Is
early
virological
response
as
predictive
of
the
hepatitis
C
treatment
response
in
dialysis
patients
as
in
non-uremic
patients?
Patricia
da
Silva
Fucuta
Pereira
*
,
Silvia
Naomi
de
Oliveira
Uehara,
Renata
de
Mello
Perez,
Ana
Cristina
Amaral
Feldner,
Isaura
Cunha
de
Melo,
Ivonete
Sandra
de
Souza
e
Silva,
Antonio
Eduardo
Benedito
Silva,
Maria
Lucia
Gomes
Ferraz
DivisionofGastroenterology,HepatitisSection,FederalUniversityofSa˜oPaulo,Sa˜oPaulo,Brazil
1. Introduction
Although the adoption of universalprecaution methods has reduced the transmission of hepatitis C virus (HCV) among hemodialysis patients,1 the prevalence of this infection has
remained high in these patients compared to the general population.TheprevalenceofHCVinfectionalsovariesaccording to geographic region; the rates are less than 5% in northern Europeancountries,2approximately8%intheUSA,3andashighas
70%inSaudiArabia.4Inaddition,theprevalenceofthisinfection
varieswidelybetweendialysiscentersinthesamecountry. InBrazil,theBrazilianSocietyofNephrologyhasconductedan annualcensusofpatientsondialysistherapysincethebeginningof thiscentury.Datafromthe2010census,recentlyreported,5show
that340ofthe638activedialysiscentersansweredthesurvey questionsandinformationwasobtainedfor49077patientsofthe 92091 estimated total number of patients on dialysis in the country.TheprevalenceofHCVinfectionamongdialysisunitswas
5.8%,andfortunatelyithasbeendeclining–theprevalencewas 19.9%in1999.6
The treatment of HCV in patients under renal replacement therapyisofcriticalimportance.TheimpactofchronichepatitisC infectionin these patients is high, as recent observationshave documentedagreaterprobabilityofdeathduetolivercirrhosis, hepatocarcinoma,andcardiovasculardiseaseindialysispatients infected withHCVcompared touninfected subjects.7,8
Further-more,alargecohortstudythatcomparedthefrequencyofcancer amongdialysispatientstothatofthegeneralpopulationfounda higheroverallriskforcancerinthesepatients,whichincludedthe riskoflivercancerattributabletoexposuretohepatitisBandC viruses.9Severepost-transplantcomplicationsof HCVinfection,
suchasglomerulopathies,lossofrenalgrafts,10,11andareduced
10- and 20-year survival rate,12,13 have been demonstrated in
HCV-positive kidney transplanted patients. In addition, kidney transplantedpatientswithhepatitisCshowedhighermorbidity and mortality due toliver diseasethan didimmunocompetent patientswithhepatitisC.14
Asthepost-transplantadministrationof interferon(IFN)has been associated with the risk of renal graft loss,15–17 its
administrationisgenerallynotrecommended.18Instead,allefforts
shouldbemadetoeradicatetheinfectionbeforerenaltransplant.
InternationalJournalofInfectiousDiseases17(2013)e50–e53
ARTICLE INFO
Articlehistory: Received30April2012
Receivedinrevisedform23August2012 Accepted3September2012
CorrespondingEditor:MarkHolodniy, California,USA
Keywords: Dialysis HepatitisC HCVRNA Interferon Predictivevalue
SUMMARY
Objective:TheaimofthepresentstudywastodeterminewhetherhepatitisCvirus(HCV)RNApresentat week12isagoodpredictoroftheresponsetointerferon(IFN)monotherapyinhemodialysispatients withhepatitisC.
Methods:HemodialysispatientswithhepatitisCwhoweretreatedbetween1997and2008withIFN monotherapyfor48weekswithoutdosereductionwereincluded.ThepredictivevalueofHCVRNAat week12forachievingasustainedvirologicalresponse(SVR)wasdetermined.
Results:Fortypatients(meanage479years;75%malesand80%withgenotype1)wereincluded.Septal fibrosisorcirrhosiswasobservedin38%ofthesepatients.Twelve(30%)ofthe40patientsachievedSVR.HCV RNAwasundetectableatweek12in68%.ThepositivepredictivevalueofHCVRNAatweek12was45%and thenegativepredictivevaluewas100%.
Conclusions: ThepresenceofHCVRNA atweek 12had ahighnegativepredictivevalueforSVRin hemodialysispatientswithchronichepatitisCtreatedwithIFNfor48weeks.Therefore,ifHCVRNAis detectedatweek12,treatment shouldbediscontinued dueto thelowprobability ofasustained response.
ß2012InternationalSocietyforInfectiousDiseases.PublishedbyElsevierLtd.Allrightsreserved.
*Correspondingauthor.Tel.:+551731216965.
E-mailaddress:[email protected](P.d.S.FucutaPereira).
ContentslistsavailableatSciVerseScienceDirect
International
Journal
of
Infectious
Diseases
j o urn a l hom e pa ge : ww w. e l s e v i e r. c om/ l o ca t e / i j i d
1201-9712/$36.00–seefrontmatterß2012InternationalSocietyforInfectiousDiseases.PublishedbyElsevierLtd.Allrightsreserved.
Accordingtoarecentmeta-analysis,19theestimatedsustained
virologicalresponse(SVR;i.e.,nodetectableHCVRNAat24weeks after cessation of therapy) rate for hemodialysispatients who received conventional IFN monotherapy was 39%, which was greater than that estimated for immunocompetent patients. However,thelowtoleranceofthesepatientstoIFNmayleadto high rates of treatment discontinuation.20 Despite the large
number of studiesevaluating thepredictivevalue of HCVRNA duringtheearlystagesoftreatment(weeks4to12)forasustained responseinnon-uremicpatients,21,22thisparameterhasnotbeen
establishedinhemodialysispatients.Thisanalysiswouldbeuseful becauseofthelowtoleranceofthesepatientstotreatment.
The objective of the present study was to evaluate the predictive value of HCV RNA at week 12 in dialysis patients treatedwithconventionalIFNfor48weeks.
2. Methods
2.1. Patients
Aretrospectivestudywasconductedonhemodialysispatients withchronichepatitisC(anti-HCVreactiveandHCVRNA-positive) whowereattendedattheHepatitisUnitoftheFederalUniversity of Sa˜o Paulo between 1997 and 2008. Patients treated with conventionalIFN monotherapyfor48 weeksand whohadHCV RNAtestsatweek12oftreatmentandatweek24post-treatment wereselectedforthisstudy.
PatientsinfectedwithHIV and/orhepatitisBvirusandthose previously treated for hepatitis C or who had their treatment discontinuedwereexcluded.
Thestudywasapprovedbythelocalethicscommitteeandwas conductedinaccordancewiththeDeclarationofHelsinki.
2.2. VariablesanalyzedanddeterminationofHCVRNA
Thefollowingvariableswereanalyzed:gender,age,etiologyof chronicrenaldisease,typeofdialysis,historyofkidney transplan-tation,timeon dialysis,estimatedduration ofinfection,alanine aminotransferase (ALT) level, stage of hepatic fibrosis, HCV genotype,andthepresenceofHCVRNAatweek12oftreatment and at week 24 post-treatment. The duration of infection was estimatedbasedonthefirstyearofdialysisortheyearofthefirst bloodtransfusionifbefore1992.
The HCV RNA content of stored serum samples (freezer temperature 208C)wasdeterminedbyqualitative PCR(Cobas Amplicor HCV Test, Roche Diagnostic Systems, USA) using a detectionlimitof50IU/ml.TheHCVgenotypewasdeterminedby sequencingofthe50-untranslatedregion.23
2.3. Therapeuticregimen
Treatment was indicated for patients whose liver biopsies showedinterfacehepatitisand/orthepresenceofstage2fibrosis, accordingtotheMetavirclassification.24Thetherapeuticregimen
consisted of conventional IFN alpha-2a or IFN alpha-2b (3000000IU,threetimes perweek)for48 weeks,which inall caseswasadministeredfollowingdialysissessions.
2.4. Evaluationofvirologicalresponse
Anearlyvirological response(EVR) toantiviral treatment is usuallydefinedaspartial(pEVR)whena 100-folddecreasein viralloadoccursatweek12,andascomplete(cEVR)whenHCV RNAatweek12isundetectable.InthepresentstudytheEVRwas evaluated by qualitative HCV RNA level at week 12 (cEVR). QualitativedeterminationofHCVRNA24weeksaftertherapywas
used for analysis of SVR. Per-protocol analysis was used to determinetheresponserate.
2.5. Statisticalanalysis
Adescriptiveanalysisofthevariablesofinterestwasperformed and the association between variables was determined. When indicated,categoricalvariableswerecomparedusingFisher’sexact test. Thepositive andnegativepredictivevalues ofHCVRNAat week12forSVRwerecalculated.Alevelofsignificanceof<0.05
wasused.PASW18.0software(SPSS,Inc.,Chicago,IL,USA)was usedforthestatisticalanalysis.
3. Results
Atotalof113patientsweretreatedduringthestudyperiodand 40 ofthesefulfilledtheinclusioncriteria.Theother73patients were excluded from the study due to an early interruption/ abandonment of treatment or a dose reduction in 31 patients (42%),theabsenceofserumforanalysisatweek12in24patients (33%),andthepresenceofHBVco-infectionin18patients(25%). Therewasnodifferencebetweenexcludedandincludedpatients regarding age, time on dialysis, stage of fibrosis, or genotype distribution.
The meanage ofthe40 patients included inthe studywas 479years,andthemajorityofpatientsweremale(75%).Thetime ondialysisrangedfrom1to19years(medianof6years),andthe main causeofknown chronicrenal disease wassystemic arterial hypertension.
AccordingtotheMetavirclassificationforthestagingofhepatic fibrosisonbiopsy,itwasabsentin5%ofpatients(stage0),57% patientshadstage1,15%hadstage2,13%hadstage3,and10%had stage4.Thepretreatmentepidemiological,clinical,andlaboratory characteristicsofthepatientsareshowninTable1.
3.1. HCVRNAatweek12andthesustainedvirologicalresponse
HCVRNAwasundetectableatweek12in27patients(68%),and theoverallSVRratewas30%(12/40).AccordingtoHCVgenotyping performedin26patients,SVRwas24%ingenotype1,andtheonly
Table1
Baselinedemographicandclinicalcharacteristicsofthestudypatients(n=40)
Characteristics
Age,years,meanSD 479
Malegender,n(%) 30(75)
Hemodialysis/peritonealdialysis,n 38/2 Timeondialysis,years,median(IQR) 6(4–7) Previouskidneytransplant,n(%) 11(28) Etiologyofkidneydisease,n(%)
Hypertension 14(35)
Glomerulonephritis 3(8)
Diabetesmellitus 2(5)
Other/unknown 21(52)
DurationofHCVinfection,years,median(IQR) 8(6–14) HCVgenotype,n(%)
Type1 21(80)
Type2 1(4)
Type3 2(8)
Type4 1(4)
Type5 1(4)
Liverhistology,n(%)
Bridgingfibrosisorcirrhosis 15(38)
ALT(ULN),median(IQR) 1.02(0.62–1.63)
Hemoglobin(g/dl),meanSD 121.5
Plateletcount(109/l) 183.02572.318
ALT,alanineaminotransferase;HCV,hepatitisCvirus;IQR,interquartilerange;SD, standarddeviation;ULN,upperlimitofnormal.
five patients with genotype non-1 were non-responders (one genotype2,twogenotype3,onegenotype4,andonegenotype5). Forty-fivepercentofpatientswithnegativeHCVRNAatweek 12achievedSVR.However,noneofthepatientswithdetectable HCVRNAatweek12hadSVR(p=0.004),asshowninFigure1.Thus thecEVRhad a negative predictivevalue (NPV)of 100% and a positivepredictivevalue(PPV)of45%.
4. Discussion
This study showedthat detectable HCV RNAat week 12 of treatmenthadahighNPV(100%)forSVRindialysispatientswith chronichepatitisCgiven conventionalIFN monotherapy for 48 weeks.HCVRNAwasevaluatedqualitativelyatweek12,asthisis theconventionalstrategyusedtoevaluatetheearlyresponseto IFNmonotherapy.25ThisanalysisisimportantbecausehepatitisC
dialysis patients require a special therapeutic approach. The consequencesofchronicHCVinfectioninthispopulation,which include decreased survival during the post-transplant period, enforce the need to eradicate the virus. However, prolonged therapycancauseseveresideeffectsandcannegativelyimpactthe stabilityofthesepatients.
ThelowtoleranceofpatientswithrenalfailuretohepatitisC treatmenthasbeen establishedand maybedue tothegreater bioavailability of the drug or associations with co-morbid-ities.20,26–28InthestudybyRochaetal.,20mildtomoderateside
effectsofIFN therapy wereobservedin almostallpatients and includedflu-likesymptoms,bonemarrowsuppression,diarrhea, depression, dermatological alterations such as hair loss and itching,infections,andhypothyroidism.Furthermore,severeside effectsthatresultedinthediscontinuationoftreatmentwereseen in24%ofthepatients.Severesideeffectswerealsothecauseof earlytreatment interruption in 19 of 37 hemodialysis patients treatedwithconventionalIFNtherapy.26
Thesixmeta-analysesregardingtheefficacyandtoleranceof IFNtreatmentindialysispatientswithchronichepatitisCconfirm thelowtoleranceofthispopulation.Inearly2000,twoofthese studies29,30demonstratedahighrateoftreatmentdiscontinuation
duetosideeffects(30%and17%,respectively).Thesedatawere later confirmedby further meta-analyses conductedby Fabrizi etal.19andGordonetal.31thatreporteddropoutratesof19%and
26%,respectively.Inthemostrecentmeta-analysesbyAlavianand Tabatabaei32andFabrizietal.,33thereweredropoutratesof29.7%
and23%,respectively,followingpeginterferontherapy.
DespitemajoradvancesinthetreatmentofchronichepatitisC in thelast decade, approximately a half of immunocompetent patientsdonotachievesustainedeliminationoftheviruswiththe current recommended therapeutic regimen (peginterferon and ribavirin).34Furthermore,this proportionisevengreater(about
60%)amongdialysispatientsgivenpegylatedorconventionalIFN monotherapy.19
The factors associated with a positive response to antiviral treatmenthavebeenextensivelystudiedinpatientswithnormal renalfunctionandincludeHCVgenotype,stageofhepaticfibrosis, race, presence of steatosis/insulin resistance,35–39 treatment
compliance,ribavirindose,40,41andviralkinetics.35
Overthelastdecade,studieshaveestablishedtheprobabilityof aresponsetoIFNtreatmentaccordingtothekineticsoftheHCV RNA level during therapy. For example, patients who did not achieveanEVRdidnotachieveSVRin97%and100%ofcases,21,22
whichconferredahighnegativepredictivevaluetothepresenceof HCV RNAat week 12. Theresultsfrom thesestudiesfavor the discontinuationoftreatmentinpatientswhodonotachieveEVRat week12oftreatment.
Inregardsofhemodialysispatients,Gordonetal.31showedthat
patientswithlowerratesofbridgingfibrosisorcirrhosis,lower serumbaselineHCVRNAlevels,andinfectionswithgenotype non-1tendedtoachievehigherSVRrates,althoughthesefindingsdid not reach statistical significance. However, that study included onlybaselinevariablesanddidnotallowfortheinterruptionof treatment in patients with a lower likelihood of response. Therefore, theidentificationof HCV RNAduring treatment is a highlyattractivetoolfortheearlyidentificationofpatientswitha lowerprobabilityof response.Furthermore, thiswould indicate whentherapyshouldbeinterruptedinthispopulationinwhich thetolerancetotreatmentissignificantlylower.
Studieson thekineticsofHCV RNAasa predictorof SVRin dialysispatientsarescarceandhaveinvolvedsmallnumbersof patients. Inaddition,many studiesarenotcomparable because theyhaveevaluateddifferenttreatmentregimensandHCVRNAat different periods. Furthermore, these studies have included patientswithdosereductionsand/orearlytreatmentinterruption, whichcanimpairtheanalysisoftherelationshipbetween viral kinetics and SVR. Liu et al.42 reported treatment failure in all
patients who did not achieve a rapid virological response (undetectable HCV RNAat week 4 oftreatment). In that study thepatientsreceivedconventionalorpegylatedIFNmonotherapy for 24 weeks.In anotherstudy that evaluated37 hemodialysis patients,26 conventional IFN monotherapy for 48 weeks was
ineffectiveatinducingSVRinpatients whohaddetectableHCV RNAinthesecondmonthoftreatment.Finally,astudyofonly12 patientsshowedthattheSVRratewasinfluencedbytheclearance of virus within the first 2 months of treatment.43 Although
insufficient to draw definitive conclusions, all these studies suggestthat HCVRNAkineticshavea highpredictivevaluefor SVR.Arecentmeta-analysisbyGordonetal.44supportsthesedata,
asanassociationbetweenSVRandviralnegativityanytimeinthe first3monthsoftreatmentwasdemonstrated.
ThepresentstudyevaluatedthepredictivevalueofHCVRNAat week12ofconventionalIFNtreatmentin40dialysispatients.This groupofpatientswascarefullyselectedfrom113dialysispatients treatedforhepatitisCandincludedonlypatientstreatedfor48 weekswithoutdosereduction.Therefore,this studycontributes data towardsthis unresolved issue.As weobserved anNPV of 100%,thesedatashowthatthelackofcEVRisastrongindicatorfor thefailureofIFNtherapyindialysispatients.
Allpatientsreceived48weeksoftreatmentirrespectiveofHCV genotyping.Therelationship between HCVgenotypeand treat-mentresponse inthis specialpopulation hasnotyetbeenwell established. In 2008 the Kidney Disease Improving Global
Figure1.Sustainedvirologicalresponse(SVR)ratesaccordingtoHCVRNAatweek 12ofantiviraltreatmentwithinterferon(IFN).
Outcomes (KDIGO) working group published guidelines with recommendations for the length of therapy based on HCV genotype (48 weeks for genotypes 1 and 4, and 24 weeks for genotypes2and3)thatweremadebyextrapolatingdatafromthe generalpopulation;45howevertheserecommendationswerenot
basedonrandomizedclinicaltrials.Inthiscontextitisalsovery importanttoevaluatethepredictivevalueofHCVRNAduringvery earlyweeksoftreatmentforpatientswithHCVreceivingantiviral therapyfor24weeksonly.
Theresultsofthisstudyaremeaningfulduetothelargenumber of co-morbidities and the high rate of potentially severe side effects of IFN treatment in this group of patients. Furthermore determiningstoppingrulesforhemodialysispatientsisextremely importantforkidneytransplantcandidatesbecause transplanta-tionisdelayedduringIFNtreatment.Inconclusion,interruptionof treatment should be indicated for hemodialysis patients with chronichepatitisConconventionalIFNmonotherapywhodonot achieveacEVR,duetothelowprobabilityofaresponseafter48 weeks.
Conflictofinterest:Theauthorsdeclarenoconflictofinterest.
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