Reply to: Single-dose rifampicin and BCG to prevent leprosy

Letter

to

the

Editor

Replyto:Single-doserifampicinandBCGto

preventleprosy

DearEditor,

Wethank Lockwoodetal.fortheircommentsonourarticle

‘Effectivenessofsingle-doserifampicinafterBCGvaccinationto

prevent leprosy in close contacts of patients with newly

diagnosed leprosy: A cluster randomized controlled trial’

(Richardus etal.,2019),and greatlyappreciatetheopportunity

toreply.

First,theauthorscomparetheMALTALEPtrialandtheCOLEP

trial(Moetetal.,2008), becauseboth trialsaddress

chemopro-phylaxisinleprosywithsingle-doserifampicin(SDR).Yetthereare

crucialdifferencesthatrenderdirectcomparisonprecarious.The

COLEP trialexamined theeffectiveness ofSDR (alone) given to

contactsofleprosypatientsinandoutsidethehousehold.Overall,

asignificantreductionintheincidenceofleprosyof57%(95%CI:

33–72%;P=0.0002)wasseen.Thisresultwasobservedaftertwo

yearsanddecreasedtheincidenceofleprosyamongthecontactsto

theincidenceofleprosyinthegeneral,untreatedpopulation,and

this was sustained at 4- and 6-years follow-up. The authors’

remarkthat“TheCOLEPtrialidentifiedthattheshort-termbenefitsof

SDRwereonlysignificantinmoredistantcontactsofindexcases”is

simplynotfactual.Incontrast,thebenefitofSDRwaslong-lasting

andthestatisticallysignificantprimaryoutcomemeasureof57%

appliedtoallcontactscollectively.Foradetailedexplanationofthe

COLEPtrialwerefertoourpreviouscommunication(Richardus

andSmith,2018).

Adecadelater,theMALTALEPtrialhadaveryspecificcontext,

differentfromtheCOLEPtrial:itwasbasedontheobservationthat

BCGvaccinationprovidedtocontactsofleprosypatientsinthelong

termhadshownaprotectiveeffectagainstleprosy.However,the

possibilityofleprosyappearingduringthefirstyearafter

vaccina-tion,beforeBCG’sprotection waseffective,neededfurtherstudy.The

aimoftheMALTALEPtrialwastodeterminewhetherpossibleexcess

casesinthefirstyearafterimmunoprophylaxis(withBCG)couldbe

prevented with chemoprophylaxis (with SDR) without affecting

BCG’sprotectiveeffect. Thus, theresultsoftheMALTALEPtrial should

beconsideredinthislight,wherecontactswerefirstgivenBCG,and

subsequentlySDR,inonearmofthetrial.Thus,contactsreceiving

SDR in this study were immunologically different from those

receiving this form of chemoprophylaxis in the COLEP study.

Furthermore,theresultsareconfoundedbecauseonethirdofall

new leprosy cases among contacts arising after BCG appeared

(unexpectedly) already 8–12 weeks after BCG vaccination, and

(crucially!)beforetheadministrationofSDR.Theprimaryoutcome

measureofnewleprosycasesat1and2yearswasnotsignificantly

different(atalevelof5%)betweenthetwoarmsofthetrial.

Inthe MALTALEParticlewe describedthe reductioninPB

leprosy (mostofournew patients)of42%inthe SDRarmas

notable,althoughnotstatisticallysignificantduetoinsufficient

statisticalpower.RegardingMBleprosy,weindeedfoundmore

cases at1-and2-yearsfollow-upinthe SDRarmofthe trial

(5 vs. 3 and 6 vs. 0, respectively). This is certainly peculiar.

Importantly,thenumbersareverylow,andwehesitatetodraw

any conclusions on findings of secondary subgroup analysis,

particularlyaboutclinicalrelevance(Burkeetal.,2015).

Further-more,MBwasdiagnosedinitiallybylesioncountaccordingtothe

WHOclassificationsystemandsubsequentlytestedforbacterial

index(BI)byslitskinsmear.OfallMBcasesintheMALTALEPtrial

(before and after SDR intervention), onlyone case had a BI of

2+(classifiedasborderlinelepromatousleprosy).Allotherswere

negative(BIzero)andclassifiedasborderlinetuberculousleprosy

(BT).

Theauthorsendwithasweepingconclusionthat“theevidence

forSDRasastrategytopreventleprosyorachievethetargetofzero

transmissionofM.lepraeremainslimited”.Wehopetohavemade

clear that this opinion cannot be based onthe findings of the

MALTALEP trial, because this trial was primarily about the

possibilityofSDRaugmentingtheimmunoprophylacticeffectof

BCGvaccination.Formoreinformationonchemoprophylaxiswith

SDR we refer to the 2018 WHO Guidelines for the Diagnosis,

TreatmentandPreventionofLeprosy,inwhicharecommendation

for chemoprophylaxis with SDR is given based on the GRADE

process(Anonymous,2018).

Conflictofinterest

None. Fundingsource None. Ethicalapproval Notapplicable. References

Anonymous.Guidelinesforthediagnosis,treatmentandpreventionofleprosy.New

Delhi:WorldHealthOrganization,RegionalOfficeforSouth-EastAsia;2018.

https://apps.who.int/iris/bitstream/handle/10665/274127/9789290226383-eng.pdf?ua=1.

Burke JF, Sussman JB, Kent DM, Hayward RA. Three simple rules to ensure reasonablycrediblesubgroupanalyses.BMJ2015;351:h5651,doi:http://dx.doi. org/10.1136/bmj.h5651.

MoetFJ,PahanD,OskamL,RichardusJH.Effectivenessofsingledoserifampicinin preventingleprosyinclosecontactsofpatientswithnewlydiagnosedleprosy: clusterrandomisedcontrolledtrial.BMJ2008;336:761–4,doi:http://dx.doi.org/ 10.1136/bmj.39500.885752.BE.

https://doi.org/10.1016/j.ijid.2020.01.052

1201-9712/©2020TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND

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

InternationalJournalofInfectiousDiseases92(2020)271–272

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

RichardusJH,SmithWCS.ThreecommonmisinterpretationsoftheCOLEPtrial.Lepr Rev2018;89:173–5(LettertotheEditor).

RichardusR, AlamK,KunduK,Chandra RoyJ,Zafar T,ChowdhuryAS,et al. Effectivenessofsingle-doserifampicinafterBCGvaccinationtopreventleprosy in close contacts of patients with newly diagnosed leprosy: a cluster randomizedcontrolledtrial.IntJInfectDis2019;88:65–72,doi:http://dx.doi. org/10.1016/j.ijid.2019.08.035.

JanHendrikRichardus*

DepartmentofPublicHealth,ErasmusMC,UniversityMedicalCenter

Rotterdam,Rotterdam,TheNetherlands

AnnemiekeGeluk

DepartmentofInfectiousDiseases,LeidenUniversityMedicalCentre,

Leiden,TheNetherlands

* Correspondingauthor.

E-mailaddress:j.richardus@erasmusmc.nl(J.Richardus).

Received27January2020