Is Visceral Leishmaniasis the same in HIV-coinfected adults?

(1)

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

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Is

Visceral

Leishmaniasis

the

same

in

HIV-coinfected

adults?

Guilherme

Alves

de

Lima

Henn

a,b,∗

_,

_Alberto

_Novaes

_Ramos

_Júnior

b

_,

Jeová

Keny

Baima

Colares

c,d

_,

_Lorena

_Pinho

_Mendes

c

_,

_João

_Gabriel

_Colares

_Silveira

e

_,

Anderson

Alberto

Fac¸anha

Lima

e

_,

_Bárbara

_Pontes

_Aires

f

_,

_Mônica

_Cardoso

_Fac¸anha

b a_Universidade_Federal_do_Ceará,_Programa_de_{Pós-Graduac¸ão}_em_Saúde_Coletiva,_Fortaleza,_CE,_Brazil

b_Universidade_Federal_do_Ceará,_Departamento_de_Saúde_{Comunitária,}_Fortaleza,_CE,_Brazil

c_Secretaria_de_Saúde_do_Estado_do_Ceará,_Hospital_São_José_de_Doenc¸as_Infecciosas,_Fortaleza,_CE,_Brazil d_Universidade_de_Fortaleza,_Faculdade_de_Medicina,_Fortaleza,_CE,_Brazil

e_Universidade_Federal_do_Ceará,_Faculdade_de_Medicina,_Fortaleza,_CE,_Brazil f_Universidade_Estadual_do_Ceará,_Faculdade_de_Medicina,_Fortaleza,_CE,_Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received13October2017

Accepted8March2018

Availableonline27March2018

Keywords:

Leishmaniasis HIV

Coinfection

a

b

s

t

r

a

c

t

Introduction:VisceralLeishmaniasisisthemostsevereformofdiseasecausedbythe Leish-maniadonovanicomplex,withsigniﬁcantmorbidityandmortalityindevelopingcountries.

WorseoutcomesoccuramongHIV-positiveindividualscoinfectedwithLeishmania.Itis

unclear,however,iftherearesigniﬁcantdifferencesonpresentationbetweenVisceral

Leish-maniasispatientswithorwithoutHIVcoinfection.

Methods:We reviewed medicalrecordsfromadultpatientswithVisceral Leishmaniasis

treatedatareferencehealthcarecenterinFortaleza–Ceará,Brazil,fromJuly2010to

Decem-ber2013.DatafromHIV-coinfectedpatientshavebeenabstractedandcomparedtonon-HIV

controlsdiagnosedwithVisceralLeishmaniasisinthesameperiod.

Results:Eightyone HIV-infectedpatientsand365controlswereenrolled. Thediagnosis

inHIVpatientstooksigniﬁcantly longer,withhigherrecurrenceanddeathrates.

Kala-azar’sclassicaltriad(fever,constitutionalsymptomsandsplenomegaly)waslessfrequently

observedinVisceral Leishmaniasis-HIVpatients,aswellasjaundiceandedema, while

diarrheawasmore frequent.Laboratory featuresincluded lower levels ofhemoglobin,

lymphocytecountsandliver enzymes,as wellashighercounts ofbloodplatelets and

eosinophils.HIV-infectedpatientswerediagnosedmainlythroughamastigotedetectionon

bonemarrowaspiratesandtreatedmoreoftenwithamphotericinBformulations,whereas

incontrols,rK39wasthemaindiagnostictoolandpentavalentantimonywasprimarilyused

fortreatment.

∗ _{Corresponding}_author.

E-mailaddress:guialhenn@gmail.com(G.A.Henn).

https://doi.org/10.1016/j.bjid.2018.03.001

(2)

Conclusions:ClinicalandlaboratorypresentationofVisceralLeishmaniasisinHIV-coinfected

patientsmaydifferfromclassickala-azar,andthesedifferencesmaybe,inpart,responsible

forthedelayindiagnosingandtreatingleishmaniasis,whichmightleadtoworseoutcomes.

anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/

licenses/by-nc-nd/4.0/).

Introduction

Leishmaniasisisthesecondmostprevalentcauseof

proto-zoaldiseases intheworldand visceralpresentation(VLor

kala-azar)isthemostsevereform.WorldHealthOrganization

(WHO)estimates300millionnewcaseseachyearworldwide,

withover 20,000deaths.1 _In_Brazil,_between₂₀₀₁_and_2013,

46,642caseswere reported,and sevenstates(Ceará,Minas

Gerais, Maranhão, Bahia, Piauí, Tocantins, and Pará)

con-tributedwithnearly75%ofnotiﬁcations.Inthesameperiod,at

least3058deathsduetothediseaseoccurredthroughoutthe

country.AmongVLpatients,thenumberofcasesreportedin

HIV-infectedindividualshasincreasedsubstantially.Between

2007and 2013,1602casesofleishmaniasis inHIV-infected

individualswerereportedinBrazil.2

Mostcases ofVL inHIV-coinfected patients are caused

by reactivation of a latent infection which becomes

clini-callyapparentastheimmunosuppressionprogressesandthe

parasite overcomes the contingency capacity of the host’s

immunesystem.3,4 _Classic_kala-azar, _{characterized} _by

pro-longedfever,constitutionalsymptoms,hepatosplenomegaly,

cytopeniasandhypergammaglobulinemiaisnotalways

man-ifestedinimmunocompromisedindividuals.Ingeneral,the

clinicalpresentationissimilartothenon-coinfected,although

thereisatendencytoinvolveorgansandsystemsnotusually

parasitized,likelungs,skin,andgastrointestinal(GI)tract.5–7

Itisunknownifpotentialdifferencesinclinicalandlaboratory

presentationsmighthindertheinclusionofVLinthe

differ-entialdiagnosis,potentiallyleadingtodelayeddiagnosisand

therapy,whichmightleadtomoreseverecourseofthedisease

andpooreroutcomes.

InBrazil,Cearáisthestatewithmorecasesofkala-azar

reported in the period of2007–2013, with or without

HIV-coinfection.2_Local_data_describing_clinical_features_peculiar_to

coinfectedindividualsarescarce.Ourgoalwastoidentifysuch

featuresinrelationtomonoinfectedpatientswithVL,inorder

toalertcliniciansaboutdifferencesandsimilaritiesin

clini-calpresentationthatmightexpeditediagnosisandtreatment

initiation.

Material

and

methods

Studydesign

Thiswas across-sectional study inadultpatients withVL

andHIV-coinfection,aimingtodescribetheirepidemiological,

clinicalandlaboratorypresentationsatdiagnosis,aswellas

thedrugprescribedfortherapy.Alldatagatheredfrom

coin-fectedsubjectswerecomparedtomonoinfectedVLcontrols.

Populationandstudyplace

MedicalrecordsofallpatientswithconﬁrmedVLdiagnosis

treatedatSãoJoséInfectiousDiseasesHospital(HospitalSão

José de Doenc¸asInfecciosas), in the period ofJuly 2010to

December 2013were reviewed.SãoJoséHospitalisthe

ref-erencehealthcarecenterfortreatmentofinfectiousdiseases

inthestateofCeará.Individualsunder18years,patientsnot

testedforHIV,andthosewhohadpriordiagnosisof

leishma-niasisorhadbeenpreviouslytreatedwithamphotericinBfor

anydiseasewereexcluded.

Datacollection

Epidemiologicaldata(age,gender,educationlevel,andorigin),

clinical information(comorbidities, duration of symptoms,

clinical symptoms atdiagnosis),laboratory tests (complete

blood count, biochemical blood tests, and diagnostic tests)

andtreatmentofHIV-coinfectedpatients(VL-HIVgroup)were

comparedwithHIV-negativecontrols(VLgroup)diagnosedat

thecenterduringthesameperiod.

Thesymptomswereconsideredpresentifreportedbythe

patientatdiagnosisorveriﬁedonphysicalexaminationbythe

doctorwhoassistedthepatient.Inaddition,signsor

symp-tomswithintheﬁrst24hofhospitalizationwereconsidered,

unlessobservedaftertheﬁrstdoseoftherapy.Regarding

lab-oratory tests, onlythose collected immediately before the

ﬁrstdoseoftherapywereconsidered;forbloodcount,urea

and creatinine(moresensitivetochangesinmedical

inter-ventions non-directly related with the treatment, such as

intravenoushydration),weoptedforthecorresponding

exam-inationonarrivalatthehospitalorimmediatelypreviousto

thatmoment.

Patients weretreated atthediscretionoftheirassisting

physiciansandmostpatients receivedtreatmentaccording

tonationalguidelinesatthetime.

Diagnosticcriteria

Diagnosis of HIV infection was performed in accordance

to the Brazilian Health Ministry guidelines, and included

Enzyme-Linked Immunosorbet Assays (ELISA), plus a

con-ﬁrmatory method (usually IndirectImmunoﬂuorescence or

Immunoblot).Immunochromatographicrapidtestswereonly

consideredasdiagnosticifconﬁrmedbyoneofthe

(3)

VisceralLeishmaniasisconﬁrmationcriteriaincluded:(1)

visualizationofamastigotesinbonemarrowaspirateorother

clinicalmaterials(exceptwhendetectedexclusivelyonskin

ornasal/oralmucousmembranes);(2)serology(detectionof

anti-rK39antibodies byimmunochromatographyorindirect

immunoﬂuorescencereactioninatitleequalorgreaterthan

1:80),associatedwithclinicalandlaboratoryﬁndings

compat-iblewiththedisease.

Statistics

Data were compiled in Microsoft Excel version 2007 and

thestatisticalanalyseswereperformedusingStataSE,

ver-sion 11.2. Numerical variables were described as median

and range and were compared using Mann–Whitney test.

Categoricalvariablesweredescribedasfrequenciesand

ana-lyzed by Pearson’s chi-square test or 2-tailed Fisher exact

test.Forstatisticalsigniﬁcance,p-valueoflessthan0.05was

admitted.

Ethics

Theresearch project was approvedbythe Research Ethics

CommitteeofSãoJoséHospital(CAAE26007713.3.0000.5044)

andfollowedthenationalandinternationalstandardsin

clin-icalresearch.

Results

The selection process is detailed in Fig. 1. Six hundred

and thirty-three subjects were initially identiﬁed. A total

of 187 subjects did not meet the eligibility criteria. Four

hundred and forty-six subjects with VL – 81 coinfected

with HIV and 365 non-coinfected – were included in the

study.

Epidemiologicaldata

Themedianageofbothgroupswas38yearsand themale

gender was predominant (86.4%and 81.6% ofthe subjects

onVL-HIV andVLgroups, respectively).Therewereno

dif-ferencesconcerningeducationallevel,with71.6%and75.1%

ofthesubjectshavingstudieduptoprimaryschool.Atthe

timeofdiagnosis,onlytwopatientsineachgrouplived

out-sideCeará.Approximatelytwothirdsofindividualsineach

grouplivedinthecapitalcity.

Comorbidities

Table 1 shows habits and comorbidities at diagnosis. The

most frequentlyused illicitdrugswere cocaine, crack, and

Table1–ComparisonofhabitsandcomorbiditiesofVL patients,accordingtoHIVstatus.

VL-HIV VL p-Value n(%)

Alcoholabuse 43(53.1) 133(36.4) 0.006a Smoking 33(40.7) 98(26.9) 0.013a Illicitdruguse 17(21.0) 20(5.5) <0.001a Hypertension 6(7.4) 37(10.1) 0.45 Diabetesmellitus 2(2.5) 30(8.2) 0.09

Asthma 4(4.9) 9(2.5) 0.26

Chronickidneydisease 0 8(2.2) 0.36 Chronicheartfailure 1(1.2) 10(2.7) 0.69 Chronichepaticdisease 2(2.5) 13(3.6) 1.0 Activetuberculosis 4(4.9) 8(2.2) 0.29

Activeleprosy 0 10(2.7) 0.22

Immunodepressantdruguse 1(1.2) 12(3.3) 0.70 VL,VisceralLeishmaniasis.

a _{Statistically}_{signiﬁcant.}

VL diagnosis (n = 633)

13 exclusions due to lack of lab confirmation

142 exclusions due to lack of HIV testing Confirmed VL diagnosis

(n = 620)

Confirmed VL with available HIV test results

(n = 478)

32 exclusions due to other reasons: Previous VL episode with no available data (20) Previous AmB therapy for other conditions (7) Partial unavailability of medical record data (5) Patients suiable for data collection

(n = 446)

VL controls (n = 365) VL-HIV coinfected

(n = 81)

(4)

marijuana.Severalpatientsreportedcombineduseofthese

substances. Useofevery substancewas more prevalent in

VL-HIVgroup(datanotshown).

Clinicalpresentation

Table2 depicts the clinical presentation ofthe patients at

the time of diagnosis. Although there was no difference

between groups in the frequency of bacterial

superinfec-tion, when each infection site was analyzed separately,

there was signiﬁcantly more skin and soft tissue

infec-tionsincoinfectedpatients(p=0.04).TheclassictriadofVL

(fever+constitutionalsymptoms+splenomegaly)waspresent

moreoftenintheVLgroup(86.7%vs.75.9%,p=0.01).Median

duration of symptoms attributableto the disease reported

by patients also varied signiﬁcantly between the groups.

Patients in VL-HIV group had a median of three months

(range,0.4–24),versustwomonthsinVLgroup(range,0.2–12)

(p=0.0001).

Laboratorytests

AllresultsshowninTable3refertotimeofdiagnosis.Table3

alsoshowsthepositivityofdiagnostictests.Thepositivityof

bonemarrowaspiratewasbetterintheVL-HIVgroup,while

theanti-rK39provedsuperiorinVLgroup(p<0.001forboth

comparisons).

When analyzingonlypatients who had beendiagnosed

withbone marrowexamination, consideringit asthe gold

Table2–ComparisonofclinicalpresentationofVL patients,accordingtoHIVstatus.

VL-HIV VL p-Value n(%) Fever 71(87.7) 357(98.1) <0.001a Anorexia 55(67.9) 291(80.0) 0.018a Asthenia 61(75.3) 320(87.9) 0.003a Weightloss 67(82.7) 320(87.9) 0.20 Cough 32(39.5) 105(28.9) 0.06 Diarrhea 36(44.4) 74(20.3) <0.001a Jaundice 5(6.2) 59(16.2) 0.02a Peripheraledema 6(7.4) 69(18.9) 0.012a Bacterialinfection 12(14.8) 37(10.2) 0.22 Dyspnea 10(12.4) 37(10.2) 0.56 Bleeding 15(18.5) 49(13.5) 0.24 Hepatomegaly 59(76.6) 250(85.3) 0.06 Splenomegaly 69(87.3) 273(90.7) 0.37 VL,VisceralLeishmaniasis.

Note:Onepatient,whowasdisorientedandhadnorelativeswith him on admission, had no clinical data.Not all patients had informationabout thepresenceorabsenceofvisceromegaly at diagnosis.

standard,anti-rK39sensitivitywassigniﬁcantlylowerin

HIV-infected individuals (48.7% versus 85.9% in the LV group,

p<0.001).

Table3–ComparisonoflaboratoryanddiagnostictestsofVLpatients,accordingtoHIVstatus.

VL-HIV VL p-Value Median(range) Hemoglobin(g/dL) 7.8(2.7–13.0) 8.7(4.2–14.0) 0.005b WBC(/mm3₎ ₁₉₄₅_(390–7540) ₂₀₀₅_(167–9420) _0.84 Neutrophils(/mm3₎ ₁₁₈₃_(231–5702) ₁₀₉₂_(0–7724) _0.06 Lymphocytes(/mm3₎ ₄₈₅_(44–2421) ₇₂₉_(71–2916) _0.0001b Eosinophils(/mm3₎ ₁₃_(0–2397) ₀_(0–535) _0.0002b Platelets(/mm3₎ _96,500_{(1000–302,000)} _72,000_{(0–300,000)} _<0.0001b AST 43(10–2830) 77(5–1198) <0.0001b ALT 24(4–527) 46(2–646) <0.0001b Creatinine(mg/dL) 0.8(0.3–3.2) 0.9(0.2–4.7) 0.34 Albumin(g/dL) 2.9(1.2–4.2) 2.9(1.1–4.8) 0.64 Globulins(g/dL) 4.4(0.9–11.3) 4.2(2.0–13.0) 0.42 Conjugatedbilirubin 0.2(0–8.6) 0.4(0.1–8.3) 0.0003b VL-HIV VL p-Value Positive/tested(%)

Amastigotesvisualizationinbonemarrow 56/67(83.6) 91/195(46.7) <0.001b

Anti-rK39 42/65(64.6) 333/343(97.1) <0.001b

Indirectimmunoﬂuorescence 6/11(54.5) 5/6(83.3) 0.51

Othera ₁₄ ₆ _–

VL,VisceralLeishmaniasis;WBC,whitebloodcells;AST,alanine-aminotransferase;ALT,aspartate-aminotransferase.

a _Other_diagnostic_methods_included_{visualization}_of_amastigotes_in_peripheral_blood,_buffy_coat,_and_{histopathological}_exams_of_stomach,

duodenumandlymphnodes.

(5)

Table4–DrugsusedfortreatingVLpatients,according toHIVstatus.

Drugprescribed VL-HIV VL p-Value n(%)

Pentavalentantimonial 17(21.0) 227(62.4) <0.001a AmphotericinB,deoxycholate 58(71.6) 102(28.0)

AmphotericinB,liposomal 5(6.2) 34(9.3) AmphotericinB,lipidcomplex 1(1.2) 1(0.3) VL,VisceralLeishmaniasis.

Note:OnepatientonVLgroupdiedbeforestartingtreatment.

Treatment

Data showninTable 4describetheinitialdrug prescribed.

Treatmentdatareferonlytotheﬁrstdruginitiatedfor

treat-ment,notconsideringtherapyswitches.

Discussion

Despitehavinggreatepidemiologicalimportanceinthe

Brazil-iancontext,thestateofCearáhasfewlocalpublisheddata

about the features of VL in HIV-coinfected patients.

Previ-ousBrazilianstudieshavemadesigniﬁcantcontributionson

thissubject8–10_;_however,_these_studies_have_either_enrolled_a

limitednumberofpatientsorusedofﬁcialdatabaseof

manda-torydisease notiﬁcation.Inthis research, arelatively large

numberofpatientswereevaluated,bothHIV-infectedand

-uninfected,anditseemsclearthatthepresentationofVLin

HIV-coinfectedindividualsmaydeviatefromwhatisexpected

inaclassicalVLpatient.Thismayleadtodelayeddiagnosis,

sinceleishmaniasis maynotbeincludedinthedifferential

diagnosisearlyon.Thishypothesismayexplain,atleastin

part,thelongerdurationofsymptomsuntilthediagnosisVL

wasmadeintheHIV-infectedgroup.

Inourseries,theclassicsymptomswerecommonin

abso-lutetermsinbothgroups,asdescribedinotherstudiesfrom

Brazil,Ethiopia,India,andSpain.11–15_However,_the_classical

clinicaltriadwhichhasbeenusedtodeﬁneasuspectedcase

ofVL –fever,constitutional symptomsandsplenomegaly–

was foundless frequently inthe coinfected group, aswell

as jaundice and peripheraledema. These ﬁndings did not

correlatewithlevelsofalbumin(similarinbothgroups)or

with the magnitude of liver dysfunction. The less intense

immuneresponseagainsttheparasiteinHIV-infected

indi-vidualsmayberesponsibleforthesedifferences.Dynamicsof

formationandmaturationofhepaticgranulomasinanimals

experimentallyinfected withviscerotropicspecies of

Leish-maniahavebeenstudiedbysomeresearchers.16,17 _Cytokine

proﬁlegeneratedbyinfectedKupffercellsandstimulatedCD4

Tlymphocytesseemstoinﬂuencethequantityandqualityof

formedgranulomas,whichdetermines,tosomeextent,the

levelofinﬂammationgenerated.Itislikelythat,in

individu-alswithimpairedcellularimmunity,suchasinHIV-infected

patients, less macrophage activation and lower levels of

proinﬂammatorycytokinesleadtoformationofdisorganized

granulomas,causingpoorcontrolofparasitemultiplication,

alongwithlesssecondaryinjuryofhepatocytesand

intrahep-aticbilecanaliculi.Thistheoryissupportedbylowerlevelsof

aminotransferasesandconjugatedbilirubinfoundinourHIV

coinfectedpatients.Onsystemiclevel,decreasedproduction

ofcertainmacrophageactivatingcytokinesinthispopulation

(e.g.IFN-y)mayexplainthelowerfrequencyoffeverand

con-stitutionalsymptoms.18

Ontheotherhand,diarrheaandcough,considered

non-typicalsymptomsweremorefrequentinHIV-infectedpatients

(althoughonlydiarrheareachedstatisticalsigniﬁcance).The

commonpresenceofthesesymptomsintheclinicalpictureof

coinfectedindividualscanadditionallymisleadthe

diagnos-ticreasoning.TheymayrepresentAids-relatedmalabsorption

syndrome,otheropportunisticdiseases,orgreaterparasitism

inorgansnotregardedasimportantinclassickala-azar

(espe-cially digestive tract).13,19–22 _We _have _no _{conﬁrmation} _that

therewasgreaterparasitedensityinGItractinoursample,

butthisﬁndingisusuallyassociatedwithagreaterlikelihood

ofrelapseinHIV-infectedindividuals,astheyareseenmore

ofteninassociationwithlowerTCD4+cellcounts.15,23

The longer duration ofsymptoms reported byour

HIV-infected patients at the time of diagnosis may be due to

lessintensesymptoms,notpromptingthesepatientstoseek

medical care. On the other hand, health care teams may

takelongertoincludekala-azarinthedifferentialdiagnosis,

while investigatingother opportunistic diseases that could

have similar clinical presentation (e.g. disseminated

histo-plasmosisormycobacteriosis).Whateverthereason,delayin

diagnosingandappropriatelytreatingthesepatientscanlead

tofurtherspreadoftheparasiteand,deepeningof

immuno-suppression,mayreducethechanceoflong-termcure.

Hematologicresultsareclearlydifferentinthethreeseries.

HIV-coinfected patientshad signiﬁcantlylower hemoglobin

levelsandlymphocytecountsatdiagnosis.MostHIVpatients

diagnosedwithVLhadlowTCD4+countsatdiagnosisand

importanthematopoieticdisturbanceduetoHIVinfectionor

other opportunisticdiseases.8,15,24_{Interestingly,}_unlike

clas-sicalkala-azar, inwhicheosinophilsare oftenabsent from

peripheralblood,inmorethanhalfofcoinfectedpatientsthis

cellwaspresentintheinitialhematologicevaluation.Platelet

count, inturn,washigher incoinfectedindividuals,which

could berelatedtodifferentpathwaysconcerningimmune

activationinacontextofHIVinfection.8,13,25

Unfortunately, molecular biology tests, which could

increasethediagnosticaccuracy,areunavailableinourcenter.

Ourserviceusesamastigotesvisualization,primarilyinbone

marrowaspirate,andrapidanti-rK39testasdiagnostictools.

Becauseofitsconvenience,ourinternalprotocolrecommends

performing the rapid test inpatients who have suspected

VL,andnotifying andtreatingpositivecases,if thepatient

presentsclinicalandlaboratoryﬁndingscompatiblewiththe

disease.Thistestisknownashavinggoodpositivepredictive

valuewhenclinicalsuspicionishigh.26_However,_the

sensi-tivityofthistestdropssigniﬁcantlyinimmunocompromised

individuals,particularlyinthoseinfectedwithHIV.27,28Inthis

population,theperformanceofparasitologicaltestwasmuch

better,perhapsbecauseofthelargestparasitedensityinthe

bonemarrow,aspreviouslysuggested.29,30_Other_factors,

how-ever,mayhaveinﬂuencedthisﬁnding.Inthesepatients,bone

(6)

suchasdisseminatedhistoplasmosis(whichisprevalent in

ourstateandmayhaveaverysimilarclinicalandlaboratory

presentationasVL).Furthermore,itispossiblethatexaminers

spendmoretimeanalyzingsmearsofHIV-infectedpatients

thanofnon-coinfectedindividuals.Somepatientswere

diag-nosed by ﬁnding the parasite incidentallyin other tissues

(e.g.,buffy-coatwheninvestigatingdisseminated

histoplas-mosis;lymphnode,wheninvestigatingtuberculosis;biopsy

samplesofstomachandduodenum,afterperforming

endo-scopieswheninvestigatingpersistent digestivesymptoms).

Theseﬁndingshaveoftensurprisedphysiciansinchargeof

patientcare, becauseinmost ofthese casesVL wasnot a

strongdiagnostichypothesis.

Asexpected,clinicians prescribed preferentially

ampho-tericinBratherthanpentavalentantimonialswhentreating

coinfectedpatients.Patientsweretreatedaccordingto

guide-lines of the Ministry of Health of Brazil, which considers

antimony as the ﬁrst-choice therapy for non-HIV-infected

patientsandrecommendsamphotericinBforthosewhoare

HIV-infected.LiposomalamphotericinB(AmBisome®,Gilead)

hadrestrictedindicationsand,becauseofitshighcost,was

prescribedonlyforpatients whohad failedtreatmentwith

deoxycholate amphotericin B or for those who developed

renalfailure.31_Preference_for_amphotericin_B_formulations_for

VL-HIVcoinfection isbasedmostly on itssuperior invitro

potencyagainstamastigotes,betteroutcomesinclinicaltrials

when comparedto antimonials, and potentially fatal

toxi-city reports(especiallypancreatic) when usingpentavalent

antimonialsonsuchpatients.32–34_More_recently,_these

recom-mendationshavebeenmodiﬁedandindicationsofliposomal

amphotericinBwereexpanded,butmostofthepatientsinour

cohortwerestilltreatedaccordingtothenational

recommen-dationsprevailingatthetime.Still,approximatelyone-ﬁfth

ofcoinfectedindividuals were inappropriatelytreated with

antimonials.

Somelimitationsare noteworthyinthis study.

Epidemi-ological, clinical and laboratory data were collected from

medicalrecords.Althoughutmostcarehasbeentakeninthe

collectingprocess,somedata(especiallyclinical)maynothave

beenregisteredinthepatientrecord.Otherconditions(e.g.

opportunisticinfections)commonlyfoundinadvancedHIV

disease werenot analyzedand mayhave contributed with

someofthedifferencesdescribedhere.Regardingthestudy

design,thiswasadescriptivestudy,andoutcomeswerenot

analyzed,asthefocusedonclinicaland laboratory

presen-tation.Finally,thecenterwherethestudywasconductedis

areferencecenter forinfectiousdiseases,which may have

increasedtheproportionofpatientswithseveredisease,

espe-ciallyinthenon-infectedgroup.Nevertheless,theservicestill

treats and monitors many patients with mild VL, and we

believethatnon-severecaseshaveindeedbeenwell

repre-sentedduetotherelativelylargesamplesize.

Conclusion

Ourresultsshow signiﬁcantdifferencesinclinical and

lab-oratorypresentationofVL inHIV-coinfectedpatientswhen

comparedtothenon-coinfectedpatients.

Weconsider that optimizingthe recognition ofthe

dis-easeandstartingspeciﬁctherapyforleishmaniasisandHIV

asearlyaspossiblecouldberelevantbecausetheyare

mod-iﬁable factors.Wepropose that, inendemicareas forboth

diseases, clinicians assisting HIV-infected patients should

increasetheirdegreeofclinicalsuspicionandincludeVLmore

ofteninthedifferential diagnosisofthesepatients,evenif

someoftheclassicclinicalandlaboratoryfeatures(likefever,

splenomegalyoreosinopenia)areabsent,andthe

immunoas-saytestisnegative.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

Acknowledgments

TheauthorsarethankfultoallhealthcareworkersfromSão

JoséHospitalwhocollaboratedwiththisstudy.

r

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