Factors associated with mortality in HIV patients failing antiretroviral therapy, in Salvador, Brazil

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brazjinfectdis2019;23(3):160–163

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

Factors

associated

with

mortality

in

HIV

patients

failing

antiretroviral

therapy,

in

Salvador,

Brazil

Tatiana

Haguihara

a,∗

_,

_Márcio

_da

_Oliveira

_Silva

a

_,

_Monaliza

_Cardozo

_Rebouc¸as

a

_,

Eduardo

Martins

Netto

b

_,

_Carlos

_Brites

b

a_Specialized_Center_for_Diagnosis,_Assistance_and_Research,_Department_of_Health_of_the_State_of_Bahia,_Salvador,_BA,_Brazil

b_Federal_University_of_Bahia,_{Post-graduation}_Program_in_Medicine_and_Health,_Salvador,_BA,_Brazil

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Articlehistory:

Received26November2017 Accepted6June2019 Availableonline10July2019

Keywords:

Virologicfailure Mortality HIV

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Highlyactiveantiretroviraltherapy(HAART)hassignificantlyimprovedsurvivalofpeople livingwithHIV/Aids(PLWHA).However,poortreatmentadherencetoHAARTandother problems,stillcausetherapyfailureandcontributetoincreasedmorbidityandmortality ofPLWHA.Inthisretrospectivecohortstudy(2013–2015),wesoughttoevaluatethe fac-torsassociatedwithmortalityofPLWHAfailingHAARTin2013,whowerereceivingcare atareferencecenterforsexuallytransmitteddiseases(STD)andHIV/AIDS.Atotalof165 individualsover18yearsofagewhowerefailingantiretroviraltherapywereevaluated.In two-yearfollow-up,19(11.5%)deathsweredocumented.Therewereasignificant associa-tionbetweenmortalityandreportofillicitdruguse(53%,p<0.01),beingattendedbyalarger numberofmedicalprofessionals(6.3±3.2,p=0.02),useoffirstlinenon-nucleosidereverse transcriptaseinhibitor(74%,p=0.01),andhistoryofinterruptingHAART≥3months(90%),

p=0.02).Patientswhodiedhadasigniﬁcantlyhigherviralload(mean49,192.4±35,783.6 copies/mL)than survivors(26,389.2±27,416copies/mm3_, _p_<_0.01), _lower _mean _CD4 _cell

counts(127.8±145.6cells/mm3_vs._303.3_±_202.4_cells/mm3_,_p_<_0.01),_and_higher_frequency

ofpreviousvirologicfailure(89%vs.74.7%,p<0.01).Ourresultsreinforcetheimportanceof earlydetectionandpreventionofvirologicfailure,toreducethemortalityassociatedwith thisevent.

In 2017, UNAIDS (Joint United Nations Programme on

HIV/AIDS)reportedtheexistenceof36.9millionpeople liv-ingwithHIV.1_In_Brazil,_136,945_cases_of_HIV_infection_were

reportedbetween2007andJuneof2016.2_In_the_same_period,

thestateofBahia,themostimportanteconomyinthe

North-∗ _{Corresponding}_author.

E-mailaddress:tatyha@gmail.com(T.Haguihara).

easternregion,reported5433newcasesofHIV.3 _In_the_last

10years,theNortheasternregionpresenteda34.3%increase inthemortalitycoefﬁcient,from3.2to4.3deathsfor100,000 inhabitants.2

In December of 2013, Brazil became the world’s third country to recommend immediate start of highly active antiretroviraltherapy(HAART)forpeoplelivingwithHIV/Aids (PLWHA),regardlessofCD4Tlymphocytecount.Early treat-https://doi.org/10.1016/j.bjid.2019.06.001

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A B C D Patient selection _1,0 0,8 0,6 0,0 400 350 300 250 200 150 100 50 0 200,0 400,0 600,0 800,0 1000,0 CD4 ≤200 CD4 >200 1200,0 8527 Routine HIV RNA test in 2013

Days Since Virological failure

Cumulative survival

404 PLHA, enrolled under ART on CEDAP

CD4+ T

-L

YMPHOCYTE

MEDIAN CD1+ T-LYMPHOCYTE

Naive Virological failure 2013 Last follow up Naive Virological failure 2013 Last follow up

Deaths Survivor Deaths Survivor

MEDIAN HIV VIAL LOAD (LOG10) 8123 excluded

- 6601 HIV RNA<1000 copies/mL - 143 duplicates tests - 868 other institutions - 511 < 18 years 239 excluded - 198 ART < 6 months - 41 pregnant women

165 PLHA whit virology failure include in Cohort 250000 200000 150000 100000 50000 0 p=0,18 p<0,01 p=0,10 p=0.62 p < 0,01 p < 0,01

HIV-1 viral load

Fig.1–(A)Flowchartofpatientselectionandfollow-up;(B)Kaplan-MeiersurvivalcurveanalysisaccordingtoCD4T>200 or≤200cells/mm3_,_(C)_Mean_CD4_T,_(D)_Mean_VL_baseline,_at_virologic_failure_in₂₀₁₃_and_after_two_years_of_follow-up_in

PLWHAwhodied(N=19)andinsurvivors(N=146),Salvador,Bahia.

mentofHIVinfectionmayimprovequalityoflifeofPLWHA and reduce the riskof virus transmission ofHIV patients. However,issuesrelatedtoadherencetotherapy,medication tolerability,andlackofaccesstohealthcareforPLWHAcan increasetheriskofvirologicfailure.4

AdvancesovertimewithHAARThaveresultedindecreased virologicfailurerates.However,irregularuseofHAARTmay selectviralstrainswithmutationsthatallowthemaintenance ofHIVreplication.Inthissetting,anewantiretroviralregimen isrequiredforaneffectivetreatment.Thetestusedtodetect resistanceisHIVgenotyping,whichisnotsystematically rec-ommended by the Brazilian public health care guidelines. Virologicfailureisoftenassociatedwithprogressiveincrease ofHIVviralload,decreaseofCD4Tcellcount,and progres-sionofopportunisticdisease.Allthesemarkersaredirectly associatedwithhigherprobabilityofdeath.4_Poor_adherence

toHAART andother problemscontributetotherapyfailure andincreasedmorbidityandmortalityofPLWHA.

Inthisstudy,wesoughttoevaluatethefactorsassociated withmortalityofPLWHAfailingHAARTin2013.

ThiswasaretrospectivecohortstudyinvolvingPLWA fol-lowedattheStateReferenceCenterforDiagnosis,Careand Research(CEDAP),thelargestreferencecenterforthe treat-mentofPLWHA,inthecity ofSalvador,Brazil,where3500 patientsareontherapy.Tobeincluded,patientsmustbeover 18yearsofage,withaconﬁrmeddiagnosisofHIVinfection, andpresentingvirologicalfailureintheperiodfromJanuaryto December2013.Eligiblesubjectswereprospectivelyfollowed untilDecember2015.Sociodemographic,behavioral,clinical, andlaboratorydatawereobtainedfromclinicalrecordsand pharmacyreportsofantiretroviraltherapy(ART)andinthe

fol-lowingdatabases:(a)InternalRegistrationCEDAPLaboratory data—CompLab;(b)LogisticsManagementSystemDrugs— SICLOM;(c)SystemLaboratoryTestsControloftheNational NetworkofLymphocyteCountCD4/CD8andviralload— SIS-CEL;and(d)BrazilianInformationSystemonMortality—SIM. VirologicalfailurewasdeﬁnedasdetectableHIVRNAabove 1000copies/mL(Abbotmolecular,Illinois,USA)inindividuals on ARTfor atleastsixmonths. Informationon deathwas obtainedfrom SIM.Thesurvivaltimewascalculatedasthe timeelapsedbetweendiagnosisofvirologicalfailureanddate ofdeathordateoflastvisittotheCenter.

Statistical analysis was performed with the Statistical PackagefortheSocialSciences(SPSS)version19.0(IBMCorp. Released 2010). Simple and relative frequencieswere esti-matedforcategoricalvariables.Chi-squaretestwasusedto assesstheassociationbetweencategoricalvariablesmortality ofPLWHA.Meansofcontinuousvariables(age,viralload,CD4 count,numberofdoctorsinvolvedincare,andtimebetween theHIVdiagnosisandfirstvirologicfailureandfailurein2013), werecomparedwiththeStudent’st-test.Resultswere consid-eredstatisticallysignificantatp<0.05.Variableswithap-value ≤0.20onunivariateanalysiswereincludedinthe multivari-atemodel.Thefinalmodelincludedallvariableswithp<0.05. ThisstudywasapprovedbytheResearchEthicsCommitteeof theHealthDepartmentofBahiaState(SESAB),number452782. A total of165 patients with HIVinfection and virologi-calfailurein2013wereidentifiedandincludedinthecohort (Fig.1A);53.9%males,67.3%heterosexuals,and40.6%hadless than four years ofeducation.Themean age was 38.4±9.5 years.Nineteenpatients(11.5%)died afterbeingdiagnosed withvirologicfailure.Theirsociodemographiccharacteristics

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Table1–Demographic,clinical,andlaboratorycharacteristicsofpeoplelivingwithHIV/Aidsdiagnosedwithvirological failurein2013,StateHIV/AidsReferenceCenter,accordingtodiagnosisofdeath,Salvador,Bahia,Brazil.

N=165(%) Death,n(%) p-value RR(CI)c

n(%) Yes(n=19) No(n=146)

Socialanddemographiccharacteristics

Age(mean±SD) 38.4(9.5) 36.9(9.8)b _38.6_(9.5)b _0.33

Malesex 89(53.9) 12(63.2)a ₇₇_(52.7)a _0.39

Heterosexual 111(67.3) 13(68.4)a ₉₈_(67.1)a _0.91

Self-reportedblacks 61(39.6) 11(57.9)a ₅₀_(34.2)a _0.08

Lessthan8yearsofschooling 67(43.3) 10(52.6)a ₅₇_(39.0)a _0.38

LivinginSalvador 123(74.6) 15(78.9)a ₁₀₈_(74.0)a _0.64

Smoking 56(33.9) 8(42.1)a ₄₈_(32.9)a _0.42

Alcoholconsumption 114(69.1) 14(73.7)a ₁₀₀_(68.5)a _0.64

Useofdrugs 43(26.1) 10(52.6)a ₃₃_(22.6)a _<0.01 _3.1_(1.3–7.2)

Laboratoryandclinicalcharacteristics

FirstCD4(mean±SD) 293.2(±224.0) 317.1(±278.9)b _290.0_(±216.8)b _0.62

FirstCD4≤200 67%(±40.6)b ₁₂_(63.2)a ₅₅_(37.7)a _0.03 _2.5_(1.1–6.0)

CD4invirologicalfailure(mean±SD) 283.1(±204.2)b _127.8₍_±145.1)b _303.3₍_±202.4)b _<0.01

LastCD4(mean±SD) 333.5(±272.1)b _113.4_(±178.4)b ₃₆₂_(±269.5)b _<0.01

FirstVLd_(mean_±_SD) _170,615.1_{(±440,167.3)}b _120,789.5_{(±160,409.6)}b _177,099.2_{(±464,298.4)} _0,18

VLd_in_virological_failire_(mean_±_SD) _29,015.02_(±29,298.5) _49192.4_(±35783.6) _26389.2_(±27416.0)b _<0.01

LastVLd_(mean_±_SD) _89,921.5_(±_401,559.6)b _207,217.5_{(±308,210.0)}b _74,657.9_(±_410,548.2)b _0.10

Numbersofdoctors(mean±SD) 4,9(±3.2)a _6,32_(±3.2)a _4,91_(±2,3)b _0.02

Comorbiditye ₉₆_(58.2)a ₁₅_(78.9)a ₈₁_(55.5)a _0.05 Cytomegalovirusretinitis 15(9.1)a ₂_(10.5)a ₁₃_(9.2)a _0.82 Cryptococcosis 2(1.2)a ₂_(10.5)a ₀ _<0.01 _9.3_(6.1–15.0) HepatitisB 8(4.8)a ₀ ₈_(5.7)a _0.30 HepatitisC 7(4.2)a ₀ ₇_(5.0)a _0.33 Herpeszoster 48(29.1)a ₅_(26.3)a ₄₃_(30.5)a _0.78 HTLVf ₁_(0.6)a ₀ ₁_(0.7)a _0.71 Otherneoplasms 4(2.4)a ₂_(10.5)a ₂_(1.4)a _<0.01 _9.6_(6.1–15.0) Kaposi’ssarcoma 4(2.4)a ₂_(10.5)a ₂_(1.4)a _<0.01 _9.6_(6.1–15.0) Syphilis 34(20.5)a ₇_(36.8)a ₂₇_(19.1)a _0.06 CNStoxoplasmosisg ₂₉_(18.2)a ₄_(21.0)a ₂₆_(18.4)a _0.73 Tuberculosis 55(33.3)a ₁₃_(68.4)a ₄₂_(29.8)a _<0.01 _4.3_(1.7–10.8)

Othervirologicalfailurepriorto2013 126(76.4)a ₁₇_(89.5)a ₁₀₉_(74.7)a _0.05 _1.2_(1.1–1.2)

HIVGenotypingperformed 96(58.2)a ₁₀_(52.6)a ₈₆_(58.9)a _0.60

UseofNNRTIsh_(1st_line) ₇₈_(47.3)a ₁₄_(73.7)a ₆₄_(43.8)a _0.01 _3.1_(1.2–8.3)

Historyof≥3monthswithoutHAARTi ₁₀₉_(66.1%)a ₁₇_(89.5%)a ₉₂_(63.0)a _0.02 _4.4_(1.1–18.2)

p<0.05and95%CIforallcomparisons. a _{Categoricals:}_Chi-square_test. b _Continuous_variables:_Student’s_t-test. c _RR,_risk_ratio;_CI,_conﬁdence_interval.

d_{Comorbidities}_associated:_diabetes,_{hypertension,}_{dyslipidemias,}_neurological_illnesses_and_psychiatric_illness. e _Comorbidity:_diabetes,_{hypertension,}_{dyslipidemias,}_neurological_illnesses_and/or_psychiatric_illness. f _Human_T_lymphotropic_virus.

g _Central_nervous_system_(CNS)_{toxoplasmosis.} h _{Non-nucleoside}_reverse_{transcriptase}_inhibitor.

i _Highly_active_{antiretroviral}_therapy.

weresimilartosurvivors.Presenceofclinicalcomorbidities (78.9%;diabetes,hypertension,dyslipidemias,neurological ill-nesses,andpsychiatricdisorders),userofillicitdrug(52.6%), history of other virological failure prior to 2013 (89.5%), patientsusingﬁrstlinenon-nucleosidereversetranscriptase inhibitor (NNRTIs) (73.7%), previous non-adherence toART for longer than three months (89.5%), presenceof crypto-coccosis(10.5%),Kaposi’ssarcoma(10.5%),other neoplasms (10.5%),andtuberculosis(68.4%)wereassociatedwithdeath. Patients who died had a higher number of infectious dis-easesspecialistsinvolvedintheircare(6.3±3.2professionals) and only10/19 (52.6%)patientshad a genotypingtest per-formed.ThemedianCD4countatthemomentofvirological

failurewas127.8cells/mm3_(±145.1),_lower_than_that_at

diag-nosis(317.1cells/mm3_;_p_<_0.01)._In_the_last_follow-up_visit,_only

15.7%hadaviralload<50copies/mL(Table1).Highmedian viralloadandlowCD4countwereassociatedwithlower sur-vival(p<0.01)asshowninFig.1B,CandD.Aftermultivariate analysis,allvariablespreviouslyassociatedintheunivariate analysisremainedstatisticallyassociatedwiththeoccurrence ofdeath.Themeansurvivalafterdiagnosisofvirological fail-urewas13.0±5.0months.

Theoverallprevalenceofvirologicalfailureinthis study was16.1%(165/1023),comparedto10%amongadultPLWHA inBrazilasawhole,untilOctoberof2015,accordingtothe BrazilianMinistryofHealth.2

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Duringthistwo-yearcohortstudy,individualswith viro-logicfailurewereathigherriskofdeath.TheAfricancohort study reported by Petersen et al. showed a mortality rate amongpatientsfailingHAARTof5.9%inanaveragefollow-up of2.1years,whichis2.78timeslowerthantherateobserved inthepresentstudy.5

Presence of comorbities, use of illicit drugs, diagnosis oftubercuolosis,cryptocoocosis,andKaposi’sSarcomasare associationwithviralfailure andmortality,asdescribed in theliterature.6_Mean_viral_load_at_the_time_of_virologic_failure

washigheramongpatientswhodiedthanamongsurvivors, aﬁndingsimilartothatseeninNorthAmericanandAfrican cohorts.7,8_Mean_CD4_T_cell_count_at_baseline_was_lower_than

200cells/mm3_in_patients_who_died,_suggesting_late

diagno-sisofHIVinfection.Severalstudieshaveshownthatbaseline CD4Tcellcountlowerthan200cells/mm3_is_associated_with

adelayeddiagnosisand,consequently,death.7,8

Thisstudyalsoobservedthatpatientnon-ﬁdelitytoone attendingphysicianandahistoryofabandoningHAART(prior tothefailurein2013,withaperiod≥3monthswithoutART) wereassociatedwithmortality.Thesetwofactorsinﬂuence treatmentoutcomesandaredirectlyrelatedtovirological fail-ureanddevelopmentofdrugresistance.9

InBrazil,thereisanestimatedprevalenceof intermedi-arytransmittedresistanceof8.1%,varyingbyregionsofthe country.However,in2007,Pedrosoetal.foundaprevalence of11.4%oftransmittedresistancetoNNRTIsintheNortheast, especiallyinBahia.10Inthepresentstudy,theuseofNNRTIs wassignificantlyassociatedwithmortality(p=0.01),witha 3.1timesgreaterriskthanthatdetectedamongpatientswho were takingprotease inhibitors. These findingsmost likely reflectthegreatercirculationofHIVstrainsresistantto NNR-TIsinSalvador.

Thepresentstudyisrelevantbecauseitisoneofthefew real-lifestudiesconductedinareferencecenterforthe treat-mentofHIV/Aids in Brazil.Theresultsreflectthe growing concern about the incidence of virological failure and the associatedhighmortality,underscoringtheneedforgreater attentiontothisatriskpopulation.Thisstudyhassome limi-tations.Thisobservationalstudywaslimitedtoonecenterand thedatausedinthisanalysiswerefromasecondarysource, resultinginincompletedataforsomepatients.However,we conductedadditionaldatasearchesintheofficialdatabaseof Brazil(SICLOM,SISCEL,SIM)toimprovethequalityof infor-mationobtainedfrom medicalrecords.Ourevaluationwas limitedtopatientswhohadCD4countandHIVviralload test-ingin2013availableforreview.Inaddition,HIV-1viralload, consideredtobethebestpredictorofHIVdiseaseprogression wasthemeasureusedinthepresentstudy.Ourcohortwasnot verylarge;only165patientswerediagnosedwithvirological failureforinclusioninthestudy.Ontheotherhand,thestudy sitewasthelargestreferencecenterforcareofPLWHAinthe stateofBahia,andtheprevalenceofvirologicalfailurewas highenoughtodrawrelevantconclusions.Anotherlimitation ofthestudywastheinabilitytofollowaparallelgroupwithno virologicalfailureduetoinconsistencyofthesecondarydata. Ourfindingsshowthatvirologicalfailureisassociatedwith mortality.Moreover,factors suchascoinfectionwith tuber-culosis, illicit drug use, and low fidelity to one attending physicianareriskmarkersofpooradherence,virologicfailure,

andhighermortality.Strategiestominimizetheseproblems mayresultindecreasedfrequencyofvirologicalfailureand lowerriskofdeathofHIVinfectedpatients.

Funding

Thisresearchdidnotreceiveanyspeciﬁcgrantfromfunding agenciesinthepublic,commercial,ornot-for-proﬁtsectors.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

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