Diagnosis & treatment of tuberculosis in HIV co-infected ... · PDF fileDiagnosis & treatment of tuberculosis in HIV co-infected patients ... a diagnostic strategy should ideally have

Introduction

Humanimmunodeficiencyvirus(HIV)associatedtuberculosis(TB)remainsamajorglobalpublichealthchallenge. By the end of 2009, an estimated 33.3millionpeoplewerelivingwithHIV,thevastmajorityin sub-Saharan Africa and Asia. An estimated 2.6million individuals had become newly infected withHIV and 1.8 million had died ofAIDS in that yearalone1.TBisthemostcommonopportunisticinfection(OI)amongHIV-infectedindividuals,andco-infectedindividuals areathigh riskofdeath2,3.TheestimatesoftheglobalburdenofdiseasecausedbyTBin2009

Review Article

Diagnosis&treatmentoftuberculosisinHIVco-infectedpatients

C.Padmapriyadarsini,G.Narendran&SoumyaSwaminathan

National Institute for Research in Tuberculosis (Indian Council of Medical Research), Chennai, India

ReceivedOctober31,2011

Human immunodeficiency virus (HIV) associated tuberculosis (TB) remains a major global public health challenge, with an estimated 1.4 million patients worldwide. Co-infection with HIV leads to challenges in both the diagnosis and treatment of tuberculosis. Further, there has been an increase in rates of drug resistant tuberculosis, including multi-drug (MDR-TB) and extensively drug resistant TB (XDRTB), which are difficult to treat and contribute to increased mortality. Because of the poor performance of sputum smear microscopy in HIV-infected patients, newer diagnostic tests are urgently required that are not only sensitive and specific but easy to use in remote and resource-constrained settings. The treatment of co-infected patients requires antituberculosis and antiretroviral drugs to be administered concomitantly; challenges include pill burden and patient compliance, drug interactions, overlapping toxic effects, and immune reconstitution inflammatory syndrome. Also important questions about the duration and schedule of anti-TB drug regimens and timing of antiretroviral therapy remain unanswered. From a programmatic point of view, screening of all HIV-infected persons for TB and vice-versa requires good co-ordination and communication between the TB and AIDS control programmes. Linkage of co-infected patients to antiretroviral treatment centres is critical if early mortality is to be prevented. We present here an overview of existing diagnostic strategies, new tests in the pipeline and recommendations for treatment of patients with HIV-TB dual infection.

Key words Co-infection-diagnosis-drugresistance-HIV-IRIS-treatment-tuberculosis

wereasfollows:9.4millionincidentcases(range8.9-9.9million), 1.3million deaths amongHIV-negativeTB patients (range 1.2-1.5million) and 0.38milliondeaths amongHIV-positiveTB patients (range 0.32-0.45million).MostTBcaseswere in theSouth-EastAsia, African and Western Pacific regions (35, 30and20%, respectively).An estimated11-13per centof incident caseswereHIV-positive4.TBmay occuratanystageofHIVdiseaseandisfrequentlythefirstrecognizedpresentationofunderlyingHIVinfection5,6.AscomparedtopeoplewithoutHIV,peoplelivingwithHIV(PLWH)havea20-foldhigherriskofdeveloping

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TB7 and the risk continues to increase as CD4 cellcountsprogressivelydecline5.

AsaresultofWHO’s3by5campaign,>6millionHIV-infected individuals in resource limited settingshavehadaccesstoantiretroviraltherapy(ART)since20048,thoughthisisstillfarshortoftheactualneed.AlthoughART can reduce the incidence ofTB bothat the individual and population level, PLWH onARTstillhavehigherTBincidenceratesandahigherriskofdying fromTB9.Thismaybedue todelayedinitiation of ART or the fact that patients presentwith advanced TB or both10. Routine TB screeningamongPLWHofferstheopportunitytoidentifythosewithoutTB,preventTBbychemoprophylaxisaswellas to diagnose and promptly treatTB.However, co-administration of ART along with anti-TB therapypresents several management challenges, includingdrug-druginteractions,overlappingdrugtoxicitiesandimmunereconstitutionsyndrome.

Inthisreview,wesummarizeandupdateinformationonthescreening,diagnosisandmanagementofTBinHIVinfectedadults.

Diagnosis of TB in HIV-infected individuals

Clinical screening algorithms:TheWHOrecommendsTBscreeningatthetimethatHIVinfectionisdiagnosed,before the initiation of antiretroviral therapy and atregular intervals during follow up11. Currently thereis no internationally accepted evidence-based tool toscreen forTB inPLWH.Multiple studies have beenconducted todevelopasimplemethodfor rulingoutTBinpeoplewithHIVinfection,butmethodologicalissuesprecludetheuseofanyoftheseasthebasisforglobalhealthpolicy12-14.In2007,aWHOInternationalExpertCommittee issued newguidelines to improvethediagnosisofTBinHIVinfectedindividuals15.Thefeasibility, accuracy and operational performance ofthese guidelines were tested in various settings andwere found to be acceptable16. It was recommendedthatscreeningforTBshouldincludeaskingquestionsabout a combination of symptoms rather than onlyaboutchroniccough.Arecentmeta-analysisevaluatedthe performance of individual and combinations ofsymptoms as screening rules for TB among 8,148participants from 12 studies17. The best performingrule was the presence of any one of current cough,fever, night sweats or weight loss. The overallsensitivityof this rulewas79percent, increasing to90percentinclinicalsettingsbutthespecificitywasonly50percent.Thenegativepredictivevalueofthe

rulewashighacrossarangeofTBdiseaseprevalenceestimatesaswellasacrosshighandlowCD4counts.Themajor change to existing practice would be thereplacementofchroniccoughwithcurrentcoughasascreeningquestionandtheadditionofothersymptomstostandardscreening17.Whileascreening toolneedstohavehighsensitivityandnegativepredictivevalue,a diagnostic strategy should ideally have both highsensitivity and specificity. The screening tool couldbeusedinARTclinicstoidentifypatientseligibleforchemoprophylaxis as well as to identify those whoneedfurtherinvestigationsforTB.

Radiographic features:Thespectrumof radiographicmanifestation of pulmonary TB is dependent on therelative level of HIV-related immunodeficiency18.During the early phase ofHIVwhen individuals arenot immunosuppressed, the radiographic pattern issimilar to HIV uninfected individuals with moretypicallesions-upperlobeinfiltrateswithorwithoutcavities. With advancing immunosuppression, extrapulmonary involvement, intra-thoracic/mediastinallymphadenopathy,lowerlobeinfiltrateandmiliaryTBbecomemorecommon19.

Adding chest X-ray to symptom screeningincreasesthenumberofTBcasesdetectedbutisnon-specificandaddstothecostofscreening.ChestX-raycan still miss a substantial proportion of individualswithsub-clinicaldisease,oftenseeninadvancedHIVimmunosuppression20. Moreover, chest radiographsmay appear normal in 7-14% of patients with HIV/TB18,19.Thissub-populationofco-infectedindividualsisparticularlylikelytobenefitfromsputumcultureornucleicacidamplificationtestsforTBdiagnosis.

Sputum smear microscopy:ThemostfrequentmethodofTBdetectioninvolvesmicroscopicexaminationofsputumforacid-fastbacilli(AFB)21.Microscopyhastheadvantageofbeing inexpensive, relatively rapidto perform, and specific inmost settings.However,to be considered smear positive a specimen needsto contain approximately 105 mycobacteria permilliliter. The sensitivity of sputum microscopy inHIV infection ranges from 43 to 51 per cent22, andinmanyresource-limitedsettingswithhigh ratesofco-infection, the sensitivity may be much lower23.Methods that improve speed or sensitivity includefluorescence microscopy24 and alternative specimenprocessing methods, such as concentration, bleachsedimentation and same-day sputum collection (so-calledfrontloading)strategies25-27.Anyprocedurefor

PADMAPRIYADARSINIet al:HIV-TBCOINFECTION 851

digestionorliquefactionfollowedbycentrifugation,prolongedgravitysedimentation,orfiltrationincreasessensitivityby13to33percentoverdirectmicroscopy,whencultureisusedasthereferencestandard26.

Equipmentcostslimitthewideruseoffluorescencemicroscopes in resource-limited settings.Alternativetechnologies using light-emitting diode bulbs allowfluorescence microscopes at a much lower cost;field-level evaluation showed promising results andthis technology is now being widely scaled up28,29.Nevertheless, because sputum smear is the primarymode ofTB detection inmany resource constrainedsettings, a sizable number of smear-negativeindividuals often remain undiagnosed or receivedelayedanti-TBtherapy30.Itisalsoimportanttonotethatdrugsusceptibilitycannotbeascertainedbysmearmicroscopy, so treatment for drug resistant TB isinvariablyempirical.

Growth based detection: Culture of Mycobacterium tuberculosis is much more sensitive than smearmicroscopy and has been recommended to assist inthe diagnosis of TB in HIV-infected individuals31.Culturealsoallowssubsequentstraincharacterizationanddrugsusceptibilitytests.ThetraditionalmethodofinoculatingsolidmediumsuchastheLowenstein-Jenson(L-J) medium or Middlebrook medium is sensitivebutslow,asgrowthmaynotbevisibleuntilafter6-8wkofincubation.Thisresultsindelayininitiationoftherapy,withdetrimentaleffectsonoutcomeofHIV-TB co-infected patients. Automated liquid culturesystems detect growth of mycobacteria within 1-2wkbybacterialcarbondioxideproductionoroxygenconsumptionwithradiometricsensors(BACTEC460TB;BectonDickinsonDiagnosticInstrumentsSystems,USA), fluorescent sensors [BACTEC MycobacteriaGrowthIndicatorTube(MGIT)960;BectonDickinsonDiagnosticInstrumentsSystems],colorimetricsensors(MB/BacTsystem;OrganonTeknika),pressuresensors(ESPculturesystemII;DifcoLaboratories,USA),orredoxreagents,suchasAlamarblue32-35.

Microscopic observation drug susceptibility(MODS)assayisalowcostnon-commercialmethodthatcanbeusedfordetectionofmicrocolonies,cordformation and for early detection of drug resistance.It appears to have higher sensitivity, shorter time toculturepositivityandismorecosteffectivethanregularL-Jmedium36.

BacteriophagebasedassayshavebeenusedforTBdiagnostics (FASTPlaqueTB; Biotech Laboratories,

UK). The FAST Plaque TB assay can detectmycobacteria in 50-65 per cent of smear negativespecimens with a specificity of 98 per cent. Theseassayshaverelativelyhighaccuracywhenperformedon culture isolates. However, their sensitivity inHIV-TB co-infection is low with a higher risk ofcontamination37.

There are currently multiple rapid diagnostictechnologies under evaluation, such as recombinantmycobacteriophages (Luciferase reporter phage-based test “Bronx-box”)38, and colorimetric culturesystem using TK medium culture system (Salubris,Inc,MA,USA)39.Theintroductionoftheserapidandautomated systems has increased the sensitivity ofisolation of mycobacteria from clinical samples andhasbroughtdownthetimerequiredforpositiveculturesubstantially(9-10days).FastercultureresultsinHIV-infectedpatientscanresultinfasterimplementationofevidence-basedtherapy.

Molecular techniques: Nucleic acid amplificationtesting(NAAT)providesareliablewayofincreasingthe specificity of diagnosis (ruling in disease), butsensitivity is variable, especially in paucibacillarydisease. Commercial kits have the advantage ofbeing well standardized and reproducible. However,concerns about their accuracy, reliability, their highcost, requirement forproper laboratory infrastructureand strict quality control procedures limit theirapplicability in resource-limited settings. A fewmodifiedorsimplifiedversionsofNAATkitsincludeloop-mediated isothermal amplification (LAMP),fluorescence in-situ hybridization (FISH) and lineprobeassays(LPA)40.Arecentmeta-analysisshowedhigh sensitivity (>95%) and specificity (100%) forLPAwhencultureisolateswereused41.TheWHOhasendorsedtheuseoflineprobeassays,whichcandetectboth M. tuberculosis complex as well as isoniazidand rifampicin resistance on smear-positive sputumor on early positive growth on culture42. Line probeassays are being used in conjunctionwith culture intheIntermediateReferenceLaboratoriessetupbytheRevisedNationalTBControlProgramme(RNTCP)inIndia43.

GeneXpert-Rif:Recently, theWHOendorsed theuseof GeneXpert-Rif for the rapid diagnosis of TB aswell as rifampicin resistance among HIV-infectedindividualswithclinicalsuspicionofTB44.GeneXpertis a TB-specific automated, cartridge-based nucleicacid amplification assay, having fully integrated and

852 INDIANJMEDRES,DECEMBER2011

automated sample preparation, amplification anddetectionusingreal-timePCR,providingresultswithin100 minutes. Clinical validation trials done in fourdistinctlydiversesettingsshowedthat92.2percentofculture-positivepatientsweredetectedbyasingledirectXpertMTB/RIFtest(incomparisontothesensitivityof a singledirect smearof 59.5%)45.Sensitivityof asingleXpertMTB/RIFtestinsmear-negative/culture-positivepatientswas72.5percentwhichincreasedto90.2per centwhen three sampleswere tested.XpertMTB/RIFspecificitywas99percent.HIVco-infectionsubstantiallydecreasedthesensitivityofmicroscopy(to47%),butdidnotsignificantlyaffectXpertMTB/RIFperformance46. Xpert MTB/RIF detected rifampicinresistance with 99.1% sensitivity and excludedresistancewith100percentspecificity47,48.Meantimetodetection was<1dayforXpertMTB/RIF,1dayformicroscopy, 17days for liquid culture and>30daysfor solidculture45,46.Thus this test seems tohave thepotentialtocomplementthecurrentreferencestandardofTBdiagnostics and increase its overall sensitivityandspeed.Furtherimplementationresearchisrequiredtodeterminetheoptimallevelofthehealthcaresystemwherethissystemcanbecost-effectivelyutilized.

Serological diagnosis of TB

(i) Detection of antibodies: Performance of variousimmunebasedteststodetectantibodiestoM. tuberculosis antigens has been reviewed extensively40,49-51. Noneof the existing commercial serological tests showadequatesensitivityandspecificitytoberecommendedfor diagnostic use. Interestingly, the WHO recentlymade a negative recommendation against the use ofserologicaltestsforTB,basedondatasuggestingthatthese tests could neither replace sputummicroscopynor be used as an add-on test to rule outTB52.Thishasbeenendorsedby theRNTCPand isparticularlyrelevantinIndia,whereitisestimatedthatmillionsofthesetestsareperformedintheprivatesectorleadingtoahugewasteofresources53.

(ii) Detection of antigen:AttemptshavebeenmadetodetectM. tuberculosis MPB-64(TAUNS)antigensinperipheral blood, early secreted antigenic target 6 inthecerebrospinalfluid, lipoarabinomannan(LAM)intheurine,etc. byELISA–basedcommercial assays54-56.UrineLAMassays tend toperformbetter inHIV-infectedcomparedtoHIVuninfectedTBpatients.Thecombination of urine lipoarabinomannan testing andsputumsmearmicroscopyneedsfurtherevaluationforuseinsettingswithahighHIVburden57.

Tuberculin skin test: Tuberculin skin test if positiveprovidesevidenceofTBinfection.ManyHIVinfectedpatients will have a negative skin test despite TBinfectionordisease,duetoanergy.“Twostageorboostertest” is not a substitute to anergy testing; however,itmay have some utility in detectingM.tuberculosis infection in anergic HIV-TB co-infected patients51.Tuberculinskintestunderestimatestheprevalenceoflatent tuberculosis in endemic countries; it requirestrainedhealthcarestafftocorrectlyperformthetestsand accurately read the results, and also requires asecondpatientvisit58.ThetestisneitherusefultoruleindiseasenorinhighTBprevalencesettingstoidentifyeligibleindividualsforprophylaxis.

Other diagnostic techniques

(i). Interferon-γ release assay (IGRA):ThistestcanbeusedtodiagnoselatentTBinfectionandisparticularlyusefulinprofoundlyillpatientsandthosewithseveremalnutrition.Therearetwoin vitroteststodetectlatenttuberculosis:QuantiFERON-TBGold(Cellestis,USA)and theTSPOT-TB test (Oxford Immunotec,USA).Both use an enzyme- linked immunospot assay toquantifythenumberofperipheralbloodmononuclearcells producing IFN- γ in response to tuberculosis-specific antigen stimulation (ESAT-6 and CFP10).Both assays give objective results, with sensitivity(as measured in patients with active tuberculosis)comparabletothatofthetuberculinskintest,butaresignificantly more expensive59. IFN-γ assays do notdifferentiate between latent and active tuberculosisor between immune reconstitution inflammatorysyndrome (IRIS) and failure. Studies suggest thatIGRAsareidealforserialtestingbecausethesecanberepeatedwithoutboosting60-62.ThesearealsounaffectedbypreviousBCGvaccinationandrequirefewerpatientvisits.However,WHOrecommendedagainsttheuseofIGRAsfordiagnosisofactiveorlatentTB,inresource-limitedsettings63.

(ii) Sensing volatile organic compounds (VOCs):from tuberculosis bacteria in exhaled air or urineor headspace gas over sputum or bacterial culture,measuredusingsensorsorgaschromatography–massspectroscopy is a promising new technique64,65. Astudy from India compared theVOCs present in theurineofTBpatientswithVOCsintheurineofhealthysubjects, and found that infectionwithTB producesadistinct patternof certainVOCs inmuch the sameway that distinct fingerprint patterns can identifyindividuals65. Identification of these patterns sets the


stagefordevelopingaportable“electronicnose”thatcanquicklysniffurinesamplestodetectTB.

(iii) Electronic nose devices: Electronic nose (EN)devices are an array of chemical sensors combinedwith some sort of pattern recognition system,whicharebeinginvestigatedtodifferentiatebetweensputumsamplesfromTBpatientsandnon-TBpatients66.ThefunctionofanENistomimicthemammalianolfactorysystem and produce a unique classification based onthevolatileorganiccompoundsinsputum.

Screening for HIV among individuals with active TB

With regard to detectingHIV among individualswith active TB, provider initiated HIV testing isrecommendedforallTBpatients,asstandardofcare67.TherapidexpansionofHIVtestingforTBpatientshasbeenparticularlyencouraginginAfrica,whereonly4percentofTBpatientswere testedforHIVin2004,butby2008thatnumberhadincreasedto45percent4.InapilotstudyofimplementationofproviderinitiatedHIVtestingandcounsellinginIndia,HIVstatuswassuccessfullyascertainedfor70percentofTBpatientsandthiswasfoundtobefeasibleandacceptable68.Thepolicy has been rapidly scaled up with over 60 percentofTBpatientsbeingawareoftheirHIVstatusin2011.

Preventing TB among HIV-infected Individuals

The WHO currently recommends that all HIV-infectedpersonsbescreenedforTB,andHIV-infectedpersons without active TB disease be evaluated fortreatmentoflatentTBinfection69.Twometa-analyseshave shown that isoniazid (INH) taken daily for sixmonths (6H) reduces the incidence of TB by overtwo-thirds among HIV-infected individuals70,71. ThemostwidelyrecommendedregimenforTBpreventivetherapyisisoniazid300mgdailyfor6months.WHOguidelines (2010) strongly recommend the use of6Hregimen,with36H(3yearsof isoniazid)beingaconditional recommendation for countries to adoptdepending on local needs and resources72. However,very few high-burden TB countries have routinelyimplemented isoniazid preventive therapy (IPT) forPLWH, because of concerns about how to excludeTBdisease,fearsaboutselectionforINH-resistantM. tuberculosis (MTB)strains,andtheabsenceofpublichealth models for how to deliver this treatment73.Symptom screening can detect culture-confirmedTBdiseasewithgreaterthan90percentsensitivityand97

percentnegativepredictivevalue.NoneofthestudiesofIPThavedocumentedhigherratesofdrug-resistancesolelyattributabletoIPT.StudiesfromIndiaandSouthAfrica found the 6-month isoniazid regimen to beeffective,well toleratedwith low ratesof emergenceofdrugresistance74,75.TheSouthAfricancohortstudy,whichusedthreenewprophylacticregimens,didnotfind any superiority over the control regimen of 6monthsofisoniazid75.Incontrast,arandomizeddouble-blind,placebo-controlledtrialinBotswanafoundthat36months isoniazid prophylaxis wasmore effectivefor preventionofTB thanwas 6-month prophylaxis,chiefly benefitting those who were tuberculin skintestpositiveandthose initiatingART76.TheNationalAIDS Control Organization (NACO) intends to testthe effectiveness and feasibility of the WHO IPTguidelinesinARTclinicsasaprecursorforadoptingthisrecommendation77.

Treatment of TB and HIV in co-infected individuals

The basic principles of treatment for HIV-associated TB are the same as for HIV uninfectedindividuals. Certain areas of uncertainty remain,includingtheregimenduration,dosageandfrequencyofadministrationofanti-TBdrugs,optimaltimingofinitiationofARTandoptimalanti-TBdrugcombinationforpatientsonsecondlinetreatment.

(i) Anti-TB therapy: Currently, standard therapyconsists of four drugs in the intensive phase for2 months namely isoniazid (H), rifampicin (R),pyrazinamide (Z) and ethambutol (E) followedbyHand R in the continuation phase of four months. InIndia,underRNTCP,afullyintermittentthrice-weeklyregimenCategoryI(2EHRZ3/4HR3)isrecommendedfor newly diagnosedTB.This regimen is reinforcedwithstreptomycin(Sm)intheintensivephaseandthetotaldurationincreasedtoeightmonthsforretreatmentcases - Category II (2EHRZS3/1EHRZ3/5EHR3)78.Rifampicinplaysakeyrole in the treatmentofHIV-associated TB because of its ability to destroy bothintracellular and intermittently and slowly growingTB bacilli. Non-rifampicin containing regimens areassociated with inferior cure rates and prolong theperiodoftreatment79.Ameta-analysisonthedurationofrifampicinshowedthatrecurrenceswere2-3timeshigherifrifampicinusewasrestrictedto2months80.

Foralongtime,itwasbelievedthatlongerregimenscould potentially improve TB outcomes in HIVinfectedindividuals.Todeterminetheoptimalduration


of treatment, we conducted a randomized controlledclinical trial in the pre-HAART era, comparing thestandardRNTCP 6months regimen (2EHRZ3/4HR3)witha9monthextendedcontinuationphaseregimen(2EHRZ3/7HR3).Itwasfoundthatextensionto9monthsdidnot improve theoutcomeat theendof treatmentbut bacteriological recurrences were significantlyreduced during follow up. Irrespective of the lengthof the regimen, acquired rifampicin resistance washighamongfailuresintheabsenceofART81.Variousstudieshave shown that there is an increased riskoffailure with high probability of acquired rifampicinresistance, especially in ART naïve individualsreceivingintermittentregimens80,82,83.ThisinadditiontohighrecurrenceamongHIV-infectedTBpatientsledWHOtorecommendthatdailyTBregimens(atleastin the initial intensive phase) should be preferred tointermittentregimensamongHIV-infectedTBpatients84.Reviewoftheprimaryevidenceindicatesverylimited,low-qualityinformationonintermittency,mostlyfromobservational studies in the pre-antiretroviral era.DNAfingerprintingstudiesinIndiaindicatethatmostof the recurrences andmany of the failures resultedfromexogenousre-infection,indicatingpoorinfectioncontrol andhigh transmission, andnot poor regimenefficacy85. ConcurrentART duringTB treatment canturn the tide with high treatment success rates andlowfatality,failureandrecurrencerates.Asubsequenttrial conducted at the Tuberculosis Research Centre,Chennai,India(nowNationalInstituteforResearchinTuberculosis) compared the efficacyof twodifferentonce-dailyART regimens co-administered withATTandfoundthatthefavourableoutcometoTBtreatmenthad increased to 93 from83 per cent supporting thefact thatART is important for a favourable responseto ATT86. Treatment outcomes among HIV-infectedTBpatientstreatedintheprogrammeshowlowfailurerates, but high case-fatality associated with lack ofaccesstoART.

A recentmeta-analysis on the treatment ofHIV-associated TB, addressing the three key issues ofdosing schedule, duration of therapy and influenceofART concluded that relapsesweremore commonwithregimensusingrifampicinforlessthan2months,thrice-weekly regimens were associated with morefailures and greater relapses and that ART reducedfailuresandrelapsesconsiderably.Themainlimitationof thismeta- analysiswas the paucity of adequatelypoweredrandomized trials inHIV-TBaddressing theissueofdosingschedule87.Giventhepoorevidencefor

changeandoperationaladvantagesofan intermittentregimen, this recommendation has not yet beenimplementedbylargeAsiancountriesincludingIndiaand China until more evidence is generated throughrandomized controlled trials (RCT) to answer basicquestions of schedule and duration of TB treatmentamong PLWH88. TheNational Institute for ResearchinTuberculosis,Chennai, iscurrentlyaddressing thisissuethroughaRCTcomparingdailyvs.intermittentATTinHIV-associatedTB.

(ii) Anti-retroviral therapy:TheWHOguidelinesformanagementofHIV-infectedTBpatientsinresource-limited settings recommend a combination of twonucleoside reverse transcriptase inhibitors (NRTIs)alongwithonenon-nucleoside reverse transcriptaseinhibitor(NNRTI)forfirstlinetherapy89.InIndia,theNACOrecommendsaregimencontainingzidovudineor stavudine alongwith lamivudine and efavirenz90.RifamycinsinducethecytochromeCYP-450enzymesystem in the liver and intestinal wall, therebyincreasingthemetabolismofproteaseinhibitors(PIs)and NNRTIs91. The effect is weaker with rifabutinthanwithrifampin.Rifampinismetabolizedthroughdeacetylation and is not itself affectedby theCYP-3Asystem.Whenrifampicinandsomeantiretroviraldrugsaregiven together,decreased trough levelsofthe lattermay result, leading to therapeutic failure.Nevirapine levels are reduced by about 40–55 percent,efavirenzby18-25percent,delavaridineby96percentandmostPIsby80-90percent92.Ithasbeensuggested that thedoseofefavirenzbe increased to800mgwhenadministeredalongwithrifampicin,butthismaynotbenecessary insubjectsweighing<50kg93.Manystudieshaveshownexcellentvirologicaland clinical outcomes with the use of efavirenz600 mg along withATT. In India, efavirenz is thepreferred NNRTI for use in HIV-TB co-infectedindividuals at the standard dose of 600 mg once-daily90.However, inpatientswhocannot tolerateorhave contraindications to efavirenz (e.g. psychiatricdisturbances, pregnancy), a triple NRTI regimen ora combinationof twoNRTIs andnevirapine canbeused.Whileonce-dailynevirapinewas shown tobeinferior to efavirenz,with higher virological failureandmortalityrates,thiswasprobablyduetothesub-therapeuticlevelsachievedduringthelead-inperiod,in a situation of induced liver enzymes leading tofastermetabolismof nevirapine86.Manosuthiet al94 demonstrated comparable efficacy with ATT andconcomitantly administered twice-daily NVP and


efavirenz. In theirstudycomparingplasma levelsofNVPandtreatmentoutcomesbetweenpatientstreatedwith rifampicin based and non-rifampicin basedregimens, the level of NVPwas low in the formercomparedtonon-rifampicincontainingregimensbutthe virological and immunological outcomes weresimilar95.Analternatestrategyistomodifytheanti-TBregimenwithrifabutinreplacingrifampicin-thedoseofrifabutinrecommendedis300mgODtwice/thrice-weeklywithnevirapinebasedART91.

Many countries are now rolling out PI-basedsecondlineregimensforpatientswithfirstlinetherapyfailure89. Rifampicin markedly reduces the level ofunboosted PIs and hence is not recommended withnelfinavir, indinavir and atazanavir without boostingwithritonavir.Highdosesofritonavircanbeusedwithrifampicinbutattheexpenseofincreasedhepatotoxicity.RecommendeddosesofPIstobeusedwithrifampicinincludelopinavir/ritonavirat400/400mgorsaquinavir/ritonavirat1000/100mgBID.Alternatively,rifabutinwhichhas less interactionwithPIscanbeusedwithdosemodification.Rifabutinisusuallygivenatadoseof300mgdailyandthisremainsthesamewithNRTIsandsaquinavir.Thedoseneedstobeincreasedto450-600mgdailywithEFVwhileitshouldbedecreasedto150mg thrice-weeklywithamprenavir, ritonavirandlopinavir/ritonavir. 87 Rifabutin is contraindicated inleucopeniaandthrombocytopeniawhilehighdosesareknowntocauseuveitis.ThePIcurrentlyrecommendedwith rifabutinbasedATT is lopinavir/ritonavir at thestandarddoseof400/100mgBIDwhilethedosageofatazanavir/ritonaviriscurrentlyunknown.

(iii) Timing of ART & concomitant administration with ATT: It is currently recommended that HIV-infectedindividualswithTBreceiveprompttreatmentforbothdiseases, irrespective of CD4+T cell count, but theoptimal /ideal timing ofART is still under debate89.The advantages of early ART include reduction inearlymortality, improvement in cure rates, reductionin relapses, reduction in malabsorption secondarilypreventing drug resistance toATT and reduction inincidenceofHIV-associated opportunistic infectionsotherthanTB.Thedisadvantagesincludecumulativetoxicity, drug interactions of ART with rifampicin,limiting the choice of combinations and immunereconstitution inflammatory syndrome (IRIS). ThesecanhaveanadverseeffectonthelongtermadherencerequiredforthelifelongtherapyofART.ThesignificanttoxicitiesofthetwoclassesofdrugsarementionedinTableI.

Evidencefromrandomizedcontrolledtrialsshowsthat early initiation of ART during TB treatment isassociatedwith reducedmortality rates, especially inpatientswithprofound immunosuppression (CD4<50cells/μl).TheCAMELIAtrialconductedinCambodia(medianCD4count25cells/μl)showedthatmortalitywasreducedby34percentwhenARTwasinitiatedtwoweeksvs.eightweeksafteronsetofTBtreatment96.The STRIDE and SAPIT trials similarly observedlowerdeathsandAIDS-relatedeventswithcombinedandearlierARTandTB treatment,especiallyamongpeople with CD4 count <50 cells/μl97,98. Based onthese three trials, it is believed thatART should bestartedasamatterofemergency inTBpatientswithCD4 less than50cells/μlandasearlyaspossible intheremainingcases.CautionisneededinpeoplelivingwithHIVwithTBmeningitisasimmediateARTwassignificantly associated with more severe adverseeventswhencomparedtoinitiationofARTtwomonthsafterthestartofTBtreatmentwithoutsurvivalbenefit99.Our approach is to initiateARTwithin the first fewweeks as soon as TB treatment is tolerated and thepatientisstable,aftertreatmentofactiveopportunisticinfections.Table II gives the results of the availablestudiesontimingofART.

Tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS)

Transient worsening of symptoms and signs oftuberculosis or radiological deterioration after theinitiation of ART, despite a reduction in HIV load(>1 log10 copies/μl) and immunological recovery, isknown as IRIS. Consensus case definitions for TB-IRIShaverecentlybeenpublishedbytheInternationalNetwork for the Study of HIV-associated IRIS(INSHI)102. Drug resistance and other opportunisticinfectionsneed tobe ruledoutbefore adiagnosisofIRIS is made. Hypercalcaemia is a unique featureof tuberculosis IRIS103. There are two types of IRISpresentation: unmasking of undiagnosed tuberculosisandaparadoxicaldeteriorationofexistingtuberculosislesions or appearance of new lesions after initialimprovement(Fig.A-F).ManifestationsofIRISincludefever,lymphnodeenlargement,worseningrespiratorysymptomsandsigns,coldabscess,psoasabscesses,andworseningcentralnervoussystemlesions(tuberculomaand meningitis)103,104. The incidence of tuberculosisIRISrangesfrom8to43percentanditcanusuallybemanagedbyanti-inflammatorydrugsandsteroids,withdeathbeingarareoutcomeandassociatedmostlywithCNSIRIS105,110.Rarely,terminationofARTisrequired.


Table I. Adversedrugreactionswithanti-TB(ATT)andantiretroviral(ART)drugs

S.No. Toxicity ATT ART

1. HepatotoxicityIsolatedhyperbilirubinaemiaa.Transaminitiswithorwithoutjaundiceb.

-ATTexceptEmb,Sm,Of

IDV,ATVARTexcept3TC,ABC

2. NeurologicalPeripheralneuropathya.Giddinessandvertigob.Convulsionsc.Circumoralparaesthesiad.

INH,Emb,EtoAminoglycosidesINH,YSm

ddI,D4T,ABCEFV-Amprenavir,RTV

3. Psychiatric(“hangover”)Depressiona.Memoryloss,Psychosisb.

YY,INH

EFVEFV

4. GastrointestinalNausea,Vomitinga.Pancreatitisb.Diarrhoeac.

Eto,INH,PZA,RMP--

ZDV,ABC,TDF,ddI,PIsddI,d4TPIs

5. Lacticacidosis - ZDV,d4T,TDF

6. CutaneousRasha.Exfoliativedermatitisb.Acniformeruptionsc.hyperpigmentationd.

INH,RMP,Eto,PZA,AminoglycosidesRMP-

NVP,ABC,EFVNVP,ABC-ZDV

7. Haematologicala.Anaemiab.Leukopenia(neutropenia)c.Thrombocytopenia

--RMP

ZDVZDV,3TC-

8. MusculoskeletalCPKelevationa.Hyperuricaemia/Goutb.Hypophosphataemiac.Myalgia/arthralgia/arthropathyd.

-PZA,Emb-RMP,PZA,Quinolones

ZDV,SQV-TDFZDV,ABC,RTV,NFV

9. RenalAcuterenalfailurea.Nephrolithiasisb.Fanconi’ssyndromec.

RMP,Aminoglycosides--

-IDVTDF

10. EndocrineInsulinresistant/Diabetesmellitusandlipida.abnormalitiesLipodystrophyb.Thyroidc.

-

-PAS,Eto

PIs,d4T,ABC

D4T,ZDV-

12. MiscellaneousFlu-likesyndromea.Retrobulbarneuritisb.Vestibular&auditorynervedamagec.Gynaecomastiad.

RMP(intermittent)EMBAminoglycosidesINH,

---EFZ,ddI

ATT,emb-ethambutol;Eto,ethionamide;INH,isoniazid;Of,ofloxacin;PAS,paraaminosalicylicacid;PZA,pyrazinamide;RMP,rifampicin;Sm,streptomycin;Y,cycloserine.ART-ATV,atazanavir;ABC,abacavir;ddI,didanosine;d4T,stavudine;EFV,efavirenz;IDV,indinavir;NVP,nevirapine;NFV,nelfinavir;PI,proteaseinhibitor;SQV,saquinavir;RTV,ritonavir;TDF,tenofovir;ZDV,zidovudineSource:Refs6,89,90,92,96


Risk factors for IRIS include lowerCD4 cell count,higherviralloadatstartoftreatment,rapidityofviralloaddecline;bacillaryandantigenload(disseminatedtuberculosis) at initiation, startinghighly activeARTcloser to starting ATT, and genetic predisposition(HLA B-44)111-113. Although the pathophysiology ofIRISisincompletelyunderstood,itisassociatedwithanexuberantproductionofcytokines,suchasIFN-γoralackofinhibitoryimmuneresponses114.

Anti-TB drug resistance in HIV

TherearelimiteddataonTBdrugresistancefromIndia.InastudyconductedamongHIV/TBpatientsinTamilNadu,theprevalenceofdrugresistanceamongpatientswithnohistoryofprevioustreatmentwas13.2percenttoINH,2.4percenttoEMB,7.8percenttoSMand4.2percenttoRMP,eitheraloneorincombinationwithotheranti-tuberculosisdrugs115.Asmallercohortstudy revealed that the prevalence of drug resistantM. tuberculosis isolates among HIV seropositivetuberculosis patients was similar to that of HIVseronegativeTBpatients,indicatingthatHIVinfectionmaynotbeassociatedwithdrugresistanttuberculosis116.ThedatafrommostHIV-endemiccountriesshowthatthe prevalence of multidrug-resistant tuberculosis

in HIV is similar to that in the general population;however, localized mini-epidemics tend to occur insettings where there is close congregation of HIV-infected persons.As individuals with HIV infectionare more susceptible to new infections, the higherprevalenceofMDR-TBinHIVco-infectedpersonsinsomesettingscouldindicatemorerecenttransmissionof drug-resistant strains, compared to reactivation ofinfectionacquired in thedistantpast in thenon-HIVinfectedpopulation.Althoughmultidrug-resistantTBappearsnottocauseinfectionordiseasemorereadilythan drug-susceptible TB in HIV infected persons,delayed diagnosis, inadequate initial treatment, andprolongedinfectiousnesscontributetoincreasedattackratesamongcontactsandhighcasefatalityratesamongpatients117.

At least four effective drugs - including afluoroquinolone, an injectable agent (capreomycin,kanamycin,oramikacin)andatleasttwoagentsfromthe remaining second-line anti-tuberculosis drugclasses (cycloserine, thioamides like ethionamide orprothionamide,andp-aminosalicyclicacid)-alongwithpyrazinamideandEMB,ifstillsensitive,shouldbeused.Therapymay be individualized on the basis of drugsusceptibilitytestresults;however,manycountriesuse

Fig. Types of IRIS: A, B and C shows unmasking IRIS; D, E, F shows paradoxical IRIS. (A)AsymptomaticpatientwhenstartedonART;(B)developedmiliaryTBafterART–unmaskingreaction;(C)AfterATTshowingresolution;(D)PatientwithmiliaryTBatbaseline;(E)After1monthofATTtreatment;(F)AfterARTshowingflareupoflesion(paradoxicalreaction).


(A)

(D)

(B)

(E)

(C)

(F)

Table II. StudiesontimingofARTinHIV-infectedTBpatientsonantituberculosistherapy

Nameofthestudy,Country

Primaryobjective

Secondaryobjectives

TypeofTBincohort

ARTregimenusedwithATT

Treatmentarms

Followupinmonths

Samplesize

Salientfeaturesandstatusifongoing

WHOTB-HAARTstudy, Onyebujoh100

TBtreatmentoutcomesat6monthinHIV-infectedpatientswithCD4countbetween220-500cells/μl

Treatmentfailure,relapseordeathevaluatedat24monthsafterTBtreatmentinitiation,safetyandtolerabilityofconcomitantART

NewTBcases–smearandculturepositive

Zidovudine,Lamivudine,Efavirenz

Arm2:ATT+ART(asearlyaspossibleafter2wk)Arm2:ATT+placebofollowedafter6monthswithART

24 1900 recruiting2014

CameliastudyBlancFXCambodia97

Survivalrate

Safety,IRIS,Occurrenceofopportunisticinfection,TBandARToutcomes,adherence,PKofEFZ

positiveonsmear(sputum,LN,CSF,pleuralfluid,stool)

Stavudine,LamivudineandEfavirenz

Arm1:EarlyARTwithin2weeks,Arm2:LateART-after2months

12 660 Mortalitywas13.8%inthelatearmcomparedto8.28intheearlyarm,P=0.02.IRISwas2.5foldmoreintheearlyarm.

ACTG5221,Multinational98

SurvivalwithoutprogressiontoAIDS

NA confirmedorprobableTB

Efavirenz,Emtricitabine,Tenofovir

Arm1:EarlyART-within2weeks,Arm2:LateART-after2months

12 800 Overall,therewasnosignificantdifferenceinmortalitybutinpatientswithCD4<50cells/µl,lowerincidenceofdeathsintheearlyarm(15.5vs.26.6%,p=0.02)

THIRST,Tanzania97

FeasibilityandsafetyofFDCofARTwithATT

IRIS ProbableTB

Zidovudine,Lamivudine,Abacavir.

Arm1:EarlyART-within2weeks,Arm2:LateART-8weeksaftercommencingATT

15 70 EarlyARTwaswelltoleratedbyHIVco-infectedsubjectswithalowriskofimmunereconstitutionsyndromes,moreadverseeventsnecessitateregimenswitcheswithearlyART.

Contd...


Nameofthestudy,Country

Primaryobjective

Secondaryobjectives

TypeofTBincohort

ARTregimenusedwithATT

Treatmentarms

Followupinmonths

Samplesize

Salientfeaturesandstatusifongoing

SAPITtrial94 KarimSASouthAfrica

IncidenceofprogressiontoAIDSdefiningillnessandmortality

CD4,VL,opportunisticinfections

SmearpositivePTB

Didanosine,Lamivudine,Efavirenz

IntegratedArmArm1:EarlyART-within2weeksofATTArm2:atendofintensivephaseArm3: 6-8monthsafterATTcompleted(stoppedprematurelyduetoincreasedmortality)

18 700 InitiationofARTduringTBtherapyreducedmortalitysignificantlyby56%.IRISincidencewas12.4%intheintegratedarmvs3.4%inthesequentialarmbuttherewerenodeathsduetoIRIS

LN,lymphnode;CSF,cerebrospinalfluid;NA,notapplicable;FDC,fixeddrugcombination;VL,viralload;PTB,pulmonarytuberculosis

Table II (contd.). StudiesontimingofARTinHIV-infectedTBpatientsonantituberculosistherapy

standardized regimens that are basedon surveillanceofantituberculosisdrugresistanceinthecommunity117.DOTS plus regimen is currently followed in Indiacomprisingofkanamycin, levofloxacin, ethionamide,cycloserine, ethambutol, and pyrazinamide givenfor a period of 6-9 months daily in the intensivephase followed by all drugs except kanamycin andpyrazinamide during the continuation phase of 18months,withdosagesprescribedfor3weightbands115.Shorterregimensandnewerdrugsarebeingtestedbutconclusiveevidenceisstilltoemerge.Extensivelydrug-resistanttuberculosis(XDRTB)isdefinedasmultidrug-resistantTBplusresistancetoanyfluoroquinoloneandoneofthesecond-lineantituberculosisinjectableagents(kanamycin, amikacin, or capreomycin). Treatmentoptions are extremely limited and challenging, withhighfrequenciesofadverseeventsanddeath118.

TB-HIV co-ordination activities

In2007,approximately5percentofalldiagnosedTB cases in India came from Integrated CounsellingandTestingCentres(ICTCs),demonstratingthattheseareexcellentsitesforactiveTBcasefinding1.Further,the yield of cases was similar (approximately 20%)fromHIV infected and uninfected clients.One of theprogrammatic limitations encountered is the lack ofinvestigations for extrapulmonary TB at peripheralhealth facilities; another is the distance betweenDesignatedMicroscopyCentres(DMCs)andICTCsinsomedistricts.Thesystemworksmuchbetterwhenboth

are located at the same site. In a pilot study on 4000TB patients in two districts of Tamil Nadu, India, itwasdemonstratedthatover two-thirdswerewillingtoundergoanHIVtestandthemajorbarriertoacceptancewaspatientsnotperceivingthemselvestobeatrisk119.IfpatientsarecounselledandexplainedtheimportanceofhavinganHIVtest,whentheyarediagnosedwithTB,mostwillacceptthetest.Provider-initiatedHIVtestingandcounselling(PITC)isinternationallyrecommendedforTBpatients;thefeasibility,effectiveness,andimpactofthispolicyontheTBprogrammewereevaluatedina study across two districts in south India consideredto have generalized HIV epidemics, Tiruchirappalli(population2.5million)71 andMysore (population2.8million).WithimplementationofPITC,HIVstatuswassuccessfullyascertainedfor70percentofTBpatients.PreviouslyundiagnosedHIV-infectionwasdetectedin6.4percentofthoseTBpatientsnewlytested,enablingreferral for lifesaving anti-retroviral treatment. ARTuptake, however, was poor, suggesting that PITCimplementationshould includemeasures tostrengthenand supportART referral, evaluation, and initiation68.WithincreasingavailabilityofARTacrossthecountry,diagnosisofHIVisbeneficialtotheindividualashe/shecanbereferredtothenearestARTcentreforevaluationandinitiationofantiretroviraltreatment,ifindicated.TBclinics,therefore,formanimportantentrypointforHIVdiagnosis,careandsupport.Co-ordinationandcross-talkbetweenthesetwogovernmenthealthprogrammesarecrucialnotonlytoimprovetheoutcomeofHIV-infected


TBpatientsbutalsotocontroltheburdenoftuberculosisinIndia.

It isconcludedthat theHIVpandemicpresentsamassivechallengetoglobalTBcontrol.ThepreventionofHIVandTB,theextensionofWHODOTSprograms,andafocusedefforttocontrolHIV-relatedTBinareasofhighHIVprevalencearemattersofgreaturgency.

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Reprint requests:DrSoumyaSwaminathan,Scientist‘G’&HOD,DepartmentofClinicalResearch,NationalInstituteforResearchinTuberculosis,No.1,SathiyamoorthyRoad,Chetpet,Chennai600031,India

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