w w 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
Vaccination
coverage
in
a
cohort
of
HIV-infected
patients
receiving
care
at
an
AIDS
outpatient
clinic
in
Espírito
Santo,
Brazil
Lauro
Ferreira
da
Silva
Pinto
Neto
a,∗,
Julia
Vescovi
Vieira
b,
Nathália
Rossoni
Ronchi
baEscolaSuperiordeCiênciasdaSantaCasadeVitória,FaculdadedeMedicina,VitóriaES,Brazil bSantaCasadeVitória,Vitória,ES,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received17December2016 Accepted29March2017 Availableonline2June2017
Keywords: HIV AIDS Vaccination Immunizationcoverage Immunosuppressed
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b
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c
t
Thiscross-sectionalstudyassessedtheimmunizationstatusofhumanimmunedeficiency virus(HIV)-infectedpatientsreceivingcareatanoutpatientclinicinBrazil.The sociode-mographiccharacteristics,CD4countandHIVviralloadof281outof612adultoutpatients wereanalyzed.Atotalof331patientswereexcludedbecauseofnoavailabilityof vaccina-tioncards.Chi-squareorFisher’sexacttestwereused.Immunizationcoveragewashigher fordiphtheria/tetanus(59.79%)andhepatitisB(56.7%),andlowestforhepatitisA(6.8%) andformeningococcalgroupC(6%).Only11.74%ofthepatientshadreceivedtheinfluenza virusvaccineyearlysincetheirHIV-infectiondiagnosis.Novaccinationagainstinfluenza (p<0.034)orhepatitisB(p<0.029)wereassociatedwithCD4counts<500cells/mL;no vacci-nationagainstfluorpneumococcuswereassociatedwithdetectableHIVviralload(p<0.049 andp<0.002,respectively).ImmunizationcoverageisstillverylowamongHIV-infected adultsinthissettingdespiterecommendationsandhighinfection-relatedmortality.
©2017SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/).
Introduction
The new potent therapies introduced in mid-1990s significantly reduced Acquired Immunodeficiency Syn-drome (AIDS)-related mortality. Brazil was a pioneer in implementing universal access to modern antiretroviral therapy within the country’s public healthcare system. In 2014, more than 400,000 individuals were estimated to be
∗ Correspondingauthor.
E-mailaddress:lauro.neto@emescam.br(L.F.PintoNeto).
on these drugs.1 Nevertheless, likely due to latediagnosis
(26%ofpatientswere stillinitiatingtreatmentwithaCD4T lymphocyte count below 200cells/mL in October 2014)1 or
becauseofpatients’difficultyincomplyingwithtreatment, manydeathsfromAIDSwerestillreportedinthissetting.The latestepidemiologicalbulletin publishedbytheMinistryof HealthreportedthatmortalityresultingfromAIDSdeclined byonly6%inBraziloverthepasttenyears,fallingfrom6.1 deathsper100,000inhabitantsin2004to5.7per100,000in 2013.1
The main cause of mortality in HIV-infected patients between2009and2013intheBrazilianstateofEspíritoSanto wereinfectiousandparasiticdiseases.2
http://dx.doi.org/10.1016/j.bjid.2017.03.021
1413-8670/©2017SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
The National Immunization Program has specific recommendations for HIV-infected patients.3 These
rec-ommendations are also emphasized bythe National AIDS Program,initsclinicalprotocolandtherapeuticguidelinesfor the managementofHIV infection inadults.4 Nevertheless,
therehasbeennoassessmentoftheeffective implementa-tionoftheseimmunizationprotocolsinthedailyroutineof servicesdedicatedtothecareofAIDSpatientsinBrazil.
Themain objective ofthe present study was to assess immunizationcoverage inareferralcenterforHIV-infected patientsinaccordancewiththerecommendationspublished bytheMinistryofHealth.
Materials
and
methods
A cross-sectional, observational study was conducted to assess theimmunizationstatusofHIV-infectedindividuals receivingcareataninfectiousdiseases outpatientclinicin a large philanthropic hospital. The study was conducted betweenJanuary2015andFebruary2016.
Thesamplesizewascalculated takinginto accountthe proportionofindividualsimmunizedagainstvarious differ-entdiseasestobeevaluated. Consideringthepopulationof approximately1000HIV-infectedpatientsbeingfollowedupat thereferralcenter,foranexpectedprevalenceofimmunized individualsof40%,asampleerrorof5%,andsignificancelevel of5%,theminimumrequiredsamplesizewasdefinedas270 patients.Allowingforanexclusionrateof50%(patientslosing orforgettingtobringintheirimmunizationrecordcard),the minimumnumberofpatientsrequiredtoscreenfor admis-siontothestudywasestablishedas540.Thesampleconsisted ofHIV-infected individuals over 18 years of age who were selected randomlywhileconsultingwith physiciansatthe infectiousdiseasesoutpatientclinic.
TheInstitutioninternalreviewboardapprovedthestudy protocolunderreferenceCAAE42811014.4.0000.5065.Allthe participantssignedaninformedconsentform.
Thepatients’recordswerereviewedandapreviously vali-datedquestionnairewasusedtocollectdataonage,sex,mode ofHIVtransmission,antiretroviraldrugsinuse,dateofthe HIV-infectiondiagnosis,lastCD4cellcountandHIVviralload, andhepatitisBsurfaceantibody(anti-HBs)status.
ThelatestguidelinesfromtheMinistryofHealthindicate the following vaccines for HIV-infected patients: diphthe-ria/tetanus,pneumococcal,influenza,hepatitisB,hepatitisA, andmeningococcalgroupC.3Patientswereconsidered
appro-priately immunized if they had had four double doses of thehepatitisBvaccine,threedosesofthediphtheria/tetanus vaccine(withthelatestwithin10years),annualinfluenza vac-cinesfrom the dateof HIVdiagnosis until the dateofthe interview,twodosesofthehepatitisAvaccine,twodosesof the23-valentpolysaccharidepneumococcalvaccine, witha minimuminterval offiveyears between the twodoses (in the caseofpatientsdiagnosed morethan fiveyears previ-ously),andtwodosesofthemeningococcalgroupCconjugate vaccine.ForanalysisofthehepatitisBvaccine,thepatient’s statusofhepatitisBsurfaceantibodywascheckedtodefine theirantibodystatusforthedisease.Theyellowfevervaccine wasnotincludedinthisinvestigation,sinceyellowfeverwas
notconsideredendemicinthisstateatthetimethis study wasdone.Otherliveattenuatedvaccines(measles,mumps, rubella,andvaricella),particularlyrecommendedinthecase ofpediatricpatients,albeitcontingentonCD4levels,werealso notassessed,sincechildrenwerenotincludedinthisstudy sample. For the same reason,immunizationcoverage with respectto thehumanpapillomavirus (HPV) vaccine, which wasintroducedduringthestudyperiodforfemalesaged9–26 years,wasnotafocusofthisstudy.5Chi-square orFisher’s
exacttest(inthecaseofexpectedvalues<5)wasusedtoverify associationsbetweencategoricalvariables.Thestandardized residualswereanalyzedandcomparedwithacriticalvalueof 1.96,andsignificancewasestablishedat5%.
Allthepatientswhoseimmunizationwasincompletewere referredtotheSpecialImmunobiologyReferralCenter(CRIES) torectifythesituation.
Results
Initially,612patientswerescreened.Ofthese,331individuals failedtobringtheirvaccinationcardstoanyofthe consul-tationstheyattendedduringthestudyperioddespitebeing repeatedlyrequestedtodoso.Thesepatientswereexcluded fromthestudyandthefinalsampleconsistedoftheremaining 281patients,58ofwhomhadnovaccinationcardbecausethey hadneverbeenvaccinated.
Mostofthepatientsweremale(52.31%).ThemodeofHIV transmissionwasheterosexualexposurein69.39%ofcases. Only2.5%ofthepatientshad yettocommencetreatment. Overall,80.1%ofthepatientshadanHIV-1viralloadbelow detectable limits(<50copies/mL)and63.3%hadaCD4 lym-phocytecount>500cells/mL(Table1).
Inthisstudysample,223patients(79.4%)hada vaccina-tion cardand presenteditduringoneoftheconsultations. Thebestimmunizationcoverage(59.79%)wasagainst diph-theria/tetanus.Around7.45%oftheindividualshadfailedto completetherequiredimmunizationscheduleforthisvaccine andin32.74%ofcasesthisinformationwasabsentintheir vaccinationcards.
Ofthepatientsassessed,159(56.7%)hadreceivedatleast threedosesofthehepatitisBvaccine,while37.1%ofthese hadreceivedtheregimenoffourdoses,asrecommendedfor HIV-infectedpatients.1Vaccinationwasincompletein9.6%of
casesand33.8%ofthepatientshadnotbeenvaccinatedatall againsthepatitisB(Table1).Only50.17%oftheparticipants had been testedforhepatitisBsurface antibody(anti-HBs) previously.Nostatisticallysignificantassociationwasfound betweenthenumberofdosesreceivedofthevaccineagainst hepatitisBandanti-HBspositivity.
Immunization againsthepatitisA wascomplete inonly 6.8%ofthepatients,while76.9%hadnotreceivedanydose ofthisvaccine.Only11.74%ofthestudypatientshadreceived theannualinfluenzavaccinecorrectlyeversincethedateof theirHIVdiagnosis.Ontheotherhand,30.25%hadneverbeen vaccinatedagainstinfluenzaand58%hadnotcompletedthe fullimmunizationcalendar,with56.93%oftheseindividuals havingreceivedlessthanhalfoftherecommendednumber ofdoses.
Table1–Totalnumberofdosesofeachvaccineusedby theHIV-infectedpatients.Vitória,EspíritoSanto,Brazil.
Vaccines n=281 Prevalence(%)
Diphtheriaandtetanus
Nodoserecorded 91 32.4
1stdose 37 13.2
1stand2nddoses 32 11.4
1st,2ndand3rddoses 99 35.4
1st,2ndand3rddosesandboosterdose 22 7.8 HepatitisB Nodoserecorded 95 33.8 1stdose 12 4.3 1stand2nddoses 15 5.3 1st,2ndand3rddoses 55 19.6 1st,2nd,3rdand4thdoses 104 37.1 HepatitisA Nodoserecorded 216 76.9 1stdose 46 16.4 1stand2nddoses 19 6.8 Pneumococcalvaccine Nodoserecorded 108 38.4 1stdose 106 37.7 1stand2nddoses 61 21.7 1st,2ndand3rddoses 3 1.06 MeningococcalCvaccine Nodoserecorded 241 85.8 1stdose 23 8.2 1stand2nddoses 17 6.0 Influenza Nodoserecorded 84 29.9
Atleastonedose 197 70.1
Sixty-fivepatients(23.2%)had receivedtwodoses ofthe 23-valentpolysaccharidepneumococcalvaccine,with immu-nization beingincomplete in38.1%ofthe participantsand another38.8%neverhavingbeenvaccinatedatall(Table1). Only6%ofthe patients had receivedcomplete immuniza-tionwiththemeningococcalCvaccine,while85.8%hadnot receivedanydoseofthevaccine.
Astatisticallysignificantassociationwasfoundbetween detectableHIVviralloadandvaccinecoverageagainst pneu-mococcalorinfluenza(p<0.05).Fromtheresidualvalueofthe tests,thenumberofindividualswhohadnotbeenimmunized withthesetwovaccines wassignificantlygreater (adjusted residual>1.96) inthe groupwith detectable HIVviral load. TheassociationbetweeninfluenzaandhepatitisBcoverage withCD4lymphocytecountwasalsostatisticallysignificant. The number of individuals who had not been vaccinated against hepatitis B or influenza was significantly greater (adjustedresidual>1.96)inthegroupwithCD4lymphocyte count<500cells/mL(Table2).
Discussion
The present study was specifically designed to assess the effective use ofinactivated vaccines involving killed orga-nisms,whichmakeupthebasisofthevaccinesrecommended forHIV-infectedadultsinaccordancewiththeNational Immu-nizationProgram.3Traditionally,coverageinBrazilhasbeen
adequatewithrespecttochildimmunization.Immunization ofimmunosuppressedadultssuchasHIV-infectedpatients is centralized in special immunobiological referral centers (CRIES).InthestateofEspíritoSanto,suchacenterislocated inapediatrichospitalinthestatecapitalcity.
The present findings show that immunization coverage in this study sample was disappointingly low. The main biasinthisstudy wasthatwehaveonlyaccessedpatients that had broughttheir vaccination cardsafter atleasttwo repeated requests(less thanhalf ofthe patientsscreened). If thosepatients excludedfornothavingvaccination cards areassumedtobenon-vaccinated,thecoverageratesshowed herewould beoverestimatedbyatleast50%.Whatare the reasonsbehindsuchexceptionallylowcoverage?Atthe begin-ning of the AIDS epidemic it was found that vaccination could transitorily increase HIV viral load.6,7 Nevertheless,
morerecentstudiesconductedaftertheintroductionofthe morepotentantiretroviraldrugscurrentlyused(highlyactive antiretroviral therapy [HAART]), showed neither significant changes in viralload followingvaccination8–10 nor
appear-anceofresistancemutations,11 althoughsomefluctuations
occurjustifyingcurrentrecommendationsfornotmeasuring HIVviralloadintheweeksfollowingvaccination.4
ArecentreviewofthecausesofmortalityfromAIDSinthe stateofEspiritoSantobetween2009and2013showedthatthe maincausesofdeathwereinfectiousandparasiticdiseases.2
TheTEMPRANOstudy,conductedinSub-SaharanAfricaand recentlypublished,alsohighlightedtheriskofmortalityfrom infectious diseases, particularly invasive bacterial diseases andtuberculosis,risksthatarereducedwhenantiretroviral therapyisinitiatedearly.12Vaccinesconstituteoneofthemost
effectivemeansofpreventinginfectiousdiseases.Expanding immunizationcoverageisconsideredoneofthemost cost-effectivewaysofpromotinghealthandoneoftheprincipal factorsresponsiblefortheincreaseinlifeexpectancyinthe generalpopulationoverthepasttenyears.13
Of all the vaccines evaluated inthis study,the vaccine againstdiphtheria/tetanusshowedthebestrateofcomplete coverage(59.79%),whichcouldbeexplainedbythewide avail-ability of this vaccine in the health clinicsin general not just atthe CRIES. In addition, it isformally recommended in cases of accidents involving risk. Although it has been known forquite some time that the risk of hepatitis Bis greater amongHIV-infectedindividuals,14 only56.7%ofthe
participantsinthepresentstudyhadbeenimmunizedagainst hepatitisB.Thisvaccineisalsoavailableingeneralhealthcare clinics.Althoughthemostcommonlyrecommendedregimen offourdoubledosesispartofthetreatmentprotocolinBrazil, only37.1%ofthepatientshadbeencompletelyimmunized. No statistically significant association was found between immunizationcoverageagainsthepatitisBandpositivityfor anti-HBs, probably because there was no synchronization between vaccination and anti-HBs testing, since assessing responsetoimmunizationinHIV-infectedpatientsisnot rou-tinelydone.
Around70.1%ofpatientshadreceivedatleastonedose of influenza vaccine; however, only 11.74% had received the annual dose every year since the date of their HIV-infection diagnosis. Considering that the government launchesanannualcampaigntopromoteinfluenzavaccine,
Table2–AssociationbetweenvaccinecoveragewithCD4countandHIVviralload.
HIV-1viralload
Undetectable Detectable p-Valuea
Pneumococcalvaccine
Noimmunization 77(34.2%) 32(57.1%) 0.002 Completeorincompleteimmunization 148(65.8%) 24(42.9%)
Influenza
Noimmunization 62(27.6%) 23(41.1%) 0.049 Completeorincompleteimmunization 163(72.4%) 33(58.9%)
CD4(cells/mL) <500 ≥500
HepatitisB
Noimmunization 41(41.8%) 52(28.9%) 0.029 Completeorincompleteimmunization 57(58.2%) 128(71.1%)
Influenza
Noimmunization 37(37.8%) 46(25.6%) 0.034 Completeorincompleteimmunization 61(62.2%) 134(74.4%)
a Chi-squaretest.
the compliance of the public is good, and the vaccine is available in all healthcare units, the use of the influenza vaccineinthispopulationisfar fromsatisfactory.Afterall, theclinicalefficacyoftheinfluenzavaccineinHIV-infected patients has already been confirmed in a meta-analysis.15
Overall, 38% of the patients in the present study had not received the 23-valent polysaccharide anti-pneumococcal vaccine;eventhoughallcausepneumoniaisresponsiblefor 20.25%ofdeathsamongHIV-infectedpatientsinthisstate,2
andtheefficacyofthisvaccinehasalreadybeenconfirmedin otherstudiesconductedwithsimilarpopulations.16,17
In this study, the lowest immunization coverages were againsthepatitisA(6.8%) andmeningococcal groupC(6%). Thismayhavebeenduetothesevaccinesbeingrecommended for HIV-infected patients as recently as 2014,3 and
proba-bly being less incorporated into the routine care provided byattendingphysicians.Inaddition,thesevaccinesareonly availableattheCRIES.
Twoother studies conductedinBrazil,oneinSãoPaulo publishedin200818andoneinFortalezapublishedin2016,19
alsoanalyzedtheimmunizationstatusofHIV-infectedadults. Thosestudiesincluded144and99patients,respectively,and alsoreportedverylowratesofcoverage.Martinsetal.studied vaccinationcoverageagainsthepatitisBinaround300 HIV-infectedpatientsinthesouthofBrazilandfoundfairlysimilar ratestothosereportedhere(57.4%comparedto56.7%inthe presentstudy).20
Animportantlimitationofthepresentstudywasthefact thatthevaccineswerenotavailableintheoutpatientclinic inwhichtheHIV-infectedpatientswereseen.Ifthisservice hadbeenoffered,itcouldhaveservedasastimulusforthe patientstobringtheirvaccinationcardstoallthe consulta-tionstoenabletheirvaccinationstatustobebroughtupto dateinrealtime.
Centralizingvaccines forimmunosuppressedindividuals at the CRIES, although facilitating public service logistics, may hamper patient compliance, since they need to take
anotherdayoffworkinadditiontothatalreadyrequiredto attendtheconsultation.Moreover,theextratripfor vaccina-tion involvespaying formorepublictransportation. During thestudyperiod,therewasashortageofcertainvaccinesat the CRIES,particularlythe hepatitisB,hepatitisA,and the 23-valentpneumococcalvaccines,whichmayalsohave con-tributedtothepoorcoveragedetectedinthisstudy.Themain reasonsdisclosedbythepatientsfornothavingreceivedtheir vaccineswerenoavailabilityinlocalunitsclosetotheirhome address,ornoavailabilityevenattheCRIESwhentheyhad enoughtimetolookforthesevaccinesattheonlyreference centerexistinginVitoria,EspiritoSanto.
We observed an association between CD4 cell count<500/mL and detectable levels of HIV viral load in plasma with non-vaccination against flu, pneumococcal, or hepatitis B, the most commonly prescribed vaccines to HIV-infected patients. We suggest that the patients in whomcompliancewithantiretroviraltherapywaspoorestor whoseresponsetotreatmentwaspoorerwerelesslikelyto followrecommendationsregardingimmunization.However, guidance on immunizationshould begiven and constitute aformal partoftheconsultationsprovidedbydoctorsand other healthprofessionals responsibleforthe treatmentof thesepatients.Inourbelief,itisamatterofreplicatingthe immunization framework practiced by pediatricians and incorporating it into the practice of physicians who treat adults, making the prescription of vaccines part of every medicalconsultationinvolvingHIV-infectedpatients.
Conclusions
Immunization coverage remains very low in HIV-infected adultsin this settingdespite the officialrecommendations from the health authorities in the country and the high infection-related mortality that persistsin this population. The availability of those vaccines for immunosuppressed
individuals only at reference centers distant from where patientsliveandworkcontributestolowcoverage.Vaccines shouldbeavailableasantiretroviraldrugswherepatientsare cared.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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