Letter
to
the
Editor
The efficacy of ribavirin in Crimean-Congo
hemorrhagicfever—randomizedtrialsare
urgentlyneeded
TheonlyantiviraldrugusedtodayinCrimean-Congo
hemor-rhagicfever(CCHF)isribavirin;however,itsefficacyis
controver-sialduetothelackofrandomizedcontrolledtrials.
Thestudiesexaminingtheefficacyofribavirinin CCHFhave
generallybeenretrospectivestudiesincludinginsufficient
num-bersofpatients,resultinginlowpower.Wethinkthatribavirin
shouldnotbeusedinCCHFuntilrandomizedcontrolledstudies
havebeenconducted,andthatonlysupportivetreatmentshould
beused.1
In response to the letter from Professor Onder Ergonul
suggesting that our conclusions are wrong, we provide the
scientificevidenceoutlinedbelow.
First, Professor Ergonul suggests that a study published in
2013 showed ribavirin to decrease the mortality from CCHF.2
However,inthatretrospectivestudy,thepatientsweregroupedby
severity as mild, moderate, and severe cases, and ribavirin
decreasedmortalityonlyinmoderatecases.Itwasreportedthat
two of 134cases receiving ribavirin and three of 18 cases not
receivingribavirindied,andthatthisdifferencewasstatistically
significant.Themortalityrateswerelowintheribaviringroup,but
becausethestudywasnotrandomized,thepatientselectionmay
havebeenbiased;forexample,severecasesmaynothavereceived
ribavirinifthisdrugwasnotavailableatthehospitalofadmission
andthendiedbeforeitbecameavailableorafterjustafewdoses.
Therefore,webelievethatthestudyresultshowingthedecreased
mortalityintheribaviringroupisduetoatype1error.
Second, Professor Ergonul suggests that some studies
per-formed recently in Turkey have revealed as an outcome that
ribavirindecreasedmortalityinCCHF.2–5Oneofthesestudiesis
relatedto healthcareemployeescoming intocontact withthe
CCHFvirusorbeinginfectedfollowingCCHFexposure.4Inthat
study,ninehealthcare employeeswere administered ribavirin
following injury with contaminated tools, two before any
symptoms developed and seven after they had developed
symptoms. It was suggested that the development of
CCHF-relatedsymptomswasprevented intwohealthcareemployees
coming intocontact withthe CCHFvirus. However, CCHF is a
diseasewitha high probabilityofasymptomatic presentation,
thus this invalidates that comment. Additionally, stating that
ribaviriniseffectiveinCCHFbasedononlytwocasesdoesnot
coincidewithscientificstudyprinciples.Further,inthatstudy,
ribavirin was administered to seven healthcare employees
developingCCHF,andit wasreportedthatonly onecasedied.
When these seven study cases are examined in detail, it is
observedthatfourcaseswereofmoderateseverity,twoofmild
severity,andonewasofseveregrade–thehealthcareworkerwho
diedwastheseveregradecase.Therefore,itismoreprobablethat
survival is related to disease severity rather that the use of
ribavirin.
Inanotherstudy,mortalitywasfoundtobe0%ineightcases
receivingribavirinand4.5%in22severecases(onepatientdied)
whodidnotreceiveribavirin;itwasclaimedthatmortalitywas
muchhigherinthepatientsnotreceivingribavirin.5However,the
differencebetweenthegroupswasnotstatisticallysignificantand
thepatientswerenotrandomizedprospectively.
Professor Ergonul suggests that ribavirin use in CCHF is
supportedbytwootherstudiesincludedinourarticle.6,7However,
thesestudiesdidnotfindthatribavirinreducedmortality,only
that some laboratory parameters improved more rapidly in
patientsreceivingribavirin.
Professor Ergonul indicates that the study reported in a
reference we cited was biased and that an editorial has been
publishedinrelationtothissubject.8,9Hefurther suggeststhat
therewasabiasinthatstudyarisingfromribavirinadministration
tomoreseverecases.However,itisknownthatcliniciansinTurkey
in2004,theyearinwhichthestudywasperformed,administered
ribavirin toall cases,withoutdifferentiating between mild and
severeones.
Third,intheonlyrandomizedcontrolledstudyexaminingthe
efficacyofribavirininCCHF,nostatementabouttherecruitmentof
onlylate casesisavailableassuggestedbytheauthor.10Inour
opiniontheonlydeficientaspectofthisstudywasthattheeffectof
ribavirinonmortalitywasnotexaminedinthegroupsinwhichthe
caseswereseparatedintoearlyandlatecases.
Professor Ergonul suggests that the conduct of a study
examiningthe efficacyof ribavirin in CCHFis in contravention
to the Declaration of Helsinki. This Declaration finds the
administrationofplacebotoagroupofpatientstobeinappropriate
when a treatment method of proven benefit in a disease is
available.However,itisourfirmbeliefthattheefficacyofribavirin
in CCHF is not proven, and on the contrary it has been
demonstrated in many non-randomized, retrospective studies
and caseseriesthatithasnoeffectonmortality.Therefore,we
think that it is ethically acceptable to perform a randomized,
placebo-controlled study in CCHF in relation to ribavirin use,
stratifying for disease stage. Furthermore, ribavirin usage rates
have decreasedto11.8%in Turkeyaccordingtothe2004–2007
data oftheTurkishMinistry ofHealth,Department ofZoonotic
Diseases,asreportedbyCeylanetal.1andTurhanetal.11Inother
words,thedrugisnolongerusedinthetreatmentofthedisease.
Fourth,ProfessorErgonulhassuggestedthatinastudyonthe
early administration of ribavirin in CCHF the mortality rate
was2.9%(10/342)andthatthisratewaslowerthantherateof
5%(20/400)reportedinanotherstudyinwhichthecaseswerenot
administeredribavirin.3,12Inthestudymentioned,thecasesusing
ribavirinwerenotgroupedasearlyandlatecases,andearly-and
late-presentingcaseswerenotcomparedintermsofmortality,in
factallcaseswereacceptedasearlyapplyingcases;neverthelessit
InternationalJournalofInfectiousDiseases29(2014)297–298
ContentslistsavailableatScienceDirect
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
http://dx.doi.org/10.1016/j.ijid.2014.08.015
1201-9712/ß2014PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http:// creativecommons.org/licenses/by-nc-nd/3.0/).
wasclaimedthatmortalitydecreasedincasesusingribavirininthe
earlyphase.
Fifth, Professor Ergonulhas attributedthe demonstrationof
highermortalityinthefirst8daysofpatientsreceivingribavirin
compared to patients not receiving ribavirin to the clinicians’
preference for the initiation of ribavirin administration only
inseverecases.8However,asitisknownthatin2004,theyearin
which the study was conducted in our country, ribavirin
administrationwasinitiated foreverycase regardlessofdisease
severity,thiscommentisnotvalid.
ItisclearthatthestudiesinrelationtoribavirinuseinCCHF
are insufficient and conflicting. We think that the persistent
recommendationofa drugof unprovenefficacyfor aparticular
diseasemaymislead thephysicians involvedwiththis disease.
Furthermoreribavirinhasseveresideeffects,andtheeffectsand
sideeffectsneedtobebalanced.
Therefore, we thinkthat until ribavirin usein patients with
CCHFhas been clarifiedby a randomizedcontrolled trial,it is
appropriatetomonitorpatientsusingsupportivetreatmentonly.
Theuseofribavirinshouldberestrictedtopatientsincludedin
astudyprotocol.
We believe that performing a prospective, randomized,
placebo-controlledstudyofribavirininCCHFisethically
accept-ableandurgentlyneeded.
Conflictofinterest:Noconflictofinteresttodeclare.
References
1.CeylanB,CalicaA,AkO,AkkoyunluY,TurhanV.Ribavirinisnoteffectiveagainst Crimean-Congohemorrhagicfever:observationsfromtheTurkishexperience. IntJInfectDis2013;17:e799–801.
2.DokuzoguzB,CelikbasAK,GokSE,BaykamN,ErogluMN,ErgonulO.Severity scoringindexforCrimean-Congohemorrhagicfeverandtheimpactofribavirin andcorticosteroidsonfatality.ClinInfectDis2013;57:1270–4.
3.OzbeySB,KaderC,ErbayA,ErgonulO.Earlyuseofribavirinisbeneficialin Crimean-Congohemorrhagicfever.VectorBorneZoonoticDis2014;14:300–2.
4.CelikbasAK,DokuzoguzB,BaykamN,GokSE,ErogluMN,MidilliK,etal. Crimean-Congohemorrhagicfeveramonghealthcareworkers,Turkey.Emerg InfectDis2014;20:477–9.
5.ErgonulO,CelikbasA,DokuzoguzB,ErenS,BaykamN,EsenerH.Characteristics ofpatientswithCrimean-Congohemorrhagicfeverinarecentoutbreakin Turkeyandimpactoforalribavirintherapy.ClinInfectDis2004;39:284–7.
6.OzkurtZ,KikiI,ErolS,ErdemF,YilmazN,ParlakM,etal.Crimean-Congo haemorrhagicfeverinEasternTurkey:clinicalfeatures,riskfactorsandefficacy ofribavirintherapy.JInfect2006;52:207–15.
7.Tasdelen-FisginN,ErgonulO,DoganciL,TulekN.Theroleofribavirininthe therapyofCrimean-Congohaemorrhagicfever:earlyuseispromising.EurJClin MicrobiolInfectDis2009;28:929–33.
8.ElaldiN,BodurH,AsciogluS,CelicbasA,OzkurtZ,VahabogluH,etal.Efficacyof oralribavirintreatmentinCrimean-Congohaemorrhagicfever:a quasi-experi-mentalstudyfromTurkey.JInfect2009;58:238–44.
9.ErgonulO.DEBATE(seeElaldiNetal.,Efficacyoforalribavirintreatmentin Crimean-Congohaemorrhagicfever:aquasi-experimentalstudyfromTurkey. JournalofInfection2009;58:238–244):biasesandmisinterpretationinthe assessmentoftheefficacyoforalribavirininthetreatmentofCrimean-Congo hemorrhagicfever.JInfect2009;59:284–6.authorreply286–9.
10.KoksalI,YilmazG,AksoyF,AydinH,YavuzI,IskenderS,etal.Theefficacyof ribavirininthetreatmentofCrimean-CongohaemorrhagicfeverinEastern BlackSearegioninTurkey.JClinVirol2010;47:65–8.
11.YilmazGR,BuzganT,IrmakH,SafranA,UzunR,CevikMA,etal.The epidemi-ologyofCrimean-CongohemorrhagicfeverinTurkey,2002–2007.IntJInfectDis 2009;13:380–6.
12.DuyguF,KayaT,BaysanP.Re-evaluationof400Crimean-Congohemorrhagic fevercasesinanendemicarea:isribavirintreatmentsuitable?VectorBorne ZoonoticDis2012;12:812–6.
BahadırCeylana,*
VedatTurhanb
aDepartmentofInfectiousDiseasesandClinicalMicrobiology,
MedicalFaculty,MedipolUniversity,Istanbul,Turkey
b
DepartmentofInfectiousDiseasesandClinicalMicrobiology,
GATAHaydarpasaTrainingHospital,Istanbul,Turkey
CorrespondingEditor:EskildPetersen,Aarhus,Denmark
*Correspondingauthor.
E-mailaddress:bceylan2004@yahoo.com(B.Ceylan).
Received24July2014
Accepted20August2014
LettertotheEditor/InternationalJournalofInfectiousDiseases29(2014)297–298 298
