High-risk human papillomavirus and cervical lesions among women living with HIV/AIDS in Brazilian Amazon, Brazil

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

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

High-risk

human

papillomavirus

and

cervical

lesions

among

women

living

with

HIV/AIDS

in

Brazilian

Amazon,

Brazil

Leila

da

Silva

_,

_Angélica

_Miranda

_,

_Rosieny

_Batalha

_,

_Luiz

_Ferreira

_,

Mayara

Santos

_,

_Sinésio

_Talhari

a_{Fundac¸ãodeVigilânciaemSaúdedoAmazonas,Manaus,AM,Brazil}

b_{Fundac¸ãodeMedicinaTropicalDr.HeitorVieiraDourado,Manaus,AM,Brazil}

c_{FaculdadedeMedicina,UniversidadeNiltonLins,Manaus,AM,Brazil}

d_{PostGraduationPrograminTropicalMedicine,Fundac¸ãodeMedicinaTropicalDr.HeitorVieiraDourado/UniversidadedoEstadodo}

Amazonas,Manaus,AM,Brazil

e_{InfectiousDiseasesUnit,UniversidadeFederaldoEspíritoSanto(UFES),Vitória,ES,Brazil}

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Articlehistory:

Received20February2015 Accepted6July2015

Availableonline7August2015

Keywords: HPV HIV Cervicalcancer BrazilianAmazon

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Objective:Thegoalofthisstudywastodeterminetheprevalenceofhumanpapillomavirus

infection infection and cervicallesions and its associatedfactors among HIVinfected womenattendinganAIDSclinicinAmazonasstate,Brazil.

Methods:Cross-sectional study.Womenattending anAIDS clinicinthe cityofManaus

betweenMarch andDecember2011forgynecologicalexaminationwereinvited to par-ticipate. Enrolledpatientsanswereda standardizedinterviewincluding demographical, behavioral,andclinicaldata.Additionally,patientsunderwentagynecologicalevaluation withcollectionofcervicalsamplesforcytologicalanalysisandhigh-riskhuman papillo-mavirusinfectionhybridcapture.AbloodsamplewasalsoobtainedtodetermineCD4and viralloadlevels.

Results:Atotalof310(82.9%)womenparticipatedinthestudy.High-riskhuman

papillo-mavirusinfectionwasdetectedin191(61.6%)cases;24(13.5%)hadlow-gradesquamous intraepitheliallesion(SIL)and4(2.2%)high-gradeSIL.Noinvasivecervicalcancerwas diag-nosed.Medianagewas32(interquartilerange(IQR):27–38)yearsandmedianofeducation was8.5(IQR4–11)yearsofschoolingand56.1%hadamonthlyincomeuptoUS$180.In mul-tivariateanalysis,beinglessthan30yearsold[OR=1.7(95%CI:1.2–2.4,p=0.005)],high-grade SIL[OR=6.5(95%CI:1.6–23.0,p=0.009)],andCD4counts<200cells/mm3_{[OR=1.6(95%CI:}

1.2–2.0,p<0.001)]wereassociatedwithhighriskhumanpapillomavirusinfectioninfection.

Conclusions: Inthepresentstudyhigh-riskhumanpapillomavirusinfectionwasfrequent

anditwasassociatedtohigh-SIL.Theseresultsshowtheimportanceofgynecologic exam-inationsinroutinecareandfollow-uprequiredbythosewhopresentwithcervicallesions. ©2015ElsevierEditoraLtda.Allrightsreserved.

∗ _{Correspondingauthorat:HealthSurveillanceFoundationofAmazonas,Km09,s/n}◦_{DeputadoVitaldeMendonc¸aHighway,TerraNova,}

Manaus,AmazonCEP69.093-415,Brazil.

E-mailaddresses:leilac1994@gmail.com,leilac@fmt.am.gov.br(L.daSilva). http://dx.doi.org/10.1016/j.bjid.2015.07.001

Introduction

Althoughscreeningforcervicalcancerisrecommendedfor womeninmostcountries,withvaryingagerangeand peri-odicity oftesting, the incidenceof cervical cancer and its relatedmortalityisfargreaterindevelopingcountries.1

Inva-sivecervicalcancer(ICC)isthesecondmostcommoncancer inwomenofchildbearingageinBrazil2 andabout15.1%of womeninthegeneralpopulationareestimatedtobeinfected bycervicalhumanpapillomavirusinfection(HPV)in2012.2_An

estimated15,590newICCcaseswillbediagnosedinBrazilin 2014(15.33/100,000women).3

Cervical cancer isthe most incident in northernBrazil (23.57/100,000).InthestateofAmazonastheICCisaconcern becauseithasthehighestincidencerateestimatedinBrazil (630cases;35.13/100,000women)in2014.Inthesameyear,the capitalcityofManaushadanestimatedrateofthreeandahalf timesgreaterthanthatexpectedforthecountrybesides hav-ingthehighestincidencerateamongBraziliancapitals(510 cases;53.3/100,000women).3

ThespreadofHIV/AIDSinnorthernBrazilandintheState ofAmazonas,inparticular,isworrisomeespeciallybythe vul-nerabilityofthisgeographicalarea,whichisdeterminedby theethnic-culturaldiversityoftheirinhabitants.4,5_The

pre-cariouslivingconditions ofthe population,and thelackof accesstobasicneedsandhealthcare,giventhemagnitudeof thediseaseandcurrentepidemiologicaltrends,areimportant issuesinthispopulation,especiallyregardinghospitalbeds availability.6

In Brazil the total cumulative cases of AIDS from 1980 toJune2014was757,042casesand35.0%ofthistotalwere women.Themortalityrateforwomenwas4.3/100,000 inha-bitants(2013),observinganincreaseof3.9deathsper100,000 inhabitantsin2004to4.3in2013.In2013,theincidencerateof AIDSintheAmazonstatewasthesecondlargestinthe coun-try(37.4/100,000inhabitants), andthemortalityrateforthe thirdlargest(8.7/100,000inhabitants).Thecapitalcityof Man-aushad thethirdhighestincidencerateofAIDSamongall Braziliancapitalcities(59.7/100,000inhabitant),witha mor-talityrateof12.5%.7

WomeninfectedbyHIVpresentsignificantlyhigherrates ofsquamousintraepithelial lesions(SIL)and aremore sus-ceptible to invasive cervical carcinoma progression than HIV-negative women.8–11 _{The prevalence of HPV infection}

isusually greater in HIV-infectedwomen12,13 _{and it might}

be explained by the maintenance of high plasma14 _and

genital15 _{viralloadand persistentHPVinfection}10,15–17 _asa

resultofHIVinfection,whichincreases therisktodevelop SIL.14–18

WhereverHIV-infectedwomenhaveaccessandgood cov-erage to cervical cancer screening, they will have better prognosisasaconsequencetoearlydiagnosisandtreatment ofcervicallesions,avoidingprogressiontocancer.Thereare notpublisheddatafocusingonthisprobleminAmazonasand theseresultsofthepresentcanbeusedtoelaborate preven-tionstrategiesforthispopulation.Thegoalofthisstudywasto evaluatetheprevalenceofHPVinfectionandcervicallesions inwomeninfectedbyHIVattendinganAIDSclinicinManaus, Amazonas,Brazil.

Material

and

methods

This was a cross-sectional study conducted among HIV-infectedwomen whoattended the AIDSclinicofa tertiary referral hospital in the city of Manaus, Amazonas, Brazil, between March and December 2011.The hospital was the TropicalMedicineFoundationDr.HeitorVieiraDourado (FMT-HVD)inthecityofManaus.ThetotalofwomeninfectedbyHIV registeredatFMT-HVDwas2062cases.Inthestudyperiod419 patients,attendingtheclinicforroutinegynecological exam-ination, wereinvitedtoparticipate.Inordertobeincluded inthestudywomenhadtohaveaconfirmedanti-HIVresult, beaged18–49years,andagreedtoparticipate.Theexclusion criteriawerepregnancyatthetimeofstudy,previous hysterec-tomy,orhistoryofcervicalconization(Fig.1).

Enrolled patients answered a face-to-face standardized interviewincludingdemographic,behavioralandclinicaldata, after signingthe informed consentform.They also under-went agynecologicalevaluationandcervical sampleswere collected for cytological analysis, which followed the rec-ommendations of the Brazilian Ministry of Health.19 _The

classification usedforcytologicalresults wasthe Bethesda Systemforepithelialcellabnormalities–atypicalsquamous cellsofundeterminedsignificance(ASC-US);Cannotexclude HSIL (ASC-H); Low-grade squamous intraepithelial lesion (LSIL); High-grade squamous intraepithelial lesion (HSIL).19

Colposcopic abnormalities werebiopisiedand submittedto histologicalanalyses.Abloodsamplewasobtainedto deter-mineCD4andviralloadlevels.

Samplesformolecularbiologytestswere collectedprior tothecollectionforcytology.Thetestusedfordetecting HPV-DNAwasthe(HC2)low(6,11,42,43e44)andhighrisk(HPV16, 18,31,33,35,39,45,51,52,56,58,59e68)HybridCapture2V2®_. The samples were collected using brush-type “cytobrush,” whicharepartofHC2(DIGENE®)tomicrowellhybridization signalamplificationbydetectingchemiluminescenceto qual-itatively detectHPV.Hybridcapturewasalsoperformedfor

Chlamydiatrachomatis.

Samplesweretransportedinroomtemperatureconditions rightafterspecimencollectionorinlowtemperatures(−2to 8◦C)whentherewasadelayofuptotwodaysaftercollection beforesendingtotheLaboratoryofMolecularBiologyofthe FMT-HVDinManaus,Amazonas.

TheprimaryoutcomevariablewasHPVpositivityforlower and/orhigh-riskgenotypes,definedasanypositiveHC2.To determine factors associated with the prevalence of high risk HPV,predictingvariables suchasdemographic, behav-ioral,andclinicaldatawereexamined.Demographicvariables includedwerestateoforigin,ageinyears,yearsofschooling, maritalstatus,monthlyincome,andtobaccouse.Behavioral variableswereageatfirstsexualintercourse,regularcondom use,previoussexualviolence,commercialsexwork,practice of anal sex, homosexual relationship, illicit drug use, and injecting drug use. Clinicalvariables were genital bleeding, cervicalcytologyresultsandChlamydiatrachomatistestresults, CD4countsandviralloadlevelatHPVdiagnosis,aswellas infectionstatus(categorizedasHIVinfectionorAIDS).

Data were analyzed using the SPSS 17.0. A prelimi-naryanalysiswas performedusingexploratory techniques.

Recruitment of HIV-infected women or with AIDS of the SAE/FMT-DHVD

n=2.062

Accessed eligible women n=419

Inclusion criteria HIV-infected women or with AIDS Age 18 to 49 years

They agreed to participate

conducted interview and collection of material for laboratory tests Women included n=374 Study population n=310 Exclusion criteria Diagnosis of pregnancy at the time

n = 01 of study sampling

n = 01 Previous hysterectomy

n = 00 History of cervical conization

n = 01 Age greater than 49

n = 05 Duplication of participation

Women did not perform sample

n = 56 collection

Fig.1–Flowdiagramofstudyparticipants.

Chi-square tests,Student’s ttestsand analysisofvariance wereused.Theoddsratiowasusedasameasureof associa-tion,estimatedwitha95%confidenceintervalandthosewith

p<0.05wereconsideredtobesignificantlyassociatedwiththe outcomevariable(high-riskHPV).Multivariateanalysiswas performedtodeterminevariables independentlyassociated theoutcome ofinterest,throughtheuse oflogistic regres-sionmodels.Allvariableswithap≤0.15inunivariateanalyses wereincludedinmultivariateanalysis.

Thisstudy wassubmittedtoandapprovedbythe inter-nalreviewboard of the AmazonasFMT-HVD #327-09/2009. Writtenconsent was givenby the patients for their infor-mation tobestored inthe hospitaldatabase and used for research.

Results

Thisstudyevaluated419women,374mettheeligibility crite-ria.Eightcaseswereexcludedbecauseofpregnancy,previous hysterectomy,agegreaterthan49yearsold,andduplicationof participation.Aftertheinterview,56womendidnotundergo samplecollection.Atotalof310(82.9%)womenwereincluded inthestudy(Fig.1).Allwomenwereonantiretroviraltherapy (ART).

High-riskHPVwasdetectedin191(61.6%)cases;24(13.5%) hadLSILandfour(2.2%)HSIL.Therewerenocasesofinvasive cervicalcancer.

Medianagewas32(interquartilerange(IQR):27–38)years andmedianofeducationwas8.5(IQR4–11)yearsof school-ing.A totalof56.1% had amonthly incomeup toUS$180. Table1showsdemographicdata;agewastheonlyvariable significantlydifferentbetweengroups.

Behavioral features are described in Table 2: 9.7%were tobaccousers,49(15.8%)illicitdrugabusers,220(71.0%)used condomsregularlyinlastyear,and49(15.8%)were commer-cialsexworkers.Therewasno differencebetweenthetwo groups.

ThemedianofCD4+Tcell countsand ofviral loadwas 338.5(IQR=211.5–513.3)cells/mm3_{and497.5(IQR=49–11,288)} copies/mm3_{respectively.Atotalof165(53.2%)HIVinfected} women were classified as patients with AIDS. The HPV infectedwomenwere differentfrom HPVuninfectedgroup regardingCD4countless than200(28%vs.10.2%,p<0.001) andHSIL(3.7%vs.0.8%,p=0.001).Clinicaldataaredescribed inTable3.

In multivariate analysis, being less than 30 years old [OR=1.7 (95% CI:1.2–2.4, p=0.005)], HSIL [OR=6.5(95% CI: 1.6–23.0, p=0.009)],and CD4count <200cells/mm3 _[OR=1.6 (95%CI:1.2–2.0,p<0.001)]wereassociatedwithhighriskHPV infectioninthefinalmodel.

Discussion

ThisstudyfoundahighprevalenceofhighriskHPVinHIV infected women in Manaus. These results underscore the

Table1–Demographicalcharacteristicsofthe310 participantsHIVwomen,attendeesoftheserviceof specializedcareforAIDSinManaus,Amazonas,Brazil.

Variables HPVpositive n(%) HPVnegative n(%) pvalue Stateoforigin AmazonasState 157(82.2) 91(76.5) 0.143 OtherStatesinNorth 25(13.1) 19(16.0)

OtherRegions 9(4.7) 9(7.5) Ageinyears 18–29 80(41.9) 28(23.5) 0.002 30–39 81(42.4) 60(50.4) ≥40 30(15.7) 31(26.1) Educationinyears Upto4 50(26.2) 30(25.2) 0.916 5–8 48(25.1) 27(22.7) ≥9 93(48.7) 62(52.1) Maritalstatus Single 61(31.9) 33(27.7) 0.621 Married/livingtogether 97(50.8) 69(58.0) Separated/divorced 21(11.0) 12(10.1) Widow 12(6.3) 5(4.2) Monthlyincome UptooneBMIa _{116(60.7) 58(48.7) 0.194} 1.1–3BMI 60(31.4) 46(38.7) Morethan3BMI 15(7.9) 15(12.6)

a _{OneBMI=US$180in2011.}

Table2–Behaviorcharacteristicsofthe310participants HIVwomen,attendeesoftheserviceofspecializedcare forAIDSinManaus,Amazonas,Brazil.

Variables HPVpositive n(%) HPVnegative n(%) pvalue Ageatfirstintercourse ≤15years 95(49.7) 51(42.7) 0.233 >15years 96(50.3) 68(57.3)

Regularcondomuse

Yes 135(70.7) 85(71.4) 0.777

No 56(29.3) 34(28.6)

Previoussexualviolence

Yes 70(36.6) 41(34.5) 0.779

No 121(63.4) 78(65.5)

Sexworkers

Yes 35(18.3) 14(11.8) 0.333

No 156(81.7) 105(88.2)

Practiceofanalsex

Yes 59(31.4) 37(31.1) 0.836

No 131(68.6) 82(68.9)

Homosexualrelationshipever

Yes 9(4.7) 5(4.2) 0.317

No 182(95.3) 124(95.8)

Illicitdruguse

Yes 33(17.3) 16(13.4) 0.368

No 158(82.7) 103(86.6)

Injectingdruguse

Yes 3(1.6) 1(0.8) 0.579

No 188(98.4) 118(99.2)

Table3–Clinicalcharacteristicsofthe310participants HIVwomen,attendeesoftheserviceofspecializedcare forAIDSinManaus,Amazonas,Brazil.

Variables HPVpositive n(%) HPVnegative n(%) pvalue Genitalbleeding Yes 20(10.5) 11(9.2) 0.735 No 171(89.5) 108(90.8)

Cervicalcytologyresults

Normal 157(82.2) 116(97.5) <0.001 LowgradeSILa _{27(14.1) 2(1.7)}

HighgradeSIL 7(3.7) 1(0.8)

Chlamydiatrachomatistest

Positive 11(5.8) 3(2.5) 0.262 Negative 180(94.2) 116(97.5) CD4countsatHPVdiagnosis ≤200cells/mm3 _{54(28.0) 12(10.2) <0.001} 201–349cells/mm3 _{56(29.1) 36(30.5)} 350–500cells/mm3 _{48(25.4) 20(16.9)} >500cells/mm3 _{33(17.5) 51(42.4)}

Viralload(copies/ml)

≤1000 94(49.2) 71(59.7) 0.073 >1000 97(50.8) 48(40.3)

Infectionstatus

HIV 89(46.6) 56(47.1) 0.725 AIDS 102(53.4) 63(52.9)

a _{SIL,squamousintraepitheliallesions.}

importanceofroutinegynecologicexaminationsand follow-upinthosewhopresentwithcervicallesions.Theseresults areinagreementwithotherBrazilian10,20–23andinternational studies12–14,24,25_{thatshowedhighprevalenceofhighriskHPV}

amongHIVinfectedwomen.

Itisimportanttoemphasizethatitwasfoundlow preva-lenceofHSILinthisgroupandtherewasnoinvasivecervical cancer.These findings couldbe explainedbythehigh rate ofARTuseandbythehigheraccessofHIVinfectedwomen togynecologicalcareinBrazil.Astheygototheclinictobe followedfortheHIVinfectiontheyarealsomorefrequently submittedtopapsmearandcanthereforebediagnosed ear-lier.

HPVisconsideredoneofthemostimportantriskfactors forcervicalcancer.26–28_{InthepresentstudyhighriskHPVwas}

associatedtoHSIL.HPVinfectionandSILarecommoninHIV infectedwomen,12–14,29–31_{whomaybeasymptomatic.AsHIV}

infectedwomenmayhavefasterprogression,allwomenwith SILmust betestedforHIV,becauseit mightbeasignalof immunosuppression.14,31_{FactorsrelatedtoHPVinfectionalso}

contributetoprogressionoftheinfectiontocancer,suchas HPVgenotype,viralvariants,persistenceofinfection,andviral load.15,32,33_{Thehigh-risktypesaremorelikelytocause}

persis-tentlesionsandbeassociatedwithprecancerouslesions.25,34

Other associatedfactor withhigh riskHPVinthis study was lower CD4 lymphocyte cells counting (<200cell/mm3_). Other studies suggestedthat the frequencyof HPV persis-tence varied inversely withCD4+ count, and found higher HPV prevalence and incidence of oncogenic HPV types in HIV infected patients, especially those with lower CD4+

counts.13,18,31 _{These data suggest that the level of CD4 is}

importantinthepathogenesisofHPVinfectioninHIVinfected patients.25,31

Cross-sectionalstudies canbecarriedout toinvestigate associationsbetweenriskfactorsandtheoutcomeof inter-est.Theyarelimited,however,bythefactthattheyarecarried outatonetimepointandgivenoindicationofthesequence ofevents.Forthisreason,itisimpossibletoinfercausality.Its applicationisjustifiedinthisstudyforassessingthe preva-lenceofandtheassociatedfactorsforhighriskHPVamong HIVinfectedwomen.Itisimportanttodemonstratethe sus-ceptibilityofthisgroupofwomentothecomplicationsofthis infection.Inthisstudy,thepossibilityofresponsebiascould notberuledout.Thereisalwaysageneraltendencytogive sociallyacceptableanswers.

Performing routinely cervical cytological exam is recommended25,35 _{and in case of any degree of}

abnor-mality in this evaluation women should be referred to colposcopy assessment.36–38 _{HIV-infected womenwith}

cer-vical invasive carcinomanormally present fasterevolution andgreaterchancefordiseaserecurrence.13_{Cervicalcancer}

incidence in HIV-infected women is not altered by use of ARVtherapy.27,38_{Therapeuticmanagementisthesameasfor}

uninfectedwomen,irrespective ofHIVserology,35 _{but with}

poorerprognosisinwomenwithAIDS.26,35

Cancerpreventionprogramsexistandhavebeenshownto besuccessfulatavoidingdiseaseprogressionamongwomen infected byHIV. Although this is encouraging,much work stillremainsinordertoidentifyadditionalinnovative inter-ventions that address social, cultural, and environmental influencesofHPVinfectionandcervicalcancer.Thereisalso aneedtofindbetterwaysofdisseminatingevidence-based approachestoHIVprevention,sothateffectiveinterventions aremorewidelyused.35

In conclusion, it was demonstrated high prevalence of high-riskHPVinfectioninwomenlivingwithHIVinManaus, beingsignificantlyassociatedwithagelessthan30yearsold, presenceofhigh-gradeSILandCD4counts<200cells/mm3_.In citiesoftheBrazilianAmazon,accesstosexualand reproduc-tivecare,contributeeffectivelytopreventlesionsandcervical cancerinthispopulation.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

TheteamwouldliketothanktheInternationalClinical, Oper-ational, and Health Services Researchand Training Award (ICOHRTA) Program, the Fogarty International Center/US NationalInstitutesofHealth#U2RTW006885ICOHRTA-NIH AI066994forgrantsupport.

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