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Chronic Hepatitis C virus (HCV) increases the risk of chronic kidney disease (CKD) while effective HCV treatment decreases the incidence of CKD

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Chronic Hepatitis C virus (HCV) increases the risk of chronic kidney disease (CKD) while effective HCV treatment decreases the incidence of CKD
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Park, Haesuk
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Wiley
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We aimed to assess the risk of chronic kidney disease (CKD) in chronic hepatitis C virus (HCV) infected patients and the incidence reduction of CKD after receipt of HCV treatment. We also evaluated the risk of membranoproliferative glomerulonephritis (MPGN) and cryoglobulinemia in chronic HCV patients. A retrospective cohort analysis of the Truven Health MarketScan Database (2008-2015) in the United States was conducted. In a cohort of 56,448 HCV-infected patients and propensity score (1:3) matched 169,344 non-HCV patients, we examined the association of HCV infection with the incidence of CKD. Of 55,818 HCV patients, 6.6 % (n=3666), 6.3% (n=3534), and 8.3% (n=4628) patients received either interferon-based dual, triple, or all-oral direct acting antiviral agents (DAA) therapy, respectively, whereas 79% of patients did not receive any HCV treatment. Cox proportional hazards models were used to compare the risk of developing CKD in HCV patients compared to non-HCV patients and treated patients compared to non-treated HCV patients. In a multivariate time-varying Cox regression model, HCV-infected patients had a 27% increased risk of CKD compared to non-HCV patients (hazard ratio (HR),1.27; 95% confidence interval (CI),1.18-1.37). Among HCV patients, individuals who received the minimally effective HCV treatment for dual, triple, or all-oral therapy had a 30% decreased risk of developing CKD (HR,0.70; 95% CI,0.55-0.88). In addition, HCV-infected patients experienced a twofold and a nearly 17-fold higher risk of MPGN (HR,2.23; 95% CI,1.84-2.71) and cryoglobulinemia (HR,16.91; 95% CI,12.00-23.81), compared to non-HCV patients. CONCLUSION: Individuals infected with HCV infection in U.S. are at greater risk of developing CKD, MPGN, and cryoglobulinemia. Minimally effective treatment of HCV infection can prevent the development of CKD, although the association was not significant for all-oral therapy. 
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Collected for University of Florida's Institutional Repository by the UFIR Self-Submittal tool. Submitted by Haesuk Park.

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ChronicHepatitisCVirus(HCV) IncreasestheRiskofChronicKidney Disease(CKD)WhileEffective HCVTreatmentDecreases theIncidenceofCKDHaesukPark,1ChaoChen,1WeiWang,1LindaHenry,1RobertL.Cook,2andDavidR.Nelson2Weassessedtheriskofchronickidneydisease(CKD)inchronichepatitisCvirus(HCV)-infectedpatientsandtheincidencereductionofCKDafterreceiptofHCVtreatment.Wealsoevaluatedtheriskofmembranoproliferativeglomerulonephritis(MPGN)andcryoglobulinemiainchronicHCVpatients.AretrospectivecohortanalysisoftheTruvenHealth MarketScanDatabase(2008-2015)intheUnitedStateswasconducted.Inacohortof56,448HCV-infectedpatientsand 169,344propensityscore(1:3)…matchednon-HCVpatients,weexaminedtheassociationofHCVinfectionwiththeincidenceofCKD.Of55,818HCVpatients,6.6%(n 5 3666),6.3%(n 5 3534),and8.3%(n 5 4628)patientsreceived eitherinterferon-baseddual,triple,orall-oraldirectactingantiviralagenttherapy,respectively,whereas79%ofpatients didnotreceiveanyHCVtreatment.CoxproportionalhazardsmodelswereusedtocomparetheriskofdevelopingCKD inHCVpatientscomparedwithnon-HCVpatientsandtreatedpatientscomparedwithuntreatedHCVpatients.Ina multivariatetime-varyingCoxregressionmodel,HCV-infectedpatientshada27%increasedriskofCKDcomparedwith non-HCVpatients(hazardratio[HR],1.27;95%con“denceinterval[CI],1.18-1.37).AmongHCVpatients,individuals whoreceivedtheminimallyeffectiveHCVtreatmentfordual,triple,orall-oraltherapyhada30%decreasedriskofdevelopingCKD(HR,0.70;95%CI,0.55-0.88).Inaddition,HCV-infectedpatientsexperiencedatwofoldandanearly17foldhigherriskofMPGN(HR,2.23;95%CI,1.84-2.71)andcryoglobulinemia(HR,16.91;95%CI,12.00-23.81) respectively,comparedwithnon-HCVpatients. Conclusion: HCV-infectedindividualsintheUnitedStatesareatgreater riskofdevelopingCKD,MPGN,andcryoglobulinemia.MinimallyeffectivetreatmentofHCVinfectioncanpreventthe developmentofCKD,althoughtheassociationwasnotsigni“cantforall-oraltherapy.(HEPATOLOGY2018;67:492-504).Theburdenoffatalliverdiseaseisincreasingin theestimated3.2millionadultsintheUnited Stateswhoarechronicallyinfectedwithhepatitis Cvirus(HCV).(1)Furthermore,chronicHCVinfection isassociatedwithextrahepaticmanifestations,reported inupto74%ofpatients,whichmaybepresentlong beforeadvancedliverdiseasepresentsitselfandresponsiblefornon…liver-relateddeaths.(2-5)Chronickidneydisease(CKD)isoneofthemore commonextrahepaticmanifestationspresentin patientswithchronicHCV;however,reportsonthe riskofCKDinthechronicallyinfectedHCV Abbreviations:ACEI,angiotensin-converting-enzymeinhibitor;ARB,angiotensinIIreceptorblocker;CKD,chronickidneydisease;CI,con“denc e interval;DAA,directactingantiviralagent;HCV,hepatitisCvirus;HIV,humanimmunode“ciencyvirus;HR,hazardratio;ICD-9-CM,InternationalClassi“cationofDiseases,NinthRevision,ClinicalModi“cation;MPGN,membranoproliferativeglomerulonephritis;PS,propensityscore ReceivedApril30,2017;acceptedAugust29,2017. AdditionalSupportingInformationmaybefoundatonlinelibrary.wiley.com/doi/10.1002/hep.29505/suppinfo. CopyrightVC2017TheAuthors.HEPATOLOGYpublishedbyWileyPeriodicals,Inc.,onbehalfoftheAmericanAssociationfortheStudyofLiverDiseases. ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttribution-NonCommercial-NoDerivsLicense,whichpermitsuseand distributioninanymedium,providedtheoriginalworkisproperlycited,theuseisnon-commercialandnomodificationsoradaptationsaremade. Viewthisarticleonlineatwileyonlinelibrary.com. DOI10.1002/hep.29505 Potentialconflictofinterest:DavidNelsonhasreceivedresearchgrantsupportfromAbbVie,Bristol-MyersSquibb,Gilead,Jassen,andMerck.492HEPATOLOGY,VOL.67,NO.2,2018VIRALHEPATITIS AHES T UD Y O FLIVER D I S E A SESTM ERI CANASSOC IA T I ON F O R

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populationareinconsistentwithintheUnited States.(6-10)TworecentstudiesconductedinUSVeteranpopulationsassessedtheassociationofchronic HCVinfectionwiththedevelopment/progressionof CKDandreporteddivergentresults.(6,9,10)Molnar etal.(6)foundthatchronicHCVwasassociatedwith higherincidenceofdecreasedkidneyfunction,whereas Rogaletal.(10)concludedthatchronicHCVwasassociatedwithdecreasedincidenceofCKD.TwometaanalysesdeterminedthatpatientswithHCVhada23%43%greaterriskofpresentingwithCKD,(11,12)whereas anothermeta-analysisfoundthatHCVwasnotassociatedwithreducedglomerular“ltrationrate.(8)ThemostcommonHCV-relatednephropathyis membranoproliferativeglomerulonephritis(MPGN), usuallyinthecontextofcryoglobulinemia.(8,13-15)Mixedcryoglobulinemiarepresents60%-75%ofall cryoglobulinemias,(16)leadingtoclinicalmanifestationsrangingfromthemixedcryoglobulinemiasyndrometomoreseriouslesionswithneurologicand kidneyinvolvement.(17)Recently,twostudiesreported theprevalenceofMPGN(0.3%)andcryoglobulinemia (0.4%-0.9%)inchronicallyHCV-infectedpatientsin theUnitedStates.(18,19)However,thereislimitedevidenceregardingtheincidenceoftheserenalmanifestationsinHCVpatients.(20,21)Untillate2013,interferonandribavirinwerethemain componentsofHCVtreatment.Despitethepositive effectsonslowingtherenaldiseaseprogression,supported byrecentTaiwanesestudies,(22-24)interferonandribavirin treatmentcarriessubstantialsideeffects,leadingtovery pooradherenceandrelativelylowcurerates.(25-30)In 2014,theUSFoodandDrugAdministrationapproved the“rstall-oraldirectactingantiviralagents(DAAs), whichhaverevolutionizedtheHCVtreatmentlandscape asaresultofexcellentadherenceandveryhighcurerates ( > 95%)inaslittleas8weeksevenforpatientswhoare verydif“culttotreat.(28-30)However,itisunclearwhether thenewDAAscarryanimprovementinrenalfunction andorreducetheincidenceofCKDamongchronically infectedHCVpatientsresidingintheUnitedStates. Therefore,theaimsofthisstudywereto1)determinetheincidenceofCKDamongchronicallyHCVinfectedbene“ciariesenrolledinalargehealthcare planintheUnitedStates,2)determinetheimpactof treatmentontheCKDincidentrateinchronically HCV-infectedpatientswithinUnitedStates,and3) determinetheincidenceofMPGNandcryoglobulinemiainchronicallyHCV-infectedpatients.PatientsandMethodsDATASOURCEWeconductedaretrospectivecohortstudyusingthe TruvenHealthAnalyticMarketScanCommercialand MedicareSupplementaldatabases(January2008 throughAugust2015,priortotheimplementationof InternationalClassi“cationofDiseases,TenthRevision codes).This8-yearnationwideadministrativeclaims databasecontainsperson-levelinformationofdiagnoses, procedures,andprescriptionsforover100millionindividualsinthecommercialdatasetand10millionindividualsintheMedicareSupplementdatabase.This databasecaptureshealthcareutilizationandenrollment recordsacrossallsettings,includingphysicianoutpatient of“cevisits,hospitalstays,andpharmacyclaims.The studypopulationconsistedofemployees,dependents, andretireeswithemployer-sponsoredorMedicareSupplementalinsuranceplans.Institutionalreviewboard approvalwasobtainedfromtheUniversityofFlorida.STUDYPOPULATIONIdenti“cationofHCVandNon-HCV Patients(HCVvs.Non-HCVCohorts)PatientswithnewlydiagnosedchronicHCVwere identi“edusingtheInternationalClassi“cationof ARTICLEINFORMATION:Fromthe1PharmaceuticalOutcomesandPolicy,CollegeofPharmacy,UniversityofFlorida,Gainesville,FL;and2Departmentof Medicine,UniversityofFlorida,Gainesville,FL.ADDRESSCORRESPONDENCEANDREPRINTREQUESTSTO:HaesukPark,Ph.D. DepartmentofPharmaceuticalOutcomesandPolicy UniversityofFloridaCollegeofPharmacy HPNPBuildingRoom3325 1225CenterDrive Gainesville,FL32610 E-mail:hpark@cop.ufl.edu Tel.:(352)273-6261HEPATOLOGY,Vol.67,No.2,2018PARKETAL.493

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Diseases,NinthRevision,ClinicalModi“cation (ICD-9-CM)codes070.44,070.54,070.70,070.71, andV02.62.Apatientwasdeterminedtobeinfected withchronicHCViftheyhadoneinpatientchronic HCVdiagnosisortwooutpatientdiagnosesofHCV onseparatedayswithin1year.The“rstdiagnosiswas usedastheindexdate.Toestablishanon-HCVcontrolgroup,weselected20non-HCVpatientsmatched forage,sex,andcalendaryearforeachchronicHCV patient.Fornon…HCVpatients,werandomlyselected oneoftheirmedicalservicedatesastheindexdate. Patientswereincludediftheywere18yearsoldand continuouslyenrolledinthehealthplan1yearbefore and6monthsaftertheindexdate.Patientswhohada diagnosisofCKDbeforetheindexdatewereexcluded. Furthermore,foreachchronicHCVpatient,three non-HCVpatientswerematchedusingthepropensity score(PS)thatwascalculatedtoadjustforthebaseline differencesinriskfactorsforCKDbetweenHCVand non-HCVgroups.ThePSwasestimatedusinglogistic regression-basedbaselinedemographicvariablesincludingageandgender,andmedicalconditions reportedintheliteratureassociatedwithchronicHCV andCKD,includingdiabetes,hypertension,dyslipidemia,chronicobstructivepulmonarydisease,coronary arterydisease,peripheralvasculardisease,cerebrovasculardisease,andheartfailureidenti“edbyICD-9CMcodes,aswellasdisease-modifyingmedications includingangiotensin-converting-enzymeinhibitors (ACEIs)andangiotensinIIreceptorblockers(ARBs).Identi“cationofHCVTreatment GroupsAccordingtoAntiviral Treatment(Treatedvs.Nontreated HCVPatients)ThechronicHCVpatientswerefurthercategorized basedonthereceipt,type,anddurationofHCVtreatmentusingpharmacyclaimsforHCVtreatment.For thisanalysis,weexcludedpatientswhohadundergone HCVtherapybeforetheindexdate.HCVtreatments includedthreeclasses:1)dualtherapy,acombination therapyofinterferonandribavirin(interferonalpha, interferonbeta,peg-interferonalpha-2aorpeg-interferonalpha-2bwithorwithoutribavirin);2)tripletherapy,acombinationofboceprevir,telaprevir,sofosbuvir, orsimeprevirpluspeg-interferonandribavirin;and3) all-oraltherapy,whichincludedledipasvir/sofosbuvir, sofosbuvirwithribavirinandombitasvir/paritaprevir/ ritonavir,anddasabuvirwithorwithoutribavirin.(31)Basedonthereceiptanddurationoftreatment received,weclassi“edpatientsintothreedifferentexposurestatuses:1)notreatment,de“nedaspatientswho werenotexposedtoanyHCVtreatments;2)minimum effectivelytreated,de“nedaspatientswhoreceivedone ofthreeHCVtherapeutictreatmentregimensprescribedasatleast16weeksofdualtherapy,(24)8-12 weeksoftripletherapy,(28,29)or8weeksofall-oraltherapy(30);and3)insuf“cientlytreated,de“nedaspatients whoreceivedsometreatmentbutdidnotmeetthecriteriaforminimumeffectivelytreatedyet.STUDYOUTCOMESTheprimaryoutcomewasadiagnosisofCKDstages 3-5.TheICD-9-CMcodesof585.3,585.4,and585.5 wereusedtoidentifyCKDcases.(32)CKDwasconsideredtobediagnosediftherewasoneinpatientortwo separateoutpatientclaimsforCKDwithin1year.The earliestdateofCKDdiagnosiswasde“nedasthedate ofoutcome.Follow-upstartedfromtheindexdateand continueduntilstudyoutcome,endofenrollment,or August31,2015,whichevercame“rst.Thesecondary outcomesweretheinvestigationsoftherenalconditions ofnephroticsyndromeorMPGN(ICD-9-CMcodes 581.0,581.1,581.2,581.81,581.89,581.9,orV13.03) andcryoglobulinemia(ICD-9-CMcode273.2)within thechronicallyinfectedHCVadultpopulation.(18,19)STATISTICALANALYSISBaselinecharacteristicswerecomparedbetween HCVandnon-HCVcohortsusinga t testforcontinuousvariablesandchi-squaretestsforcategoricalvariables.AfterPSmatching,thestandardizeddifference wasusedtocheckthebalancebetweentwogroups, and0.2wasde“nedasthethresholdtodeterminestatisticallysigni“cantdifferences.(33,34)Thenumberof CKDeventsandperson-yearsweredeterminedfor eachgroupandsubsequentlyusedtocalculatetheincidenceratesofCKD(numberofevents/1000personyears).Wethenstrati“edCKDbyage,sex,diabetes, andcirrhosisstatus,aspreviousstudieshavesuggested thattherewasaneffectmodi“cationontherateof CKDamongthesesubpopulations.(35,36)ACoxproportionalhazardsregressionmodelwasusedtocomparetheriskofdevelopingCKD,MPGN,and cryoglobulinemiabetweenHCVandnon-HCV cohorts.ACoxproportionalhazardsregressionmodel withtime-dependentcovariateswasalsoemployedina sensitivityanalysis(Model1)(SupportingTableS1).PARKETAL. HEPATOLOGY,February2018494

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Thecovariateswereadjustedforalcohol/drugabuse disorders,humanimmunode“ciencyvirus(HIV),hepatitisAvirus,hepatitisBvirus,cirrhosis,decompensatedcirrhosis,andhepatocellularcarcinomain additiontocovariatesadjustedinPSmatching.We didnotmatchforpresenceofliverdisease,aneffect mediatorofHCVratherthanaconfounder,andvariablesthatwerestronglyassociatedwithHCVbut weaklyassociatedwithCKD(e.g.,alcohol/drugabuse) andadjustedforregressionmodels,becauseprevious studiesfoundthatincorporatingthesevariablescan leadtolesssuccessfulmatchingandincreasedvariance.(37-39)However,weperformedsensitivityanalyses withmatching/adjustmentforallfactorsincludingliver diseaseandothercovariates. ToassesstheassociationbetweenHCVtreatment andtheriskofdevelopingCKDamongpatients infectedwithHCV,atime-dependentexposureanalysiswasperformed.ThenumberofCKDeventsand person-yearsweresummarizedforeachtreatmentstatus.Subgroupanalyseswereperformedbytypeof HCVtreatmentsincludingdual,triple,andall-oral therapy.Coxregressionmodelswithtime-dependent covariateswereusedtoadjustforallcovariatesmentionedinthepreviousanalysis,aswellascontraindicationstopegylatedinterferonandribavirin,which includedschizophrenia,depression,seizures,pregnancy,transplantation,anemia,andretinopathy (Model2)(SupportingTableS1).Alltheanalyses wereperformedusingSASversion9.4(SASInstitute Inc.,Cary,NC).ResultsPATIENTCHARACTERISTICSWeidenti“ed56,489HCVpatientsand847,113 non-HCVpatientsbetweenJanuary2008andAugust 2015(Fig.1).Table1summarizesthebaselinedemographiccharacteristics,comorbidconditions,andmedicationusebetweentwocohortsbeforeandafterPS matching.AfterPSmatching,weidenti“ed56,448 HCVpatientsand169,344non-HCVpatients.Inthe PS-matchedgroups,thepatientsdemographiccharacteristics,includingage(meanage:55),sex(60%male), andseveralcomorbidconditions(e.g.,hypertension, FIG.1. Flowchartofthecohortcreation.Abbreviations:CCAE,CommercialClaimsandEncounters;CKD,chronickidneydisease; HCV,hepatitisCvirus;MDCR,MedicareSupplementalandCoordinationofBene“ts. HEPATOLOGY,Vol.67,No.2,2018PARKETAL.495

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dyslipidemia,diabetesmellitus)werecomparable betweentwogroups.However,heartfailure(standardizeddifference 5 0.04)andperipheralvasculardisease (standardizeddifference 5 0.04)wereslightlymore prevalentintheHCVpatientscomparedwiththe non-HCVpatients,butthedifferenceswerestill withinthethresholdofacceptableimbalance.(40)The presenceofliverdisease,notincludedinPSmatching butadjustedinregressionmodels,wasmoreprevalent inHCVpatientscomparedwithnon-HCVpatients.RISKOFCKDBETWEENHCV ANDNON-HCVGROUPSWeidenti“ed1455newCKDcasesintheHCV group(n 5 56,448)and2518newCKDcasesinthe non-HCVgroup(n 5 169,344).Thecrudeincidence rateofCKDwas10.36per1000person-yearsinHCV and5.72per1000person-yearsinnon-HCVgroups. TheCoxproportionalhazardsregressionmodelindicatedthatHCVpatientshada57%(hazardratio [HR],1.57;95%con“denceinterval[CI],1.47-1.68) increasedriskofdevelopingCKDafteradjustingfor demographics,baselinecovariates,anduseofACEIs andARBs. SensitivityanalysisusingtheCoxregressionmodel withtime-dependentcovariates,whichtookthe changeofcomorbiditiesandmedicationuseduring follow-upintoconsideration,revealedthatHCVinfectedpatientshada27%increasedriskofCKD (HR,1.27;95%CI,1.18-1.37).Inasubgroupanalysis,whenstrati“edbydifferentagegroups,wefound thattheassociationbetweenHCVandCKDwas moresigni“cantamongyoungadults(age18-49years; TABLE1.BaselineCharacteristicsBeforeandAfterPropensityScore(PS)Matching BeforePSMatchingAfterPSMatching* PatientCharacteristics HCVcohort (n 5 56,489) Non-HCVcohort†(n 5 847,113) Standardized difference,%‡HCVcohort (n 5 56,448) Non-HCVcohort (n 5 169,344) Standardized difference,%‡PS-adjustedvariables Medianage,years(IQR)55(48,59)54(48,59)0.0355(48,59)54(48,59)0.01 Sex,n(%)0.03-0.01 Men34,106(60.37)499,756(59.00)34,082(60.38)103,149(60.91) Women22,383(39.63)347,357(41.00)22,366(39.62)66,195(39.09) Comorbidities,n(%) Hypertension21,141(37.42)332,581(39.26) 2 0.0421,122(37.42)62,468(36.89)0.01 Dyslipidemia140,46(24.87)331,064(39.08) 2 0.31140,34(24.86)42,143(24.89)-0.00 Diabetesmellitus9237(16.35)147,461(17.41) 2 0.039231(16.35)27,508(16.24)0.00 COPD6891(12.20)105,505(12.45) 2 0.016881(12.19)19,957(11.78)0.01 HeartFailure1845(3.27)30,010(3.54) 2 0.021842(3.26)4412(2.61)0.04 Peripheralvasculardisease2431(4.30)35,049(4.14)0.012430(4.30)6048(3.57)0.04 Cerebrovasculardisease2245(3.97)40,506(4.78) 2 0.042243(3.97)5681(3.35)0.03 Coronaryarterydisease4097(7.25)83,462(9.85) 2 0.094092(7.25)10,948(6.46)0.03 Baselinemedicationuse,n(%) ACEIs3003(5.32)58,520(6.91) 2 0.073001(5.32)8875(5.24)0.00 ARBs9969(17.65)155,696(18.38) 2 0.029955(17.64)29,175(17.23)0.01 PS-unadjustedvariables†Comorbidities,n(%) HIV1187(2.10)2749(0.32)0.161187(2.10)552(0.33)0.16 HepatitisA210(0.37)187(0.02)0.08210(0.37)31(0.02)0.08 HepatitisB1193(2.11)1416(0.17)0.181190(2.11)297(0.18)0.18 Cirrhosis2509(4.44)2440(0.29)0.282505(4.44)509(0.30)0.27 Decompensatedcirrhosis1888(3.34)6515(0.77)0.181886(3.34)1280(0.76)0.18 Hepatocellularcarcinoma368(0.65)516(0.06)0.10367(0.65)119(0.07)0.10 Alcoholabuse3138(5.56)13,288(1.57)0.223135(5.55)2578(1.52)0.22 Drugabuse8260(14.62)45,287(5.35)0.318257(14.63)8436(4.98)0.33Abbreviations:ACEIs,angiotensin-converting-enzymeinhibitors;ARBs,angiotensinIIreceptorblockers;COPD,chronicobstructive pulmonarydisease;HCV,hepatitisCvirus;HIV,humanimmunode“ciencyvirus;IQR,interquartilerange;PS,propensityscore,. *Upto20controlswithoutHCVinfectionwerematchedforage,sex,andindexdatewitheachHCVpatient.PSmatchingdidnotincludeliver-relatedcomorbidities,alcoholabuse,drugabuse,ormedicationuse;instead,thesecovariateswere adjustedastime-dependentcovariatesintheCoxregressionmodel.‚Differenceinmeansorproportionsdividedbystandarderror;imbalancede“nedasabsolutevalue > 0.20(smalleffectsize) PARKETAL. HEPATOLOGY,February2018496

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HR,1.47;95%CI,1.13-1.90)comparedwiththe elderlypopulation(age 60years;HR,1.19;95%CI, 1.06-1.33). Thisassociationappearedtobesigni“cantamong bothmenandwomenandpatientswithandwithout diabetes,butitwasnotsigni“cantamongpatients diagnosedwithcirrhosis(Table2).Inasensitivity analysis,whenadjustedafterPSmatchingincludingall covariatesassociatedwithHCVandCKD(52,185 HCVpatientsand156,567non-HCVpatients),we foundquantitativelysimilarresults(HR,1.28;95% CI,1.19-1.38)(SupportingTablesS2andS3).RISKOFCKDAMONGHCV PATIENTSWHORECEIVED MINIMALLYEFFECTIVE TREATMENT,INSUFFICIENT TREATMENT,ANDNO TREATMENTOf55,818HCV-infectedpatients,43,990patients (79%)didnotreceiveanyHCVtreatment.The remaining11,828HCVpatientsreceivedHCVtreatment,including3666whoreceiveddualtherapy,3534 whoreceivedtripletherapy,and4628whoreceived all-oralDAAtherapy(Table3).Patientswhoreceived theall-oralDAAregimenswereolderandhadsigni“cantlymoreadvancedliverdisease(i.e.,cirrhosis, decompensatedcirrhosis)andcomorbidities(e.g., hypertension,diabetes,coronaryarterydisease,HIV) thanthepatientsineitherthedualortripletherapy groups,respectively.However,althoughthepatientsin thenotreatmentgrouphadsimilaradvancedliverdiseasecomparedwithpatientsintheall-oraltherapy group,theyweremorelikelytohavealcohol/drug abuseandcontraindicationstopegylatedinterferon andribavirinsuchasschizophrenia,depression,and pregnancythanpatientsinanyofthetreatment groups. Table4showstheriskofdevelopingCKDamong theHCVpatientswhoreceivedminimallyeffective treatment,insuf“cienttreatment,ornotreatment.The majorityofCKDevents(90%)occurredinpatients whoreceivednoHCVtreatment,carryingaCKD incidencerateof10.79per1000person-years.The CKDincidenceratedecreasedamongpatientswho receivedtreatment(10.07per1000person-years)but decreasedgreatlywhenpatientswereonaminimally effectivedoseoftreatment(6.73per1000personyears).Afteradjustingforbaselineandtimedependentcovariates,overall,wefoundHCV-infected patientswhoreceivedtheminimumeffectiveduration oftherapyhada30%decreasedriskofdeveloping CKDcomparedwiththosewhoreceivednotreatment (HR,0.70;95%CI,0.56-0.88).However,inasubgroupanalysis,theseassociationswereonlysigni“cant fordual(HR,0.60;95%CI,0.43-0.85)andtriple (HR,0.59;95%CI,0.37-0.94)therapybutnotforalloraltherapy(HR,1.03;95%CI,0.68-1.55)(Table4).RISKFACTORSRELATED TOINCIDENCEOFCKD INHCV-INFECTEDPATIENTSFigure2showsriskfactorsforCKDinHCVinfectedpatients.Factorsassociatedwithanincreased riskofdevelopingCKDincludedage 60years(HR, 2.12;95%CI,1.74-2.58),diabetesmellitus(HR,1.79; 95%CI,1.60-2.00),congestiveheartfailure(HR, 2.14;95%CI,1.88-2.45),peripheralvasculardisease (HR,1.20;95%CI,1.05-1.37),cerebrovasculardisease(HR,1.20;95%CI,1.04-1.37),hypertension (HR,2.43;95%CI,2.05-2.88),HIV(HR,1.93;95% CI,1.44-2.57),alcoholabuse(HR,1.27;95%CI, 1.10-1.46),decompensatedcirrhosis(HR,1.91;95% CI,1.64-2.24),historyoftransplantation(HR,3.19; 95%CI,2.70-3.76),andanemia(HR,2.20;95%CI, 1.95-2.47),inadditiontoreceiptofACEIs(HR,7.30; 95%CI,6.12-8.71)andARBs(HR,5.57;95%CI, 4.86-6.39).RISKOFMPGNAND CRYOGLOBULINEMIABETWEEN HCVANDNON-HCVGROUPSForthisanalysis,wefurtherexcludedpatientswith MPGNandcryoglobulinemiabeforetheindexdate. Table5showstheassociationbetweenHCVandthe developmentofnephroticsyndrome/MPGNandcryoglobulinemia.ThecrudeincidencerateofMPGNwas 0.833per1000person-yearsinHCVand0.221per 1000person-yearsinnon-HCVgroups.Thecrude incidencerateofcryoglobulinemiawas0.876per1000 person-yearsinHCVand0.050per1000person-years innon-HCVgroups.TheCoxproportionalhazards regressionmodelindicatedthatHCVpatientshad3.7 and17timeshigherrisksofdevelopingnephroticsyndrome/MPGN(HR,3.74;95%CI,2.84-4.93)and cryoglobulinemia(HR,17.25;95%CI,10.91-27.26), respectively.SensitivityanalysesusingtheCoxregressionmodelwithtime-dependentcovariates,whichHEPATOLOGY,Vol.67,No.2,2018PARKETAL.497

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tookthechangeofcomorbiditiesandmedicationuse duringfollow-upintoconsideration,revealedthat HCV-infectedpatientshad2timesand17times increasedriskofMPGN(HR,2.23;95%CI,1.842.71)andcryoglobulinemia(HR,16.91;95%CI, 12.00-23.81).WealsofoundthatHCVandMPGN associationwasstrongeramongwomen(HR,3.78; 95%CI,2.66-5.36)comparedwithmen(HR,1.74; 95%CI,1.37-2.19).Incontrast,therewerenosigni“cantdifferencesinthedevelopmentofcryglobulinemia betweenHCV-infectedmenandwomen.However, wedidnot“ndanyeffectsoftheHCVtreatmentson theriskofdevelopingMPGNandcryoglobulinamong theHCVpatientswhoreceivedtreatmentscompared withnotreatment(SupportingTablesS4andS5).DiscussionThisretrospectivecohort,PS-matchedstudyprovidesUnitedStatesgeneralpopulation…basedevidence tosupportthatHCVinfectionislinkedtoan increasedriskofCKD.Infact,thecrudeincidence rateamongourcohortofchronicallyinfectedHCV patientswas10.36per1000person-yearscompared with5.72per1000person-yearsinnon-HCVgroups. Thissigni“cant“ndingwasfurthercon“rmedinour Coxproportionalhazardsregressionmodel,which indicatedthatpersonsdiagnosedwithchronicHCV hada57%increasedriskofdevelopingCKDandin ourtime-varyingCoxregressionmodelchronicHCVinfectedpatientshada27%increasedriskofCKD. Thedecreaseintheriskfrom57%to27%was explainedaswecontrolledfortheriskfactorsknown tobeassociatedwiththedevelopmentofCKDafter anHCVdiagnosis.Nonetheless,ourstudydemonstratesthatHCVissigni“cantlyassociatedwith increasingtheriskforCKDamongpatientswith HCVintheUnitedStates,whichcorroboratesother “ndingsthathaveassociatedHCVwiththeincidence andprogressionofCKD.(6,9,11,12,22-24)However,arecentstudyconductedbyRogal etal.(10)usingtheElectronicallyRetrievedCohortof HCVInfectedVeteransStudyGroup(ERCHIVES) TABLE2.IncidenceRateandHazardRatio(HR)forCKDintheHCVandNon-HCVCohorts Study Population HCV Status No.of Patients PersonYears No.ofCKD Events MeanTime to CKDEvent (Months) Crude Incidence ofCKD* AdjustedHRofCKD(95%CI) Baseline Covariates Baselineand Time-Varying CovariatesAllpatientsHCV56,448140,468145520.5310.361.57(1.47-1.68)1.27(1.18-1.37) Non-HCV169,344440,495251822.375.72ReferenceReference Age,years 18-49HCV15,86937,64313919.533.691.87(1.49-2.35)1.47(1.13-1.90) Non-HCV48,044122,66621622.781.76ReferenceReference 50-59HCV27,34472,63068521.959.431.75(1.58-1.93)1.32(1.18-1.47) Non-HCV82,304227,193108622.814.78ReferenceReference 60HCV13,23530,19463119.2220.901.38(1.25-1.53)1.19(1.06-1.33) Non-HCV38,99690,636121621.9113.42ReferenceReference Sex MenHCV34,08284,72195620.1111.281.59(1.46-1.73)1.26(1.14-1.38) Non-HCV103,149268,076167322.676.24ReferenceReference WomenHCV22,36655,74749921.348.951.54(1.37-1.74)1.26(1.10-1.43) Non-HCV66,195172,41884521.774.90ReferenceReference CirrhosisHCV2505556118320.0432.900.89(0.63-1.26)0.91(0.64-1.29) Non-HCV50910683915.5536.52ReferenceReference NocirrhosisHCV53,945134,907127222.489.431.59(1.48-1.70)1.29(1.20-1.39) Non-HCV168,835439,427247920.605.64ReferenceReference DiabetesHCV923121,65564619.3629.81.54(1.40-1.71)1.23(1.10-1.38) Non-HCV27,50869,534121821.4917.51ReferenceReference Non-diabetesHCV47,217118,81380921.476.811.67(1.53-1.83)1.32(1.19-1.46) Non-HCV141,836370,961130023.203.50ReferenceReferenceAbbreviations:CI,con“denceinterval;CKD,chronickidneydisease;HCV,hepatitisCvirus;HR,hazardratio. *Per1000person-years. PARKETAL. HEPATOLOGY,February2018498

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determinedthatotherfactors(olderage,femalesex, diabetes,hypertension,developmentofcirrhosis,and substanceabuse)ratherthanHCVwereassociated withtheincidenceandprogressionofCKD.They suggestedthatthereasonthatHCVwasprotectivefor CKDwasprobablyaresultoftheamountoftime patientswereexposedtoHCVastheirpatientpopulationwasnotnewlydiagnosedwithHCVunlikeour populationwhowerenewlydiagnosedchronicHCV patients.Wealsosuggestthatthedifferencesinour “ndingsmaybeduetothevariablescontrolledforin ourtime-varyingmultivariateanalysis.Withtheuseof time-varyingCoxregressionmodeling,weaccounted forthedynamicandcomplexrelationshipbetweenvariablesandtimeallowingustoidentifythetop“vevariablesassociatedwithCKDinthechronicallyinfected HCVpatient.Speci“callythesevariableswere:ACEIs, ARBs,congestiveheartfailure,hypertension,and transplantationvariablessimilartothevariablesRogal etal.foundtobepredictorsofCKDintheirpopulation.Becauseweaccountedforchangesthatcanoccur overtime,our“ndingslendmorestrengthoftheassociationofthesevariablesinthedevelopmentofCKD withinpatientswithchronicHCVinfection. Averypromisingstudy“ndingwasthatexposureto theminimallyeffectivedurationoftreatmentresulted inchronicallyHCV-infectedpatientsexperiencinga 30%decreasedriskofdevelopingCKD.However,in thesubgroupanalysis,theassociationwasonly observedwiththeless-toleratedHCVtreatmenttherapies(dualandtripletherapies)andnotwiththenew all-oralregimens.Webelievethisdiscrepancyresults fromshorterfollow-upforpatientswiththenew DAAsfortreatment(person-yearsatrisk)duringthe periodofstudy.Althoughthesofosbuvirplusribavirin regimenwas“rstusedin2013,USFoodandDrug TABLE3.DemographicsandClinicalCharacteristicsofHCV-InfectedPatientsbyReceiptandTypeofHCVTreatment PatientCharacteristics DualTherapy (n 5 3666) TripleTherapy (n 5 3534) All-OralTherapy (n 5 4628) NoTreatment (n 5 43,990)PMedianage,years(IQR)52(47,57)54(49,58)56(51,60)55(48,59) < 0.001 Sex,n(%) Men2224(60.67)2267(64.15)2934(63.40)26,242(59.65) < 0.001 Women1442(39.33)1267(35.85)1694(36.60)17,748(40.35) Comorbidities,n(%) Hypertension1187(32.38)1246(35.26)1842(39.80)16679(37.92) < 0.001 Dyslipidemia832(22.70)765(21.65)1112(24.03)11186(25.43) < 0.001 Diabetes457(12.47)514(14.54)794(17.16)7371(16.76) < 0.001 COPD363(9.90)283(8.01)446(9.64)5750(13.07) < 0.001 Heartfailure49(1.34)51(1.44)95(2.05)1640(3.73) < 0.001 Peripheralvasculardisease99(2.70)79(2.24)190(4.11)2045(4.65) < 0.001 Cerebrovasculardisease91(2.48)75(2.12)147(3.18)1914(4.35) < 0.001 Coronaryarterydisease185(5.05)134(3.79)288(6.22)3453(7.85) < 0.001 HIV76(2.07)45(1.27)106(2.29)960(2.11)0.006 HepatitisA22(0.60)19(0.54)18(0.39)148(0.34)0.025 HepatitisB46(1.25)32(0.91)37(0.80)1063(2.42) < 0.001 Cirrhosis106(2.89)97(2.74)198(4.28)2058(4.68) < 0.001 Decompensatedcirrhosis62(1.69)52(1.47)146(3.15)1614(3.67) < 0.001 Hepatocellularcarcinoma5(0.14)3(0.08)19(0.41)337(0.77) < 0.001 Alcoholabuse173(4.72)110(3.11)173(3.74)2665(6.06) < 0.001 Drugabuse468(12.77)409(11.57)522(11.28)6797(15.45) < 0.001 Contraindications,n(%) Schizophrenia88(2.40)68(1.92)97(2.10)1404(3.19) < 0.001 Depression455(12.41)399(11.29)515(11.13)6363(14.46) < 0.001 Seizure30(0.82)22(0.62)39(0.84)432(0.98)0.126 Pregnancy27(0.74)20(0.57)20(0.43)599(1.36) < 0.001 Transplant22(0.60)9(0.25)49(1.06)514(1.17) < 0.001 Retinopathy1(0.03)0(0.00)3(0.06)26(0.06)0.437 Anemia228(6.22)181(5.12)399(8.62)4610(10.48) < 0.001 Medicationuse,n(%) ACEIs161(4.39)173(4.90)271(5.86)2365(5.38)0.015 ARBs569(15.52)593(16.78)881(19.04)7804(17.74)0.002Abbreviations:ACEI,angiotensin-converting-enzymeinhibitors;ARB,angiotensinIIreceptorblockers;COPD,chronicobstructive pulmonarydisease;HIV,humanimmunode“ciencyvirus;IQR,interquartilerange. HEPATOLOGY,Vol.67,No.2,2018PARKETAL.499

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Administrationapprovalfortheuseofthe“rstall-oral DAAregimen(ledipasvir/sofosbuvir)didnotoccur untilOctober2014,sothepatientsinourstudyhad lessthan1yeartobeexposedtothenewerall-oral DAAregimens(thestudyperiodendedinAugust 2015).Nonetheless,wenotedatrendtowarddecreasingtheriskofCKDinHCV-infectedpatientstreated withDAAs„atrendwesuspectwillbecomesigni“cantasmorestudiesinvestigatetheincidenceandprogressionofCKDinpatientswithHCVwhoare treatedwiththenewDAAs. Ontheotherhand,adisturbingstudy“ndingwas thatthemajorityofHCVpatients(79%)withinour studywerenottreated.Althoughthenotreatment grouphadsimilaradvancedliverdisease(cirrhosis, decompensatedcirrhosis)comparedwiththeall-oral therapygroup,thenotreatmentgroupwassickeras notedbytheincreasednumberofpatientswithalcohol/drugabuseissuesaswellasthenumberofcontraindicationstopegylatedinterferon…andribavirinbasedtreatmentregimens,whichmaypartiallyexplain whytheywerenottreated.This“ndingisespecially noteworthybecauseef“caciousandsafeall-oralpangenotypictherapiesarenowavailableandapprovedfor mostpeopletoincludepatientsinwhominterferon wascontraindicated,dif“cult-to-treatpatients,HIV coinfection,andcirrhosis.Nonetheless,themajorityof patientsnotreceivingtreatmentsuggeststhatpatients withHCVarestillencounteringbarrierstotreatment evenwithinagroupwithaccesstohealthinsurance. Therefore,identifyingandthenovercomingthebarrierstoidenti“cationandtreatmentremainsasigni“cantissueineradicatingHCVaswellaseliminating theclinicalandeconomicburdenofHCV-associated extrahepaticmanifestationsincludingCKD.(3,41)Anothersigni“cantandunique“ndingofthisstudy wastheidenti“cationoftheincidenceandriskfor developingMPGNandcryoglobunemiaamong chronicallyinfectedHCVpatients.Tothebestofour knowledge,nostudyhasquanti“edtheriskofdevelopingthesediseasesinthechronicallyHCV-infected generalpopulationintheUnitedStates.Thecrude incidencerateofMPGNandcryoglobulinemiawere6 timesandover8timeshighercomparedwithnonHCVpatients,respectively.Infact,resultsfromour Coxregressionmodelsindicatedthatchronically infectedHCVpatientshad2-3timeshigherriskfor MPGNand14-17timeshigherriskofdevelopingcryoglobulinemiaafteradjustingforcovariates.Our resultsweresimilartothoseinstudiesofextrahepatic manifestationsofHCVinUnitedStatesveterans.(20,21)Ahospital-basedcase-controlstudyperformedamonghospitalizedmaleUnitedStates veterans(1992-1999)revealedagreaterproportionof MPGN(0.36%vs.0.05%)andcryoglobulinemia (0.57%vs.0.05%)amongpatientswithHCV TABLE4.HCVTreatmentAssociationwithIncidenceofCKDUsingTime-VaryingCox-ProportionalHazardsModel TreatmentStatus*Person-Years No.ofCKD Events CrudeIncidence ofCKD†AdjustedHRof CKD(95%CI)AllHCVpatients(N 5 55,818) MinimumEffectiveTX11,737796.730.70(0.55-0.88) InsufcientTX68546910.070.85(0.66-1.09) NoTX119,698129110.79Reference Dualtherapy(n 5 3666) MinimumEffectiveTX6115345.560.60(0.43-0.85) InsufcientTX32453410.480.92(0.65-1.31) NoTX108,813119011.10Reference Tripletherapy(n 5 3534) MinimumEffectiveTX3469195.480.59(0.37-0.94) InsufcientTX3023258.270.72(0.48-1.07) NoTX110,623119710.82Reference All-oraltherapy(n 5 4628) MinimumEffectiveTX21542612.071.03(0.68-1.55) InsufcientTX5851017.090.85(0.39-1.82) NoTX114,224125410.98ReferenceAbbreviations:CI,con“denceinterval;CKD,chronickidneydisease;HCV,hepatitisCvirus;HR,hazardratio;TX,treatment. *HCVtreatmentstatuswascodedasatime-dependentcovariateintheCoxregressionmodel.Therefore,eachpatientmayhaveadifferenttreatmentstatusduringthestudyfollow-up.Per1000person-years. PARKETAL. HEPATOLOGY,February2018500

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infection.(20)Inanothercohortstudyofveterans (1997-2004),investigatorsreporteda4-foldhigher riskofcryoglobulinemiainHCV-infectedUSveterans,thoughtheassociationwasnotablyweakerthan ourstudy,perhapsduetodifferencesinthestudypopulationandmethods.(21)Interestingly,inourstudy,femaleHCVpatients wereatasigni“cantlyhigherriskofdeveloping MPGNcomparedwithmaleHCVpatients(HR,3.78 vs.1.74; P > 0.05).Severalotherstudieshaverevealed astrongerassociationbetweenfemalesexandcryoglobulinemia,(42-44)butourstudydidnotrevealany signi“cantsexdifferencesindevelopmentofcryglobulinemia.DespitethefactthatHCV-relatedMPGN andcryoglobulinemiaarerelativelyuncommoninthe HCVpopulation,thesecomplicationsareconsidereda signi“cantproblemasaresultofthelargenumberof peopleinfectedwithHCVintheUnitedStatesand thepotentialforseriousandlife-threateningcomplicationstoincludeend-stagerenaldisease.Unfortunately, wedidnot“ndevidencetosupportaprotectiveeffect ofHCVtreatmentinthedevelopmentofthese conditions. Thereareseveralstrengthstoourstudydesignand theuseofalargeclaimsdatabase.First,thisstudyhas methodologicalstrengthbecauseitemployedPS matching,time-varyingCoxproportionalhazardmodelsonmatchedgroups,andadjustmentforimmortal FIG.2. AdjustedhazardratiosforchronickidneydiseaseinHCVpatientsusingtime-varyingCox-proportionalhazardsmodel. Abbreviations:ACEI,angiotensin-converting-enzymeinhibitors;ARB,angiotensinIIreceptorblockers;CI,con“denceinterval; COPD,chronicobstructivepulmonarydisease;HIV,humanimmunode“ciencyvirus;HR,hazardratio;TX,treatment. HEPATOLOGY,Vol.67,No.2,2018PARKETAL.501

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timebias,analysesthataredifferentfromotherpreviouslypublishedstudiesandwhichmayhelptoindicate astrongerrelationshipofHCVandCKDthanthat reportedelsewhere.(22-24)Second,thisstudyincludes thenumberofstronglyassociatedCKDcovariatesthat werecontrolledforinthetime-varyingCoxproportionalhazardmodels,includingACEIs,ARBs,congestiveheartfailure,hypertension,andtransplantation; nevertheless,HCVinfectionwasstillapositivepredictorfordevelopingCKD.(6,10)Third,thisstudyis notableforitslargesamplesizeandforitbeingrepresentativeofgeneralpopulationsintheUnitedStates. Finally,weconductednumeroussensitivityanalysesto assesstherobustnessofourresultsandfoundthat noneoftheseanalysesproducedsubstantiallydifferent resultsfromthemainanalysis. Severallimitationsmustalsobenoted.First,the studylackslaboratoryresults(e.g.,sustainedvirologic response,glomerular“ltrationrate)tocorroborate ICDcoding.Weadjustedforasmanyconfoundersas availableandknowntobeassociatedwithCKD;however,becauseweweredependentonadministrative data,theremayhavebeensomeunmeasuredconfoundersthatwerenotreportedandthusunavailable. Selectionbiaswaspresentbetweentreatedand untreatedgroups.Detectionbiasmaybeintroducedby differentialscreeningfrequenciesforkidneydiseases betweenHCVandnon-HCVindividuals.Finally,we hadarelativelyshortfollow-up,whichdidnotallowus tofullyexploretheuseofDAAsinthispopulation. Inconclusion,individualsinfectedwithchronic HCVintheUnitedStatesareatahigherriskofdevelopingmoderatetosevereCKD,MPGN,andcryoglobulinemia.AntiviraltreatmentforHCVisassociated withadecreasedincidenceofCKD,althoughtheassociationisyettobecon“rmedforthenewall-oralDAA therapy.These“ndingshighlightthattreatingHCV earlyhelpstochangetheextrahepaticburdenofCKD associatedwithHCV.Therefore,researchmustcontinuetoidentifybarrierstotheidenti“cationofHCVinfectedpatientsandimproveaccesstotreatmentfor allHCVpatients.Futurestudiesshouldincludealongerstudyperiodtoinvestigatetheeffectsoftheall-oral DAAtreatmentonthedevelopmentandprogression ofCKD.REFERENCES1)DennistonMM,JilesRB,DrobeniucJ,KlevensRM,WardJW, McQuillanGM,etal.ChronichepatitisCvirusinfectioninthe UnitedStates,nationalhealthandnutritionexaminationsurvey 2003to2010.AnnInternMed2014;160:293-300. 2)CacoubP,ComarmondC,DomontF,SaveyL,DesboisAC, SaadounD,etal.ExtrahepaticmanifestationsofchronichepatitisCvirusinfection.TherAdvInfectDis2016;3:3-14. 3)YounossiZ,ParkH,HenryL,AdeyemiA,StepanovaM. ExtrahepaticmanifestationsofhepatitisC:ameta-analysisof prevalence,qualityoflife,andeconomicburden.Gastroenterology2016;150:1599-1608. 4)DavisGL,AlterMJ,El-SeragH,PoynardT,JenningsLW. AgingofhepatitisCvirus(HCV)-infectedpersonsintheUnited TABLE5.IncidenceRateandHazardRatioforMPGNandCryoglobulinemiaintheHCVandNon-HCVCohorts, AdjustingforBaselineCharacteristics SecondaryOutcomes HCV Status No.of Patients PersonYears No.of Events Crude Incidence* MeanTime toEvent (Months) AdjustedHR(95%CI) Baseline Covariates BaselineandTimeVaryingCovariatesMPGN HCV55,618140,4081200.83317.393.74(2.84-4.93)2.23(1.84-2.71) Non-HCV166,854438,153970.22119.03ReferenceReference Men HCV33,39584,325830.98418.403.50(2.54-4.84)1.74(1.37-2.19) Non-HCV101,422266,423730.27418.81ReferenceReference Women HCV22,22356,082370.66015.114.40(2.59-7.47)3.78(2.66-5.36) Non-HCV65,432171,730240.14019.72ReferenceReference Cryoglobulinemia HCV55,646140,4351230.87614.1717.25(10.91-27.26)16.91(12.00-23.81) Non-HCV166,938438,946220.05024.69ReferenceReference Men HCV33,42384,363750.88914.9621.00(11.10-39.73)20.03(12.28-32.67) Non-HCV100,824265,142110.04127.25ReferenceReference Women HCV22,22356,072480.85612.9513.11(6.76-25.40)14.07(8.68-22.81) Non-HCV66,114173,804110.06322.12ReferenceReferenceAbbreviations:CI,con“denceinterval;HCV,hepatitisCvirus;HR,hazardratio;MPGN,membranoproliferativeglomerulonephritis. *Per1000person-years. PARKETAL. HEPATOLOGY,February2018502

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