plateletcount<70109 /l 31(8.1) 14(6.6) 7(6.4) 2(6.8) 8(24.2) 0.005 Plateletcount<50109_/l ₉_(2.4) ₃_(1.4) ₃_(2.7) ₀ ₃₍₉₎ _0.04 Biochemicalabnormalities

Elevatedtotalbilirubin(4–5vv) 20(5.2) 9(4.2) 7(6.4) 6(20.6) 1(3) 0.005 Discontinuationoftherapy 10(2.6) 5(2.3) 4(3.7) 0 1(3) 0.71 Atleast1adverseevent 220(57.6) 133(62.7) 50(46.2) 19(65.5) 18(54.5) 0.03 2adverseevents 87(22.8) 56(26.4) 17(15.7) 10(34.4) 4(12.1) 0.02 Severeadverseevents 17(4.5) 10(4.7) 5(4.6) 1(3.4) 1(3) 0.96

Gastrointestinalhaemorrhage 4(1) 3(1.4) 0 1(3.4) 0 0.33

Severeanaemia 5(1.3) 4(1.8) 1(0.9) 0 0 0.32

Hepaticencephalopathy 2(0.5) 1(0.5) 1(0.9) 0 0 0.87

Other 6(1.6) 2(1) 3(2.7) 0 1(3) 0.47

Deaths 2(0.5) 1(0.5) 1(0.9) 0 0 0.87

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Amongthe17patientswhodidnotachieveSVR12,twoHCV mono-infectedpatientswerelosttofollow-up,ﬁvediscontinued therapy(fourforSAEs,includingtwodeaths,andonegenotype4 HIV/HCV co-infected patient treated with SOF+LDV who had virologicalbreakthrough),and10hadarelapse:twogenotype2 andfourgenotype3treatedwithSOFandRBV;onegenotype1b treated with OMB+PTV/r+DAS; one genotype 1b and one genotype4bothtreatedwithSOF+SMV;andoneHCVgenotype 3patientwronglytreatedwithSOF+SMV+RBVfor12weeks.

Patients who did not achieve SVR, including those with virological relapse and breakthrough, underwent resistance analysis. Resistance-associated variants (RAVs) are shown in

Table4. ChangeofART

Amongthe62HIV/HCVco-infectedindividuals,60(96.7%)were onARTattheinitiationofDAAtreatmentand23/60(37%)required a change of ART because of drug–drug interactions. Patients treated with SOF+SMV (12/23, 52.1%) and OMB+PTV/r+DAS+ RBV(9/23,39.1%)weremorelikelytochangeARTbeforestarting

DAA treatment. Tenofovir/emtricitabine, raltegravir, rilpivirine, andunboosted atazanavir(forpatientstreatedwithOMB+PTV/ r+DAS+RBV) were the antiretrovirals most used in patients modifyingART.Ofthe23patientswhochangedART,ninereturned totheirpreviousARTregimenaftertheendofDAAtreatment.At theendofanti-HCVtherapy,onlyonesubject,whodidnotchange ART,hadadetectableHIVRNA(46copies/ml).Sixpatientsshowed adetectableHIVRNA(twowith>200copies/ml)at3monthsafter EOT,butallhadachievedviralsuppressionatthenextvisit. No virologicalfailurewasobserved.

OccurrenceofHCCafterEOT

Hepatocellular carcinoma(HCC) occurredin six HCV mono-infected patients with compensated cirrhosis (1.5%) after EOT. Abdominalultrasonography performedwithin 6 monthsbefore theinitiationofDAAshowed noevidenceofHCC inanyof the patients. Five of six HCC patients achieved SVR12 (four with genotype1bandonewithgenotype1a)anddevelopedHCCwithin 12 months after EOT. One of these patients died from HCC progressionat15monthsafterEOT.OneHCVgenotype2-infected

Table3

Factorsassociatedwithlowerratesofsustainedvirologicalresponse(SVR).

Baselinevariable Univariateanalysis Multivariateanalysis

OR 95%CI p-Value OR 95%CI p-Value

Sex,femalevs.male 0.10 0.014–0.822 0.03 0.16 0.02–1.25 0.08 HIVinfection,yesvs.no 1.63 0.513–5.171 0.40

Age>65years,yesvs.no 0.52 0.19–1.449 0.21 UseofRBV,yesvs.no 1.95 0.624–6.109 0.25 Cirrhosis,yesvs.no 1.19 0.41–3.455 0.75

Liverstiffness>20kPa,yesvs.no 3.05 1.038–8.966 0.04 1.61 0.42–6.22 0.48 Plateletcount<90109 /l,yesvs.no 4.12 1.503–11.301 0.006 3.63 0.91–14.46 0.06 Albumin,<3.5vs.>3.5g/dl 2.30 0.719–7.387 0.16 MELD>10vs.<10,yesvs.no 5.27 1.161–23.892 0.03 4.20 0.70–25.43 0.11 RVR,yesvs.no 0.94 0.201–4.391 0.93 HCVtreatment-experienced,yesvs.no 1.56 0.566–4.318 0.38

Genotype3vs.othersgenotypes,yesvs.no 5.49 1.907–15.794 0.002 21.64 3.81–123 0.001 CI,conﬁdenceinterval;HCV,hepatitisCvirus;MELD,ModelforEnd-StageLiverDisease;OR,oddsratio;RBV,ribavirin;RVR,rapidvirologicalresponse.

Figure1.SVR12ratesaccordingtotheuseofRBV,diagnosisofcirrhosis,plateletcount,albuminlevel,previousanti-HCVtherapy,HIVinfection,andHCVgenotype3vs.other genotypes.Abbreviations:SVR12,sustainedvirologicalresponse(undetectabilitylastingfor12consecutiveweeksafterthecessationoftreatment);RBV,ribavirin;GT, genotype.

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patient, who did not attain a SVR, had a negative abdominal computedtomographyperformedbeforeanti-HCVtherapy(SOF+ RBVfor16weeks)becauseofahighlevelofalpha-fetoproteinat baseline (47.6ng/ml). Three months after the EOT, the patient developedHCC.

Discussion

Recent real-world studies have reported high safety and efficacy ratesforDAAs, confirming theresultsalreadyobserved inrandomizedclinicaltrials(Wylesetal.,2016;Flisiaketal.,2017). However,real-worlddataforHIV/HCVco-infectedpatientsappear tobelimited(Milazzoetal.,2016;Brunoetal.,2017;Hawkinsetal., 2016;DelBelloetal.,2016;Rockstrohetal.,2016;Younossietal., 2016;Sognietal.,2016),andonlytwostudieshaveincludedboth HIV/HCVco-infectedpatientsandHCVmono-infectedindividuals (Milazzoetal.,2016;Brunoetal.,2017).Despitetheretrospective natureofthisstudy,which representsitsmainlimitation,these datafromalargesingle-centrecohortincludingpatientswithHIV/ HCVco-infectionconfirmthatdifferentDAA-basedregimensare extremelyeffectiveandsafe.Moreover,factorsassociatedwiththe achievementofSVRwereevaluated.

Inagreementwithothersstudies(Milazzoetal.,2016;Bruno etal.,2017;Hawkinsetal.,2016;DelBelloetal.,2016;Rockstroh et al.,2016;Younossietal.,2016;Sognietal.,2016),nodifferences wereobservedintermsofSVRbetweenpatientswithandwithout cirrhosis.However,patientswithabaselinePLTcount<90109_/l

werelesslikelytoachieveHCVeradicationcomparedtothosewith aPLTcount90109_/l._The_PLT_count_is _considered_an_indirect

markerof portal hypertension, and a low PLTcount has been associatedwithadvanced liverﬁbrosisandcirrhosis inreal-life cohorts(Marotet al.,2016);inparticular,a cut-offPLTcountof <90109_/l_has_been_demonstrated_to_be_a_strong_predictor_of_SVR

(Lawitzetal.,2016).Conversely,abaselinealbuminlevel<3.5g/dl,

amarkerofliversynthesis,wasnotassociatedwithlowerratesof SVRinthepresentpatientcohort.Thisis incontrastwithother studies,inwhichabaselinealbumin<3.5g/dlwasassociatedwith failure of anti-HCV treatment (Maan et al., 2016). This could probably beexplained by the limited number of patientswith advancedlivercirrhosisinthepresentstudygroup(Child–Pugh classBandC).

Moreover,theuseofRBVdidnotseemtohaveanimpactonthe achievementofSVR.Thisisnotsurprisinginclinicalpractice,as RBV was added toIFN-free regimens only in ‘difﬁcultto treat’ patients,includingthosewithdecompensatedliverdisease,those failing a prior treatment with DAAs, and genotype 1a-infected individualsreceivingcertaincombinations,accordingto interna-tionalguidelinesandclinicaljudgement(EASLRecommendations onTreatmentofHepatitisC,2016;Feldetal.,2017).

Although a high overall SVR rate was observed (95.5%), genotype 3-infected patients were more likely to fail DAA treatmentincomparisontothoseinfectedwithothergenotypes. In fact, genotype 3 infection was the only signiﬁcant factor associated witha lowerrate of SVR inboth theunivariate and multivariateanalysis.However,inthiscohort,genotype3-infected patientswithcirrhosisforwhomanti-HCVtreatmentcouldnotbe furtherdelayed,weretreatedwiththecombinationofSOF+RBV for24weeks,whichiscurrentlyconsideredsuboptimal,becauseof thenon-availabilityofdaclatasviruntilSeptember2015.Thiscould possiblyexplainthelowerrateofSVRinthisgroup.Inagreement withthestudy data,lowerrates ofSVR in genotype3-infected patientshavebeendescribedpreviously(Werneretal.,2016),and recent data suggest that genotype 3-infected patients with cirrhosis are at higher risk of hepatic decompensation during DAA-basedtreatmentincomparisontothoseinfectedwithother genotypes (Maan et al., 2016). Furthermore, the present study cohort included only a small number of genotype 3-infected patients;therefore,largerstudiesshouldbeperformedtoconﬁrm

Table4

Clinicalcharacteristicsofthe17patientswhodidnotachieveasustainedvirologicalresponse(SVR). No. HIV-pos Age (years) Sex BLHCV RNAIU/ml GT Cirrhosis CP Previous therapy Therapy Treatment duration (weeks)

CauseforTD Outcome RAVNS3 AtTF RAV NS5A AtTF RAVNS5B AtTF

1 No 83 M 3916000 1b Yes B PR SOF+LDV+RBV 8 Bleeding oesophageal varices

Death NA NA NA

2 No 55 M 49380 3a Yes B Naive SOF+DCV 2 Non-Hodgkin lymphoma

Death NA NA NA

3 No 73 M 537 400 2 Yes A PR SOF+RBV 4 Diffuserash TD NA NA NA 4 No 41 M 10200000 1a Yes A Naive SOF+LDV+RBV 12 L-FU NA NA NA 5 No 83 M 290200 2 No Naive SOF+RBV 4 Severe

anaemia

TD NA NA NA

6 No 60 M 1 950000 1b Yes A TVR/PR SOF+LDV+RBV 24 L-FU NA NA NA 7 Yes 52 M 359700 4 No PR SOF+LDV 8 Virological

breakthrough

TD NA None None

8 Yes 52 M 2552000 3a Yes A PR SOF+RBV 24 Relapse NA None None 9 No 55 M 2 173000 1b Yes B PR SOF+SMV 12 Relapse L36V,

D168V, I170V

None C451Y,S556G

10 No 57 M 1 592000 3a Yes A PR SOF+RBV 24 Relapse NA NA None 11 No 69 M 3200000 2 Yes A Naive SOF+RBV 16 Relapse NA NA NA 12 No 50 M 771 200 3a No PR SOF+SMV+RBV 12 Relapse NA NA None 13 No 77 M 4697000 1b No Naive OMB+PTV/ r+DAS 12 Relapse Q80L, D168V Y93YH C316N, C451N, S556G,L159F 14 No 47 M 107200 3a Yes A PR SOF+RBV 24 Relapse NA None None 15 Yes 53 M 568400 4 Yes A PR SOF+SMV 12 Relapse None None None 16 No 67 F 211800 2 No Naive SOF+RBV 12 Relapse NA NA NA 17 Yes 51 M 2650000 3a Yes A PR SOF+RBV 24 Relapse NA NA None BL,baseline;CP,Child–Pughclass;DAS,dasabuvir;DCV,daclatasvir;F,female;GT,genotype;HCV,hepatitisCvirus;LDV,ledipasvir;L-FU,losttofollow-up;M,male;NA,not available;OMB,ombitasvir;PR,pegylatedinterferonandribavirin;PTV/r,paritaprevir/ritonavir;RAVs,resistance-associatedvariant;RBV,ribavirin;SMV,simeprevir;SOF, sofosbuvir;TD,treatmentdiscontinuation;TF,treatmentfailure;TVR,telaprevir.

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theseobservations.Arecentreal-worldstudyreportedthehigh efﬁcacyofthecombinationofSOFwithanNS5Ainhibitor(DCVor LDV) in genotype 3-infected patients with compensated or decompensatedcirrhosis (Alonso et al., 2016). However,in the near future, further combinations will be available for the treatment of genotype 3 infections (Foster et al., 2015; Gane etal.,2016).

Inthepresentstudycohort,malesexwasassociatedwithlower SVR rates than female sex in the univariate analysis, but this differencewasnotconﬁrmedonmultivariateanalysis.However, only17patientsdidnotachieveSVR,thusdeﬁnitiveconclusions cannotbedrawn.

Furthermore, differences in the genotype distribution were observedbetweenHCVmono-infectedandHIV/HCVco-infected individuals.Infact,asexpected,genotype1aandgenotype3were found widely in HIV/HCV co-infected patients, in whom HCV transmissionwas mainlydue tointravenousdruguse, whereas HCVmono-infectedsubjectsweremostlyinfectedwithgenotype 1b and genotype 2, which are largely distributed in Europe (Hajarizadehetal.,2013;EASLRecommendationsonTreatmentof HepatitisC,2016).

Ofnote,nosignificantdifferenceineffectivenesswasobserved betweenHCVmono-infectedandHIV/HCVco-infectedindividuals (95.9%vs.93.5%;p=0.4),thusconfirmingtheexcellentefficacyof DAAs. HIV/HCV co-infected patients showed a higher baseline MELDscorecomparedtoHCVmono-infectedpatients.Apossible explanationcouldbetheimpactofcertainantiretroviraldrugs(13 patients were on atazanavir-based ART), which, by increasing indirect bilirubin, modified the baseline MELD score without clinicalsignificance.RBVwasfrequentlynotincludedinHIV/HCV co-infectedindividualsforvariousreasons.Firstly,theadditionof RBVwasbasedontheclinician’sjudgementandtheclinicalhistory ofeachpatient.Secondly,10patients(16%)hadaprevioushistory ofRBVintoleranceoracontraindicationtoitsuse.Thirdly,dueto thereducedadherencetoatreatmentincludingalargenumberof pills,RBV-sparingregimenswerepossiblypreferredinHIV/HCV co-infectedindividuals.Inaddition,HIV/HCVco-infectedpatients in the study cohort did not have more advanced liverdisease comparedtoHCVmono-infectedpatients.Althoughthismaynot representtheonlyreasonforpreferringanRBV-freecombination, someregimenshavebeendemonstratedtobeextremelyeffective regardless of the use of RBV, particularly in patients without advancedcirrhosis.Nevertheless,thereduceduseofRBVinthe HIV/HCV co-infected group did not have an impact on the achievementofSVR.

Thisstudyprovidesfurtherinformationregardingchangesin ARTandtheirimpactonimmunologicalandvirologicalparameters inHIV/HCVco-infectedpatients.Despite23patients(37%)needing a modiﬁcation of their ART due todrug–drug interactions, no virologicalfailurewasobservedfortheHIVinfection.Thesedata aresimilartothosedescribedinarecentstudyinwhichchangesof ART did not have a negative impact on HIV RNA suppression (Andreonietal.,2016).

Currently, HIV/HCV co-infected individuals are no longer considered a ‘special population’, even though there remain certainbarrierstothetreatmentofthesepatients.Infact,social andbehaviouralissues,drug–druginteractionsbetweenDAAsand ART,andhighratesofHCVre-infectionrequireadedicatedmedical teamwithexpertiseinthemanagementofHIV/HCVco-infected patients(Sulkowsky,2016).

Overall,DAA-basedtreatmentwassafe.RBVusewasassociated withmoreadverseeventsinthecourseoftreatmentincomparison tothosetreatedwithRBV-sparingregimens.SAEsoccurredinonly 17patients(4.5%),andtreatmentdiscontinuationwasreportedin 10individuals(2.6%).Thesedataaresimilartothosedescribedin otherstudies(Werneretal.,2016;Alonso etal.,2016).Patients

withaPLTcount<90109_/l,_albumin_level_<3.5_g/dl,_and_MELD

score>10werefoundtobemorelikelytohaveSAEsonunivariate analysis.Onmultivariateanalysis,aMELDscore>10wastheonly factor associated with the occurrence of SAEs, suggesting that patientswithadvancedlivercirrhosiscouldbeathigherriskof SAEs. However,thebaseline MELDscorewas available for only 184subjectsandthiscouldrepresentalimitationintheanalysis. Inthiscohort, 192individuals(50.2%)were>65yearsofageand hadahighburdenofcomorbiditiesandco-medications.Despite theseissues,overallDAA-basedtreatmentwaswell-toleratedand high rates of SVR were reported even in this population, in agreementwithrecentstudiesevaluatingtheimpactofDAAsin elderlypopulations(Vermehrenetal.,2016;Contietal.,2016a; Fabrizioetal.,2017).

SixcasesofHCCwerereportedwithin1yearaftertheendof treatment and ﬁve occurred despite the achievement of SVR. Currently, the onset of HCC following DAA-based treatment represents a debated and controversial topic (Cammà et al., 2016).Althoughsomestudieshaverevealedanincreasedriskof HCCdevelopingafterDAA-basedtreatment(Reigetal.,2016;Conti et al.,2016b), others have notconﬁrmed this trend (Nault and Colombo,2016;ANRSCollaborativeStudyGrouponHepatocellular Carcinoma(ANRSCO22HEPATHER,CO12CirVirandCO23CUPILT cohorts),2016).Apossibleexplanationforthehigherevidenceof HCCafterDAA-basedtreatmentmightbethefactthat,thanksto theavailabilityofDAAs,thepossibilitiesfortreatingsubjectswith advanced or decompensated cirrhosis have been considerably extended. In these patients with advanced liver disease, the carcinogenesisprocessmightalreadyhavestarted,evenifitwas notevidencedwithroutineimagingmethodsbeforethebeginning ofanti-HCVtherapy.

This study hassome limitations, including its observational natureandthelimitedfollow-upperiodaftertreatment.Moreover, a largestudy reportedlower rates of SVR12 than observed in clinical trials in patientswith compensated or decompensated cirrhosis(Maanetal.,2016).Inthepresentstudycohort,however, onlytwopatientshaddecompensatedcirrhosisandtheimpactof DAAsinthisgroupcouldnotbefullyassessed.

Inconclusion,thesedataconfirmthehighefficacyandsafetyof DAA-basedtreatmentinbothHCVmono-infectedandHIV/HCV co-infected patientsfroma largereal-worldsetting. Thebeneficial effectsofDAA-inducedHCVeradicationshouldbeevaluatedover longerfollow-up,intermsofthereductionofliver-and non-liver-relatedmorbidityandmortalityandassessingtheimprovementin qualityoflifeinpatientsachievingSVR.

Conﬂictofinterest Nonedeclared. Acknowledgements

Theresultsof this studywerepresented inpartas aposter (P287)attheHIVDrugTherapyCongress,Glasgow,UK,October 23–26,2016.

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