Anti-hepatitis C virus treatment may prevent the progression of liver fibrosis in non-responder human immunodeficiency virus/hepatitis C virus coinfected patients

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

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

Original

article

Anti-hepatitis

C

virus

treatment

may

prevent

the

progression

of

liver

fibrosis

in

non-responder

human

immunodeficiency

virus/hepatitis

C

virus

coinfected

patients

Caterina

Sagnelli

_,

_Caterina

_Uberti-Foppa

_,

_Laura

_Galli

_,

_Giuseppe

_Pasquale

_,

Nicola

Coppola

_,

_Luca

_Albarello

_,

_Carlo

_Doglioni

_,

_Adriano

_Lazzarin

_,

Evangelista

Sagnelli

a_{ClinicofInfectiousDiseases,Vita-SaluteUniversity,SanRaffaeleScientificInstitute,Milan,Italy}

b_{ExperimentalMedicineandSurgery“F.MagrassieA.Lanzara”,SecondUniversityofNaples,Naples,Italy}

c_{DepartmentofMentalHealthandPublicMedicine,SectionofInfectiousDiseases,SecondUniversityofNaples,Naples,Italy} d_{DepartmentofPathology,SanRaffaeleScientificInstitute,Milan,Italy}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received8January2013 Accepted18June2013

Availableonline25October2013

Keywords:

HIV/HCVcoinfection HIVinfection

HIV/HCVcoinfectionliverhistology Liverfibrosis

a

b

s

t

r

a

c

t

Aim:Toevaluate changes inliver histology inpatients withhumanimmunodeficiency virus/hepatitisCviruscoinfectionnon-responderstoasuboptimalInterferon+Ribavirine regimen.

Materialsandmethods:Weinvestigated49patientswithtwosequentialliverbiopsies:18were non-responderstoInterferon+Ribavirinetreatment(GrouphepatitisCvirusRx) adminis-teredafterthe1stliverbiopsywhounderwenta2ndliverbiopsyafteramedianperiodof 3.92yearand31werepatientswhoremaineduntreatedforhepatitisCvirusdisease(Group hepatitisCvirusuntreated)afterthe1stliverbiopsybecauseofrefusalandunderwenta 2ndliverbiopsyafteramedianperiodof5.05-years.Mostpatientsinbothgroupswere underhighlyactiveantiretroviraltherapy.Atthetimeof1stliverbiopsysimilardegreesof necro-inflammation,fibrosisandsteatosiswereobservedinbothgroups.Changesinliver lesionsbetween1stand2ndliverbiopsyswereadjustedfordifferentintervalsbetweenliver biopsysbyamathematicformula.

Results:Liverfibrosisdidnotchangein88.9%ofpatientsinGrouphepatitisCvirusRxand in77.4%inGrouphepatitisCvirusuntreated.Amarkeddeteriorationinliverfibrosiswas observedin5(16%)patientsinGrouphepatitisCvirusuntreatedandinnoneinGroup hep-atitisCvirustreated.Necro-inflammationandsteatosisremainedsubstantiallyunchanged inbothgroups.

Conclusion:Liverhistologyremainedsubstantiallyunchangedinhumanimmunodeficiency virus/hepatitisCviruspatientsnon-respondertoanti-hepatitisCvirustherapyover4years

∗ _{Correspondingauthorat:DepartmentofPublicMedicine,SectionofInfectiousDiseases,SecondUniversityofNaples,viaL.Armanni,} N◦3,80135Naples,Italy.

E-mailaddress:evangelista.sagnelli@unina2.it(E.Sagnelli).

1413-8670/$–seefrontmatter©2013PublishedbyElsevierEditoraLtda. http://dx.doi.org/10.1016/j.bjid.2013.06.005

observation,suggestinganeffectiveanti-hepatitisCvirusearlytreatmentforallhepatitis Cvirus/humanimmunodeficiencyviruscoinfectedpatientswhocanreasonablytolerate therapy.

©2013PublishedbyElsevierEditoraLtda.

Introduction

One-thirdofpatientscarryinghumanimmunodeficiencyvirus (HIV)haveaconcomitanthepatitisCvirus(HCV)infection1–3 associated with severe liver fibrosis4–6 _{and unfavorable}

outcome.3,5–12_{Morerecently,theresultsofsomestudies}

sug-gest that highly active antiretroviral therapy (HAART), by favoring the re-establishment ofthe immune-control, may induce a more favorable outcome of HCV related chronic hepatitis.11,3,13–15 _{Indeed,themethodsusedtoevaluatethe}

progressionofliverfibrosis in thesestudies are somewhat questionable,mostlybecausetheyarebasedonthe observa-tionofasingleliverbiopsy(LB).

Wemaycontributetothispointbyanalyzingthedatafrom 49patientswithHCVrelatedchronichepatitiswhohad under-gonetwosequentialLBs,18patientswithHIV/HCVcoinfection non-responders to an anti-HCV treatment and 31 patients withHIV/HCVcoinfectionnaïveforanti-HCVtreatment.The purposeofthepresentstudywastoevaluatewhether sub-optimalanti-HCV treatmentthatdidnotachievesustained virologicalresponse(SVR)influencedtheprogressionofliver fibrosis,steatosis and necroinflammation between 1st and 2ndLB.

Materials

and

methods

Out of440 HIV infected patients with chronic hepatitis C whounderwent liverbiopsyfrom 1995to2007weselected 49patientswithchronichepatitisCwhohadundergonetwo sequentialLBsatanintervalofatleast2years.

Ofthese49HIV/HCVcoinfectedpatientswithchronic hep-atitis,18werenon-responderstotreatmentwithInterferon (INF)orINFplusRibavirineafterthe1stLB(GroupHCVRx); eighthad HCVgenotype 1and10 had HCVgenotype 3.In relationtothe periodof timethey were investigated,nine patientsinthisgroupreceivedstandardINF␣2a/␣2b6MUTIW, associatedwithRibavirine800–1000mgdailyinfourpatients, and nine Peg-INF ␣2a/␣2b oneinjection weekly, associated withRibavirine800–1000mgdailyinsevenpatients.Fifteen (83.4%)ofthese18 patients were underHAART duringthe study(Table1).Allpatientsdiscontinuedtreatmentafter3–4 monthsduetolackofresponseaccordingtocurrent interna-tionalguidelines.These18patientsunderwenta2ndLB to assesspossiblechangesinliverhistologyatthetime(median 5.05years)theywerere-evaluatedforre-treatment.

The remaining 31 patients with HIV/HCV coinfection andchronichepatitisdeclined treatmentforHCVinfection afterthe 1st LB (Group HCV untreated) and were followed aswell.Patientsinthisgroupunderwenta2ndLBforanew assessmentofliverhistologyatthetime(median3.9years) they accepted to be re-evaluated for anti-HCV treatment.

Twenty-four (77.4%)patientsin this groupreceived HAART throughoutthestudy(Table1).

PatientswereenrolledattheClinicofInfectiousDiseasesof theSanRaffaeleScientificInstituteinMilanandinvestigated incooperationwiththeClinicofInfectious Diseasesofthe SecondUniversityofNaples.Theproceduresfollowedinthis study wereinaccordancewiththeethicalstandardsofthe responsiblecommitteeonhumanexperimentationandwith theHelsinkiDeclarationof1975,asrevisedin1983,andeach patientsignedaninformedconsentbeforeeachLB.

Forpatientsinbothgroups,thedatarecordedatthe base-line(timeof1stLB)andatthetimeof2ndLBincludedrisk factorsforacquiringHIVandHCVinfection,presumedtime ofHIVandHCVinfection,liverfunctiontests,CD4+andCD8+ counts,HCV-genotype,HIVandHCVviralloads,androutine tests.Thepatientswereobservedatathree-monthinterval withphysicalexaminationandlaboratorytestsexploringliver andkidneyfunctions,bloodcellcount,CD4+cellcount,HIV andHCVviralloads.

Excluded from this study were patients who had been treatedwith␣-INForPeg-INF,aloneorincombinationwith Ribavirinbeforethe 1st LB,those witha historyofalcohol abuse (>40g/dayformalesand >30g/dayforfemales forat least5years),thosewithHBsAgpositiveorautoimmune hep-atitis,andthosewithgeneticdisorderspossiblyinducingliver disease.

Liverhistology

LBwasperformedpercutaneouslyunderUSguidance; spec-imens were fixed in formalin, embedded in paraffin and stained with hematoxylin–eosin and Masson’s trichrome stains.Thehistologicaldatawereanalyzedbyapathologist who wasunawareoftheclinicaland laboratorydatausing Ishak’sscoringsystemforHAIandfibrosis16_andahomemade

scoringsystemforsteatosishehad beenusingfordecades (score1=1–10%ofhepatocyteswith fattydeposition, score 2=11–30%;score3=31–60%;score4≥60%).

Tocomparethetwogroupsofpatientsforchangesin fibro-sis,necro-inflammationandsteatosis,avoidingthebiasdue tothedifferentintervalbetweenLBs,atime-adjusted histo-logicaldifference(TAHD)wascalculatedforeachhistological lesionandineachsingleLB:

TAHD=scoreatthe_Interval2ndLB_between−score_LBsatthe1stLB×100 AnegativeTAHDindicated animprovementand apositive TAHDindicateddeterioration.

For aneasier reading ofthe data, the TAHD value was convertedintoArbitraryUnits,namedImprovement Progres-sionUnit(IPU)fornegativeTAHDorDeteriorationProgression Unit(DPU)forpositiveTAHD,whereoneUnitrepresentsthe standard difference of one degree of a histological lesion inthe fouryears medianinterval between2ndand 1stLB:

Table1–Comparisonofdemographic,epidemiologicalandimmuno-virologicaldataatthetimeof1stand2ndliver biopsy(LB)betweenGroupHCVRxandGroupHCVuntreated.

GroupHCVRx 18cases GroupHCVuntreated 31cases Significancelevel Age,years 31.5(28–37) 36(31–41) <0.05 Males,n(%) 10(55.6) 23(74.2) n.s. IVDA,n(%) 17(94.5) 26(83.9) n.s. Withgenotype1,n(%) 8(44.4) 12(38.7) n.s. Withgenotype2,n(%) 0 2(6.5%) n.s. Withgenotype3,n(%) 10(55.6) 16(51.6) n.s. Withgenotype4,n(%) 0 1(3.2%) n.s.

NadirofCD4,median(IQR) 265(212–419) 230(158–317) n.s.

IntervalbetweenLBs,years,median(IQR) 5.05(4.18–6.98) 3.92(2.33–5.09) <0.05 Atthetimeofthe1stliverbiopsy

HIV-RNAcps/mL,median(IQR) 4000(210–17000) 79(79–4900) <0.02

CD4cell/mmc,median(IQR) 626.5(357–833) 459(338–682) n.s.

ALTIU/L,n.v.=15–35,median(IQR) 107(82–307) 106(69–158) n.s.

HCVRNAIU/L,median(IQR) 1126×103_{(864–2500) 1260×10}3_{(303–2380) n.s.}

HAARTatthe1stLB,n(%) 5(27.8) 11(35.5) n.s.

PI+NRT 0 3(9.7)

NRT+NNRT 10(55.6) 9(29)

NRT 3(16.7) 8(32.3)

Untreated

Atthetimeofthe2ndliverbiopsy

HIV-RNAcps/mL,median(IQR) 5396.5(49–22788) 60.5(49–1300) n.s.

CD4cell/mmc,median(IQR) 674.5(323–856) 547(388–718) n.s.

ALTIU/L,n.v.=15–35 112.5(55–183) 95(72–184) n.s.

HCVRNAIU/L,median(IQR) 793×103_{(449–1130) 539×10}3_{(95–820) n.s.}

HAARTatthe2ndLB,n(%) n.s. PI+NRT 6(33.4) 10(32.3) PI+NRT+NNRT 0 4(12.9) PI 1(5.6) 0 NRT+NNRT 2(11.2) 5(16.1) NRT 3(16.7) 5(16.1) Untreated 7(38.9) 7(22.6)

oneProgressionUnit(IPUorDPU)=onedegreedifference/four years×100=25 TAHD points. On the basisofthis formula, weconsideredasimprovedallpatientswithanegativeTADH equivalenttotwoormoreIPUs:animprovementof2–6IPUs wasconsidered asmoderate and animprovementofmore than6IPUsasmarked.Conversely,allpatientswitha posi-tiveTAHDequivalenttotwoormoreDPUswereconsidered tohavedeteriorated:adeteriorationof2–6DPUswas consid-eredasmoderateandadeteriorationofmorethansixDPUsas marked.Thehistologicallesionswereconsideredunchanged whenvariationsinthedegreeofnecro-inflammation, fibro-sisorsteatosisbetweenthe2ndand1stLBwereminimal(<2 IPUs,or<2DPUs)orabsent.

Laboratorytests

AntibodytoHCVwasdeterminedbya3rdgeneration commer-cialimmunoenzymaticassay.HCV RNAwasdetermined in plasmasamplesbyaqualitativeretro-transcriptasePCRwith primersfor5non-codingregionoftheviralgenome,usinga commercialkitwiththelowestdetectionlimitof200copies.In HCV-RNApositivecases,HCVRNAwasassessedusing quan-titativeretro-transcriptase PCR (HCV-Amplicor Monitor 2.0; RocheMolecularSystem,Branchburg,NJ,USA),whichshows thelowestdetectionlimitof600IU/mL.

HCV genotyping was performed by a line-probe assay (INNO-LIPAHCV-II;Innogenetics,Zwijndrecht,Belgium).

AntibodiestoHIV-1and2weredeterminedbycommercial ELISA andpositiveresultswere confirmedbyWesternblot, whichidentifiesantibodiestotheHIV-1andHIV-2strains.

HIVviralloadwasassessedusingtheAmplicorHIV Moni-tor1test(RocheMolecularSystemsInc.,Branchburg,NJ,USA) withthelowestdetectionlimitof400copies/mL.

HBsAg, anti-HBs and total anti-HBc were tested using commercial immunoenzymatic assays. Lymphocyte sub-sets (CD4+, CD8+) were evaluated by flow cytofluorimetry using monoclonal antibodies and a fluorescence-activated cell sorter scan (Becton Dickinson, Mountain View, USA). Liver function tests were carried out according to routine methods.

Statisticalanalysis

TheanalyseswereperformedusingSASsoftware(version8.2; SAS Institute,Cary,NC,USA). Alltestsofsignificancewere 2-sided, andp<0.05wasconsideredstatisticallysignificant. Somecontinuousparameterswerestratifiedaccordingtotheir medianvaluesand thenusedand comparedascategorical variables.Associationsbetweendiscretevariablesweretested by2_{orFisher’sexacttest,asappropriate.}

Results

Atthetimeofthe1stLBpatientsinGroupHCVRxcompared withthoseinGroupHCVuntreatedwereyounger(p<0.05)and withhigherHIVviralload(p<0.02)(Table1).Noother demo-graphic,epidemiologicaland immuno-virologicaldifference wasfoundbetweenthesetwogroups,neitheratthetimeof the1stnoratthe2ndLB.AlsotheHAARTregimenwassimilar inthesetwogroups(Table1).

Therawhistologicalscores observedinbothgroupsare reported in Table 2 for an analytical evaluation, whereas the differences in necro-inflammation,fibrosis and steato-sisare presentedas IPUand DPU inTable 3. Liverfibrosis remained substantially unchanged in 16 (88.9%) of the 18 patients in GroupHCV Rx, whereas a moderate deteriora-tionwasobservedonlyintheremainingtwo(11.1%)(Table3). Instead,ofthe31patientsinGroupHCVuntreated,24(77.4%) remainedsubstantiallyunchanged,two(6.5%)showeda mod-eratedeteriorationandfive(16.1%)amarkeddeteriorationin liverfibrosis(Table3).Thesedifferencesarenotstatistically significant,butthedataareofclinicalrelevancesinceallthe sevenpatientswhodeterioratedinGroupHCVuntreatedhad theminimalscoreoffibrosis(score1)atthefirstLB,whereas inthe2ndLB,3.6yearslater (medianvalueintheseseven patients),onepatientprogressedtoscore3,anotheroneto score4andfivetolivercirrhosis(twowithscore5andthree toscore6).

Changesinnecro-inflammationscoreswerequitefrequent butsimilarinbothgroups(Table3).

Changesinliversteatosiswereinfrequentinbothgroups anddifferenceswerenotstatisticallysignificant(Table3).

In both groups no association was found between the degreeofliverfibrosis,necro-inflammationorliversteatosis inthe 1stLBandapeculiarprogressionoftheselesionsin the2ndLB.Nevertheless,thedataregardingliverfibrosisare reportedinTable4,becauseoftherelevanceofthislesionon thecourseofchronichepatitisandofthecontrastingdataon thepossibilitytopredicttheprogressiontofibrosisreported inliterature.6,20,21,23–26_{Table4shows,intermsofIPUorDPU,}

nocorrelation between thedegrees ofliverfibrosis, necro-inflammationandsteatosisobservedinthe1stLBandchanges inliverfibrosisfoundinthe2ndLB.

Discussion

Apparently,non-effectiveanti-HCV treatment was ofsome benefittoourHIV/HCVcoinfectedpatientswithchronic hep-atitis.Infact,nosubstantialdeteriorationinliverhistology wasobservedafteramedianobservationperiodof5years in18non-responderpatientstoanti-HCVtreatment,whereas nearlyaquarteroftheuntreatedpatientsprogressedfromthe minimaldegreeoffibrosistomoderatefibrosis(6.5%)ortoliver cirrhosis(16.1%)infouryears.Lackofprogressiontoamore severeliverfibrosiswasalsoreportedbyChungetal.in one-thirdof66HIV/HCVcoinfectedpatientswhodidnotachieve SVRfollowinganti-HCVtreatment.17

IndependentpredictorsoffibrosisprogressioninHIV/HCV coinfectionhavebeen suggested,suchasanoldage atthe timeofHCVinfection,alcoholintake,andtheentityofthe

Table2–Scoresofliverlesions(fibrosis,

necro-inflammation(HAI)andsteatosis)inthe1stand 2ndliverbiopsy(LB)inGroupHCVRxandGroupHCV untreated. GroupHCVRx 18cases GroupHCV untreated 31cases Degreeoffibrosis 1stLB,n(%) 0 1(5.6) 0 1 7(38.9) 16(51.6) 2 3(16.7) 8(25.8) 3 4(22.3) 1(3.2) 4 3(16.7) 1(3.2) 5 0 3(9.7) 6 0 2(6.5) 2ndLB,n(%) 0 0 1(3.2) 1 4(22.3) 10(32.3) 2 10(55.6) 5(16.1) 3 2(11.2) 3(9.7) 4 2(11.2) 1(3.2) 5 0 5(16.1) 6 0 6(19.4) Degreeofnecro-inflammation 1stLB,n(%) 0 0 2(6.5) 1–3 12(66.7) 13(41.9) 4–8 4(22.3) 12(38.7) 9–12 0 1(3.2) 13–18 2(11.2) 3(9.7) 2ndLB,n(%) 0 0 4(12.9) 1–3 8(44.5) 12(38.7) 4–8 9(50) 12(38.7) 9–12 1(5.6) 3(9.7) 13–18 0 0 Degreeofsteatosis 1stLB,n(%) 0 6(33.4) 7(22.6) 1 4(22.3) 11(35.5) 2 0 1(3.2) 3 5(27.8) 5(16.1) 4 3(16.7) 7(19.4) 2ndLB,n(%) 0 7(38.9) 10(32.3) 1 7(38.9) 9(29) 2 0 0 3 1(38.9) 4(12.9) 4 3(16.7) 8(25.8)

necro-inflammatorylesions.18_{However,duetothedifferent}

structureofpublishedstudiesitisdifficulttoreacha defini-tiveconclusiononthispoint.TheHIV/HCVconfectedpatients inthepresentinvestigationdidnotshowsuchcofactorsfor fibrosis progressionsince theyhad acquired HCVinfection atayoungage,mostofthemshowedalowscoreof necro-inflammationandnoneofthemadmittedahistoryofalcohol abuse.Moreover,mostofthemreceivedanoptimizedHAART regimen.

SomeauthorsfoundHCV-genotype3associatedwithliver steatosisinHIV/HCVcoinfectedpatients,19–24anassociation

Table3–Histologicalchangesbetweenthe1stand2ndliverbiopsy(LB)inGroupHCVRxandGroupHCVuntreated, expressedasImprovementProgressionUnit(IPU)orDeteriorationProgressionUnit(DPU)forliverfibrosis,

necro-inflammation(HAI)andsteatosis.

Fibrosis HAI Steatosis

GroupHCVRx 18cases n(%) GroupHCV untreated 31cases n(%) GroupHCVRx 18cases n(%) GroupHCV untreated 31cases n(%) GroupHCVRx 18cases n(%) GroupHCV untreated 31cases n(%)

Markedimprovement(>6IPU) – – 2(11.2) 4(12.9) – –

Moderateimprovement(2–6IPU) – – 1(5.6) 5(16.2) 2(11.2) 2(6.4)

Unchanged(<2IPUto<2DPU) 16(88.9) 24(77.4) 12(66.7) 14(45.2) 14(77.8) 28(90.3) Moderatedeterioration(2–6DPU) 2(11.2) 2(6.5) 3(16.7) 7(22.5) 2(11.2) 1(3.3)

Markeddeterioration(>6DPU) – 5(16.1) – 1(3.2) – –

Table4–Correlationbetweenliverfibrosis,necroinflammation(HAI)orsteatosisscoresinthe1stLiverbiopsy(LB)and changesinliverfibrosisinthe2ndLB,expressedasImprovementProgressionUnit(IPU)orDeteriorationProgression Unit(DPU)inGroupHCVRxandGroupHCVuntreated.

Changesinfibrosisinthe2ndLBinGroupHCV Rx,18cases

Changesinfibrosisinthe2ndLBinGroupHCV untreated,31cases Histological scores Moderate/marked improvement (2to>6IPU) n(%) Unchanged (<2IPUto<2 DPU) n(%) Moderate Deterior.** (2–6DPU) n(%) Marked deterior. (>6DPU) n(%) Moderate/marked improvement (2to>6IPU) n(%) Unchanged (<2IPUto<2 DPU) n(%) Moderate Deterior. (2–6DPU) n(%) Marked Deterior. (>6DPU) n(%) Fibrosis 1stLB 0 – – 1(5.6) – – – – – 1 – 6(33.4) 1(5.6) – – 9(29) 2(6.5) 5(16.1) 2 – 3(16.7) – – – 8(25.9) – – 3 – 4(22.8) – – – 1(3.2) – – 4 3(16.7) – – – 1(2.3) – – 5 – – – – 3(9.7) – – 6 – – – – 2(6.5) – – HAI 1stLB 0 – – – – – 1(3.2) – 1(3.2) 1–3 – 10(55.6) – – – 10(32.3) 3(9.7) – 4–8 – 4(22.3) 2(11.2) – – 9(29) 3(9.7) – 9–12 – – – – – 1(3.2) – – 13–18 – 2(11.2) – – – 3(9.7) – – Steatosis 1stLB 0 – 6(33.4) – – – 7(22.6) – – 1 – 3(16.7) 1(5.6) – – 6(19.4) 5(16.1) – 2 – – – – – 1(3.2) – – 3 – 5(27.8) – – – 5(16.1) – – 4 – 2(11.2) 1(5.6) – – 5(16.1) 1(3.2) 1(3.2)

deniedbyother investigators.25 _{Liversteatosiswas}

consid-ered a riskfactor fordeveloping a more severe fibrosis in HIV/HCV coinfectedpatients,22,24,26 _{adatumnotconfirmed}

byotherauthors6,27 _{andbytheresultsofthepresentstudy}

showingin both groups no correlation between the initial score ofliver steatosis and changes in fibrosis in the 2nd LB.

Indeed,nocorrelationwasalsofoundinbothgroupsof patientsbetweenthescoreofnecro-inflammationinthe1st LBandtheprogressionofthislesion,liverfibrosisandliver steatosisnor between the score ofliver fibrosis in the 1st LBand the progressionofliver fibrosisitself,steatosisand

necro-inflammationinthe2ndone.Thesedataallowto con-cludingthattheevolutionofliverfibrosis,necro-inflammation andsteatosisinpatientswithHIV/HCVcoinfectionmayhardly bepredictedbytheinitialdegreeofthesehistologicallesions. Concluding, the data ofthe present study indicate that theprogressiontoamoreseverestageofliverfibrosisorto cirrhosisobservedinnearlyaquarterofuntreatedpatients overaperiodoffouryearsmaypossiblybepreventedbyan anti-HCVtreatment.Thisstronglysuggeststoconsiderearly anti-HCV treatment, possibly including a newly developed proteaseinhibitor,allHIV/HCVcoinfectedpatientswhocan reasonablytoleratetherapy.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

r

e

f

e

r

e

n

c

e

s

1. SulkowskiMS,ThomasDL.HepatitisCintheHIV-infected person.AdvInternMed.2003;138:197–207.

2. ShermanKE,RousterSD,ChungRT,RajicicN.HepatitisC virusprevalenceamongpatientsinfectedwithhuman immunodeficiencyvirus:across-sectionalanalysisoftheUS adultAIDSClinicalTrialsGroup.ClinInfectDis.2002;34: 831–7.

3. RockstrohJK,MocroftA,SorianoV,etal.EuroSIDAStudy Group.InfluenceofhepatitisCvirusinfectiononHIV-1 diseaseprogressionandresponsetohighlyactive antiretroviraltherapy.JInfectDis.2005;192:992–1002. 4. BenhamouY,DiMartinoV,BochetM,etal.MultivirCGroup.

Factorsaffectingliverfibrosisinhumanimmunodeficiency virus-andhepatitisCvirus-coinfectedpatients:impactof proteaseinhibitortherapy.Hepatology.2001;34:

283–743.

5. PoynardT,MathurinP,LaiCL,etal.PANFIBROSISGroup.A comparisonoffibrosisprogressioninchronicliverdiseases.J Hepatol.2003;38:257–65.

6. MontoA,KakarS,DoveLM,BostromA,MillerEL,WrightTL. ContributionstohepaticfibrosisinHIV–HCVcoinfectedand HCVmonoinfectedpatients.AmJGastroenterol.

2006;101:1509–15.

7. SagnelliC,Uberti-FoppaC,PasqualeG,DePascalisS,Coppola N,AlbarelloL,etal.Factorsinfluencingliverfibrosisand necroinflammationinHIV/HCVcoinfectionandHCV monoinfection.Infection.2013;41(5):959–67.

8. Uberti-FoppaC,DeBonaA,GalliL,SitiaG,GallottaG,Sagnelli C,etal.LiverfibrosisinHIV-positivepatientswithhepatitisC virus:roleofpersistentlynormalalanineaminotransferase levels.JAcquirImmuneDeficSyndr.2006;41((January)1):63–7. 9. KleinMB,LalondeRG,SuissaS.TheimpactofhepatitisC

viruscoinfectiononHIVprogressionbeforeandafterhighly activeantiretroviraltherapy.JAcquirImmuneDeficSyndr. 2003;33:365–72.

10.BicaI,McGovernB,DharR,etal.Increasingmortalitydueto end-stageliverdiseaseinpatientswithhuman

immunodeficiencyvirusinfection.ClinInfectDis. 2001;32:492–7.

11.MohsenAH,EasterbrookPJ,TaylorC,etal.Impactofhuman immunodeficiencyvirus(HIV)infectionontheprogressionof liverfibrosisinhepatitisCvirusinfectedpatients.Gut. 2003;52:1035–4040.

12.WeberR,SabinCA,Friis-MøllerN,etal.Liver-relateddeaths inpersonsinfectedwiththehumanimmunodeficiencyvirus: theD:A:Dstudy.ArchInternMed.2006;166:1632–41.

13.SalmonD,RobainM,RockstrohJ,BenhamouY.Therapeutic managementofhepatitisandHIVinfectioninco-infected patients:resultsofasurveyperformedbeforethe2005July 29.JHepatol.2006;351:451–9.

14.TorrianiFJ,Rodriguez-TorresM,RockstrohJK,etal.APRICOT StudyGroup.PeginterferonAlfa-2aplusribavirinforchronic hepatitisCvirusinfectioninHIV-infectedpatients.NEnglJ Med.2004;351:438–50.

15.SchiaviniM,AngeliE,MaininiA,etal.Fibrosisprogressionin pairedliverbiopsiesfromHIV/HCVco-infectedpatients. HepatMon.2011;11:525–31.

16.IshakK,BaptistaA,BianchiL,etal.Histologicalgradingand stagingofchronichepatitis.JHepatol.1995;22:696–9. 17.ChungRT,AndersenJ,VolberdingP,etal.AIDSClinicalTrials

GroupA5071StudyTeam.PeginterferonAlfa-2aplusribavirin versusinterferonalfa-2aplusribavirinforchronichepatitisC inHIV-coinfectedpersons.NEnglJMed.2004;351:451–9. 18.BräuN,SalvatoreM,Ríos-BedoyaCF,etal.Slowerfibrosis

progressioninHIV/HCV-coinfectedpatientswithsuccessful HIVsuppressionusingantiretroviraltherapy.JHepatol. 2006;44:47–55.

19.Bani-SadrF,CarratF,BedossaP,etal.Hepaticsteatosisin HIV–HCVcoinfectedpatients:analysisofriskfactors.AIDS. 2006;20:525–31.

20.CastéraL,LokoMA,LeBailB,etal.Hepaticsteatosisin HIV–HCVcoinfectedpatientsinFrance:comparisonwith HCVmonoinfectedpatientsmatchedforbodymassindex andHCVgenotype.AlimentPharmacolTher.2007;26:1489–98. 21.McGovernBH,DitelbergJS,TaylorLE,etal.Hepaticsteatosis

isassociatedwithfibrosis,nucleosideanalogueuse,and hepatitisCvirusgenotype3infectionsinHIV-seropositive patients.ClinInfectDis.2006;43:365–72.

22.SterlingRK,ContosMJ,SmithPG,etal.Steatohepatitis:risk factorsandimpactondiseaseseverityinhuman

immunodeficiencyvirus/hepatitisCviruscoinfection. Hepatology.2008;47:1118–27.

23.SulkowskiMS,MehtaSH,TorbensonM,etal.Hepatic steatosisandantiretroviraldruguseamongadultscoinfected withHIVandhepatitisCvirus.AIDS.2005;19:585–92. 24.Rodríguez-TorresM,GovindarajanS,SoláR,etal.Hepatic

steatosisinHIV/HCVco-infectedpatients:correlates,efficacy andoutcomesofanti-HCVtherapy:apairedliverbiopsy study.JHepatol.2008;48:756–64.

25.MarksKM,PetrovicLM,TalalAH,MurrayMP,GulickRM, GlesbyMJ.Histologicalfindingsandclinicalcharacteristics associatedwithhepaticsteatosisinpatientscoinfectedwith HIVandhepatitisCvirus.JInfectDis.2005;192:1943–9. 26.NeauD,WinnockM,CastéraL,etal.Prevalenceofandfactors

associatedwithhepaticsteatosisinpatientscoinfectedwith HepatitisCvirusandHIV.JAcquirImmuneDeficSyndr. 2007;45:168–73.

27.GaslightwalaI,BiniEJ.Impactofhumanimmunodeficiency virusinfectionontheprevalenceandseverityofsteatosisin patientswithchronichepatitisCvirusinfection.JHepatol. 2006;44:1026–32.