Survival of HIV patients with tuberculosis started on simultaneous or deferred HAART in the THRio cohort, Rio de Janeiro, Brazil

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

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

Original

Article

Survival

of

HIV

patients

with

tuberculosis

started

on

simultaneous

or

deferred

HAART

in

the

THRio

cohort,

Rio

de

Janeiro,

Brazil

Valeria

Saraceni

_,

_Betina

_Durovni

_,

_Solange

_C.

_Cavalcante

_,

_Silvia

_Cohn

_,

Antonio

Guilherme

Pacheco

_,

_Lawrence

_H.

_Moulton

_,

_Richard

_E.

_Chaisson

_,

Jonathan

E.

Golub

a_{MunicipalHeathSecretariat,RiodeJaneiro,RJ,Brazil}

b_{UniversidadeFederaldoRiodeJaneiro(UFRJ),RiodeJaneiro,RJ,Brazil} c_{Fundac¸ãoOswaldoCruz,RiodeJaneiro,RJ,Brazil}

d_{DepartmentofInternationalHealth,JohnsHopkinsBloombergSchoolofPublicHealth,Baltimore,USA} e_{CenterforTuberculosisResearch,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,USA} f_{DepartmentofEpidemiology,JohnsHopkinsBloombergSchoolofPublicHealth,Baltimore,USA}

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Articlehistory:

Received15October2013 Accepted14February2014 Availableonline27April2014

Keywords: HIV Tuberculosis Antiretroviraltherapy Survival

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Background:Thetimingofhighlyactiveantiretroviraltherapy(HAART)afteratuberculosis diagnosisinHIV-infectedpatientscanaffectclinicaloutcomesandsurvival.Wecompared survivalaftertuberculosisdiagnosisinHIV-infectedadultswhoinitiatedHAARTand tuber-culosistherapysimultaneouslytothosewhodelayedthestartofHAARTforatleasttwo months.

Methods:TheTHRiocohortincludes17,983patientsreceivingHIVcarein29publicclinics inRiodeJaneiro,Brazil.HAART-naïvepatientsatthetimeofanewTBdiagnosisbetween September2003andJune2008wereincluded.Survivalwasmeasuredindaysfromdiagnosis ofTB.WecomparedsurvivalamongpatientswhoinitiatedHAARTwithin60daysofTB treatment(simultaneous–ST)tothosewhostartedHAART>60daysofTBtreatmentor neverstarted(deferred–DT).Kaplan–MeierplotsandCoxproportionalhazardsregression analyseswereconducted.

Results:Of947patientsdiagnosedwithTB,572(60%)wereHAARTnaïveatthetimeofTB diagnosis;135wereexcludedbecauseofmissingCD4countresults.Amongtheremaining 437TBpatients,56(13%)diedduringfollow-up:25(10%)amongSTpatientsand31(16%) inDTgroup(p=0.08).STpatientshadlowermedianCD4countsatTBdiagnosisthanDT patients(106vs.278,p<0.001).Coxproportionalhazardsutilizingpropensityscore analy-sisshowedthatDTpatientsweremorelikelytodie(adjustedHR=1.89;95%CI:1.05–3.40;

p=0.03).

∗ _{Correspondingauthorat:RuaCupertinoDurão,219,BlocoB,apto404,RiodeJaneiro,22441-030,RJ,Brazil.}

E-mailaddresses:[email protected],[email protected](V.Saraceni).

http://dx.doi.org/10.1016/j.bjid.2014.02.004

Conclusion: HAART administered simultaneously with TB therapy was associated with improvedsurvivalafterTBdiagnosis.HAARTshouldbegiventopatientswithHIV-related TBassoonasclinicallyfeasible.

©2014ElsevierEditoraLtda.Allrightsreserved.

Introduction

Highly active antiretroviral therapy (HAART) significantly improvessurvivalinHIV-infectedpatientswith opportunis-tic infections, but the optimal time to initiate HAART in patientswithHIV-relatedtuberculosis(TB)posesachallenge to clinicians and patients.1,2 _{Recent World Health}

Organi-zation recommendations state that HIV-infected patients with active TBshould initiate HAART as soon as possible afterTBtreatment, irrespective ofCD4cell count,3 _though

thequality oftheevidencesupporting these recommenda-tions is characterizedas low or moderate. The SAPiTtrial inSouthAfrica reported a56% mortality reductionamong patients starting HAART within four weeks after the start of TB therapy or within four weeks of completion of the intensive phase of TB therapy compared to those initiat-ingHAARTwithinfourweeksofTBtreatmentcompletion.4

Further analysis of the SAPiT trial suggests that the pro-tection conferred is equally strong if treatment is started at either time during TB treatment.5 _{The recent STRIDE}

trial reported no mortalitydifference between those start-ingHAARTwithintwoweeksofTBtreatmentinitiationand thosestartingwithin8–12weeksafterTBtreatmentstart,6

though both trials report a significant drop in mortality amongearlystarterswithadvancedimmunosuppression.The CAMELIAclinicaltrialinCambodiafoundareductionof34% amongpatientsstartingHAARTeightweeksafterTB treat-ment start comparedto those startingHAART within two weeksinapopulationwith72%havingaCD4<50cells/mm3_.7

Studies in developed countries have shown that patients with very advanced HIV disease have better survival if HAART is given during TBtreatment,8–11 _{though the risks}

ofimmunereconstitutioninflammatorysyndrome(IRIS),12,13

druginteractions and additive drug toxicity raiseconcerns aboutearlyinitiationofHAARTinTB/HIVco-infection.14_The

three clinical trials suggest that HAART be initiated very earlyforthosewithadvancedimmunosuppression;however, those withhigher CD4 countsat the timeof TBdiagnosis can wait to initiate HAART and not compromise survival, while also reducing the risk of IRIS and other complica-tions.

RiodeJaneiroCity,Brazil,hasalargepopulationofpatients withTB/HIVco-infection, and TBisanimportantcause of deathinindividualswithAIDS.15_{TheTB/HIVinRio(THRio)}

studywasaclusterrandomizedtrial16_{designedtoevaluate}

theimpactofTBscreeningandisoniazidpreventivetherapy inHIV-patientsreceivingcareat29publichealthunitsinRio deJaneiro.InBrazil,HIV-infectedpatientshavefreeaccessto HAARTandTBtherapyinpublichealthclinics,andtreatment intheprivatesectorisnotavailable.Weconductedasurvival analysisafterTBdiagnosisaccordingtothetimingofHAART initiationintheTHRiocohort.

Methods

Thisisanobservationalcohortsurvivalanalysisafterthe diag-nosisofTBinHIV-infectedpatientsreceivingcareinTHRio clinics. We compared survival in patients receiving simul-taneous HAART and TBtherapy (HAART started within 60 daysofTBdiagnosis)withdeferredHAART (HAARTstarted >60 days but <365 days afterTB diagnosis, or no HAART). Patients whostarted HAART >365daysaftertheir TB diag-nosiswerecensoredatthatpoint.DatacollectionforTHRio has been described previously.16 _{Inbrief, 29 pubic primary}

healthclinicstreatingHIV-infectedpatientswererandomly assignedtobeginimplementingTBscreeningandisoniazid preventivetherapy(IPT)inSeptember2005.Patientdatawere abstractedfrom medicalrecordsstartingatthedateofHIV diagnosisandincludedage,gender,HIVdiagnosisdate, his-toryofHAARTanddateofinitiation,historyofopportunistic infections, CD4counts, tuberculin skintests, IPT,and viral loads.Forthecurrentanalysis,patientswereincludedifthey (1)wereHIV-positivebyserologictesting;(2)hadafirst diagno-sisofactiveTBbetweenSeptember1,2003andJune30,2008; (3)werenotreceivingHAARTformorethan60daysatthetime ofTBdiagnosis;and(4)werediagnosedwithHIVeitherprior toTBdiagnosisorwithin30daysafterTBdiagnosis.TBwas definedaccordingtoBrazilianguidelines,andincluded symp-toms,X-rays,sputumsmearsandcultures.TBtreatmentwas giventoallpatientsusingtheBrazilianregimenofthreedrugs dailyfortwomonthsfollowedbytwodrugsforfourmonths.17

Theprimaryoutcomewasall-causemortality.Theprimary exposureofinterestwastimeelapsedsinceHAARTinitiation, whichwasdividedintotwocategories:HAARTinitiatedwithin 60daysofTBtreatmentstartdate(simultaneoustherapy(ST)) andHAARTinitiatedmorethan60daysafterTBstartdateor neverstartedduringthestudyperiod(deferredtherapy(DT)). OthercovariatesthatwereassessedincludedCD4countatTB diagnosis,gender,andage.Patientswerecensoredeitherat thelastclinicvisit,oronDecember31,2008,oratHAARTstart dateifHAARTstartdatewasmorethanoneyearafterTB treat-mentstartdatewhicheveroccurredfirst.Deathreportingwas abstractedfrompatientmedicalrecordsorfromtheNational MortalitySystem(SIM),afterlinkagewiththeTHRiocohort, usinganalgorithmdescribedelsewhere.18_DateofTB

diagno-siswasthedateofinitiationofTBtreatmentrecordedinthe cliniccharts.HAARTwasdefinedastheuseoftwonucleoside reversetranscriptaseinhibitorsplusanon-nucleosidereverse transcriptase inhibitoror oneor twoprotease inhibitorsin combination.DateofHAARTinitiationwasabstractedfrom cliniccharts.Dateofdeathwasthedaterecordedinthedeath certificate,asenteredintheSIM.HAARTwasinitiatedatthe physicians’discretion,guidedbytheBrazilian Recommenda-tions to Antiretroviral Therapyfor HIV-infectedAdultsand Adolescentsinuseatthetimeofthestudy.19

Table1–PredictorsofmortalityinHIV/TBco-infectedpatients.

Allpatients(n=437) Mortality p-Value

Died(n=56) Survived(n=381)

Medianage(years;IQR) 36(29–43) 36(29–45) 36(29–42) 0.599

Gender(%male) 306(70%) 46(82%) 260(68%) 0.041

MedianCD4atTBdiagnosis(IQR) 150(67–294) 157(72–243) 150(63–300) 0.754 HAART>60daysafterTBtreatmentstart(#,%) 194(44%) 31(55%) 163(43%) 0.004

Descriptive statistics were performed using t-tests for continuous variables and Fisher’s exact test for categor-ical variables. Survival curves were examined using the Kaplan–Meiermethod,andthelogranktestwasusedtoassess differencesinsurvivalfunctionsbygroup.

Propensity scores were calculated as follows: a logistic regressionmodelwasrunhavingDT/STastheresponse vari-ableandgender,ageandCD4countsasco-variables.Predicted probabilitiesfromthemodelwereusedtoconstructquintiles, whichwereincludedinthe modelasastratifying variable. Coxproportionalhazardsregressionanalyseswereconducted andpropensityscoresforHAARTinitiationby60dayspost-TB diagnosiswereusedtostratifythebaselinehazardfunctionin ordertominimizebiasfromtreatmentbyindication.

TheTHRiostudywasapprovedbytheResearchEthics Com-mitteeoftheMunicipalSecretaryofHealthandCivilDefense oftheMunicipalityofRiodeJaneiro,Brazil,andtheJohns Hop-kinsMedicineInstitutionalReviewBoard.Thestudyreceiveda waiverofinformedconsent,asnodirectcontactwithpatients wasundertakenbystudystaffandalldataweredeidentified priortoanalysis.

Results

Therewere17,983subjectsintheTHRiocohortforthis anal-ysis.BetweenSeptember2003andJune2008,947casesofTB werediagnosed,ofwhom572hadnohistoryofexposureto HAARTforgreaterthan60daysatTBdiagnosis.Onehundred thirty-fivepatientswereexcludedfromtheanalysisbecause theydidnothavea CD4countresultavailablewithinfour monthsoftheirTBdiagnosis.Ofthe437TB/HIVpatientsin thecurrentanalysis,78%ofthecasesweremale,themedian agewas36years(IQrange:29–43years)andthemedianCD4 cellcountatTBdiagnosiswas150cells/mm3_{(IQrange:67–294}

cells).Ofthe389(89%)whostartedHAARTatorafterTB treat-mentstartdate,243startedwithin60daysofTBtreatment startdate(ST),125startedHAART>60daysand≤365daysafter TBtreatmentstartdate(DT),and21startedHAART>365days afterTBtreatmentstart dateand werecensoredatHAART startdate(DT).Forty-eightpatientsneverstartedHAARTin the study period (DT)and were censored as described.ST patientsdidnotdifferfromDTpatientsinage,genderorRNA viralloadatthetimeofTBdiagnosis(Table2).STpatientshad lowermedianCD4cellcountsatthetimeofTBdiagnosis(106 vs.278cell/mm3_{,p<0.001).Fifty-sixpatients(13%)died}

dur-inga medianof2.1years offollow-up(2212 person-years), atamortalityrateof7.6deathsper100 person-years.The mediantimetodeathwas338days.Subjectswhodiedhad similarbaselineCD4countsandHIVviralloadsattimeofTB diagnosisasthosewhosurvived(Table1).

Among243TBpatientsintheSTgroup,25(10%)died dur-ing follow-upcomparedto31of194(16%)inthe DTgroup (p=0.085).Kaplan–MeierestimatesofsurvivalafterTB diag-nosisstratified bytimingofHAARTinitiationare shownin

Fig.1.STpatientsweresignificantlylesslikelytodieoverthe follow-upperiodthanDTpatients(log-ranktestp=0.02). Uni-variateCoxanalysisrevealedthatdelayingtherapyincreased mortalityrisk45%(HR=1.45;95%CI:1.05–2.00).AdjustedCox proportional hazards modeling revealed an 89% increased riskinmortalityamongDTpatientscomparedtoSTpatients (RH=1.89;95% CI:1.05–3.40;p=0.03), takingthe propensity scoreintoaccount(Table3).Noothercovariateswere asso-ciatedwithincreasedmortality.

Discussion

Inthiscohortof437patientswithHIV-relatedTBwhowere HAART naïve at the time of TB diagnosis, not receiving HAART within 60 days after TB diagnosis was associ-ated with an 89% increased risk of mortality. Patients who receivedHAART earlyhad significantlylowerCD4 cell counts at the time of TB diagnosis but had better over-all survival.NewWHO guidelinesstatethatHAART should be initiated as soon as possible in all patients with HIV and active tuberculosis, regardlessof CD4cell count.3 _Our

1.0 0.8 DT Not DT 0.6 0.4 0.2 0.0 0 500 1000 1500 2000 Time (days) Sur viv al

Fig.1–TimefromTBdiagnosistodeathofHAART-naïve HIV/TBco-infectedpatientswithHAARTdeferredatleast 60daysfollowinginitiationofTBtherapy(DT)andpatients startingHAARTatthetimeofTBtherapyinitiation.

Table2–PatientcharacteristicsbytimingofHAARTforTB/HIVco-infection.

TimingofHAARTforHIV/TBco-infectedpatients p-Value

ST(n=243) DT(n=194)

Medianage(years) 35.8 36.0 0.835

Gender(%male) 70.8 69.1 0.753

MedianCD4atTBdiagnosis 106 278 <0.001

MedianHIVVLatTBdiagnosis 5.1 5.0 0.574

Mortalityattheendoffollow-up(#,%) 25(10.3) 31(16.0) 0.085

Table3–Coxregressionmodel,univariateandmultivariateanalysis.

Covariates HR(95%CI) p-Value AdjustedHRa_{(95%CI) p-Value}

Female 0.94(0.68–1.30) 0.71 0.46(0.21–1.01) 0.05

Age(years) 0.99(0.98–1.01) 0.43 1.00(0.97–1.04) 0.66

CD4per100changeHR(absolute) 1.00(0.99–1.00) 0.52 0.90(0.66–1.22) 0.48

DeferredHAART 1.45(1.05–2.00) 0.02 1.89(1.05–3.40) 0.03

a _{Stratifiedbypropensityscorequintile.}

data strongly support the use of HAART in all patients with HIV-related TB as early after TB treatment as possi-ble in Brazil, with a reduction inmortality that was even greater than what has been reported in recent clinical trials.4–7

HAARThasbeenshowntodecrease theincidenceofTB inAfrica,20,21_Brazil,22,23_{andotherdevelopedanddeveloping}

countries,24–26_{andHAARTstronglyreducesmortalityamong}

patients co-infected with HIV and TB10,11 _{as seen in our}

study.TheprotectionofferedbyHAARThasbeenconsistently seenacross CD4cell strata,but mostmarkedlyinpatients withmostadvancedimmunodeficiency.26,4–7_{Inourstudy,CD4}

atthe timeof TBdiagnosis did notindependently impact survivalamongco-infectedpatients,thoughCD4was signifi-cantlylowerinpatientsstartingHAARTearly.Mostlikely,the increaseintheCD4cellcountexplainsmostofthe protec-tionaffordedbyHAART,althoughotherfactors,suchasHIV viralloadandlevelsofotherTcellsubpopulations,mayplay arole.26_{PatientswhofailtoincreasetheirCD4countsafter}

HAARTinitiationareathigherriskofrecurrentTB.27

SurvivalbetweentheSTand DTgroupsdidnotbeginto divergeuntilabout1.5yearsfollowingTBdiagnosis,wellafter TBtreatmenthadbeencompleted.TheSAPiTTrialinSouth Africaand theCAMELIATrial alsodidnotseeasignificant survivalbenefituntilaftersixmonthsofTBtherapy.4,7

Thisclinicalcohortstudyhassomelimitations.Ourdata werecollectedfrompatientmedicalrecords,andinformation ondrugtoxicityandIRISwasgenerallynotavailable. Drug-relatedtoxicityandIRISeventsoccurmorecommonlyatlower CD4countsand mayaffectmorbidity,thoughclinicaltrials shownoimpactofIRISonmortality.Inaddition,theTHRio studyisbasedondataabstractedfrommedicalcharts,and exposuretoHAART wasallocatedatphysicians’discretion, basedon theBrazilian RecommendationsforAntiretroviral TherapyforAdultsandAdolescents,19_{whichguidesHIVcare}

inBrazil.Theseguidelineshaverecentlybeenupdatedstating thatforpatientswithpulmonaryTBwithacavitarylesion,a CD4cellcountshouldbeconducted30daysafterstartingTB treatment28_{andthatHAARTshouldbestartedifCD4countis}

lessthan350cells/mm3_.

Conclusion

WeshowedthatHAARTinitiatedearlyafterTBtreatmentin co-infected patientswas associatedwithan 89%reduction in the risk of death compared to delayed HAART initia-tion.Thus,weprovidefurtherevidenceoftheimportanceof earlyHAARTinincreasingsurvivalamongHIV/TBco-infected patients. Strategies to promote the early diagnosis of HIV infection amongTBpatientsand earlyinitiation ofHAART play important roles in improving the quality of care for patientsco-infectedwithTBandHIV.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

WethanktheTHRioparticipantsandtheTHRioteam,without whomthisprojectwouldnothavebeenpossible.

Funding was provided by the Bill and Melinda Gates Foundation, grant 19790.01to the ConsortiumtoResponse EffectivelytotheAIDS-TuberculosisEpidemic(CREATE).

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