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Recent Advance

Treatment of Tuberculosis from WHO guidelines 2010

. 1, ..

2, ..

2

1,

2

WHO2010

4

3

2003

2050

- Casedefinition

- Standardtreatmentregimens

- Monitoringduringtreatment

- Co-managementofHIVandactiveTB

case

- Supervisionandpatientsupport

- Treatmentofdrug-resistanttuberculosis

- TreatmentofextrapulmonaryTBand

TBinspecialsituations

Case definition

TB suspected case: productivecough>2weeksandotherrespiratorysymptoms(shortness

ofbreath,chestpain,hemoptysis)and/orconsti-

tutionalsymptoms(lossofappetite,weightloss,

fever,night

Case of TB: definite case of TB anddecidedtotreat

Definite case of TB: oneormoresputumsmearpositiveAFBorM.tuberculosis identified

fromclinicalspecimen,eitherbycultureormo-lecularlineprobeassay

Pulmonary TB (PTB): TB involvinglungparenchymaorpatientwithbothpulmonary

andextrapulmonaryTB

Extrapulmonary TB (EPTB): TB in-volvingorgansotherthanlungparenchyma,e.g.

pleura,lymphnodes,abdomen,genitourinarytract,

skin,jointsandbone,meninges

Smear positive case: onlyone sputumspecimensmearpositiveAFB

Smear negative case: 2 specimens aresmearnegativeAFB(at leastoneearly-morning

specimen) in awell functional external quality

assurance(EQA)system

Smear not done: pulmonaryTBcaseswithoutsmearresults

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Registration group: neworpreviouslytreated patients, in previously treated patients

consideredoutcomeofmostrecentTBtreatment

astable1(NoTBtreatmentcategoryIIV)

Table 1TBregistrationgroupbyoutcomeofmostrecentTBtreatment

2

Smear positive case: only one sputum specimen smear positive AFB Smear negative case: 2 specimens are smear negative AFB (at least one early-morning specimen) in a well functional external quality assurance (EQA) system Smear not done: pulmonary TB cases without smear results Registration group: new or previously treated patients, in previously treated patients considered outcome of most recent TB treatment as table 1 (No TB treatment category I IV)

Table 1 TB registration group by outcome of most recent TB treatment

HIV status: TB register include date of HIV testing, starting co-trimoxazole, and starting ART Standard treatment regimens

HIV status: TBregisterincludedateofHIVtesting,startingco-trimoxazole,andstarting

ART

Standard treatment regimens

2fixed-dose

combinations (FDCs)

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Table 2 Recommendeddosesoffirst-lineantituberculosisdrugsforadults

3

2 fixed-dose combinations (FDCs)

Table 2 Recommended doses of first-line antituberculosis drugs for adults

New patients isoniazid rifampicin 6 2HRZE/4HR 2HRZE/6HE 2HRZE/4HR extrapulmonary TB streptomycin ethambutol 2HRZ/4HR (CAT III) guideline 2HRZE/4HR intensive phase continuation phase 3 2HRZE/4(HR)3 (directly observed) 3 intensive continuation phase 2(HRZE)3/4(HR)3 HIV

New patients

isoniazid

rifampicin 6

2HRZE/4HR

2HRZE/6HE

2HRZE/4HR

extrapulmonaryTB

streptomycin ethambutol

2HRZ/4HR(CATIII)guideline

2HRZE/4HR

intensive

phasecontinuationphase

3 2HRZE/4(HR)3

(directlyobserved)3

intensivecontinuationphase

2(HRZE)3/4(HR)3

HIV

HIV

2

intensivecontinuationphase

HIV

HIVHIV

1

HIV

5

intensivephase

HIV

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isonia-zid2HRZE/4HRE

3

intensivecontinuationphase

isoniazid7.4

Previously treated patients

13

MDR-TB155

MDR-TB

(MDR-TB

3)10

(default)

(relapse)MDR-TB32

(Failure)MDR-TB

49rifampicin

6

MDR-TB5094

(drug

susceptibility testing, DST)

rapidmolecular-basedDST(lineprobeassays)

rifampicin/isoniazid

12 conventional

DST(

10) liquidmedia

(2842)solidmedia

conventionalDST

empiricalregimenDST

(failure)

empiricalMDR regimen

(default)(relapse)

regimen first-line drugs

2HRZES/1HRZE/5HRE

HIV

MDR-TB

DST HIV-

infectedTB CD4 counts 200 /

newpreviouslytreatedcases

sputum smear positiveAFB

intensive phase

smearpositiveAFBDST

5

Monitoring during treatment AFBstaining

intensivetreatment

2smear

positiveAFB 3

smearpositiveAFBDST

MDR-TBtreatmentfailure

regimen

8(2HRZES/1HRZE/5HRE)

3smearpositiveAFB

DSTMDR-TB

treatmentfailure

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sputumsmearAFB2,56

2sputumsmearpositiveAFB

3DST56

sputumsmearpositiveAFBDST

regimen8(2HRZES/1HRZE/5HRE)

sputumsmearAFB3,58

3sputumsmearpositiveAFBDST

58sputumsmearpositiveAFB

DST

intensive

treatmentpositiveAFB

relapse, failure pretreat-ment isoniazid resistance

intensivetreatmentpositiveAFB

- intensivephase

-

-

-

(extensivecavitation)

-

- MDR-TB

first-linetreatment

- smear positiveAFB

regimen rifampicin6

intensive treat-mentpositiveAFBguideline

extensionintensivephase

3 positive

AFBMDR-TB

AFB

cohortanalysisoftreatmentout-comes 3

new pulmonary

smear-positivepatients

(pro-gramme quality)

3 cure

sputum smear

intensive phase

continuationphase

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Table 3 Definitionoftreatmentoutcome

6

- - MDR-TB first-line treatment - smear positive AFB regimen rifampicin 6 intensive treatment positive AFB guideline extension intensive phase 3 positive AFB MDR-TB

AFB cohort analysis of treatment outcomes 3 new pulmonary smear-positive patients (programme quality) 3 cure sputum smear intensive phase continuation phase

Table 3 Definition of treatment outcome

pyridoxine10mg/day

isoniazid-

inducedperipheralneuropathy

(symptom-base approach)

minoradverseeffect

majoradverseeffect

4

5

- Cutaneous reaction

antihis-

tamineskinmoisturizing

challenge

isoniazidrifampicin

doseisoniazid50

3

- Drug-inducedhepatitisfirst-

lineanti-TBdrugshepatitisisonia-zid,pyrazinamiderifampicin

jaundicerifampicinhepatitis

intensivecontinua-tionphase

LFT

streptomycin, ethambutol,

fluoroquinoloneLFT

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2challenge

rifampicinhepatotoxicity

isoniazid pyrazinamide

rifampicin

challengerifam-picin37challengeiso-niazid

challengerifampicinisoniazid

challengepyrazinamide

pyrazinamide

hepatitisintensivephase

2HRES/6HR pyrazinamide

hepatitis continuation phase

2HRZE/4HR

isoniazidRZE69

rifampicinpyracinamide

2HES/10HEisoniazid

rifamicin streptomycin,

ethambutolfluoroquinolone18

24

Table 4 Symptom-basedapproachtomanagingminorside-effectsofanti-TBdrugs

8

2HES/10HE isoniazid rifamicin streptomycin, ethambutol fluoroquinolone 18 24

Table 4 Symptom-based approach to managing minor side-effects of anti-TB drugs

Table 5 Symptom-based approach to managing major side-effects of anti-TB drugs

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8

2HES/10HE isoniazid rifamicin streptomycin, ethambutol fluoroquinolone 18 24

Table 4 Symptom-based approach to managing minor side-effects of anti-TB drugs

Table 5 Symptom-based approach to managing major side-effects of anti-TB drugs

Table 5 Symptom-basedapproachtomanagingmajorside-effectsofanti-TBdrugs

Co-management of HIV and active TB case

HIV testing antiretroviral

therapy (ART) 8

starting anti-TB drugs

survival

TB recurrence rate first-

lineARTstandard-doseefavirenz(EFV)

2 nucleoside reverse transcriptase inhibitors

(NRTIs)AZT (TDF)+ 3TC

(FTC)+EFV

efavirenzteratogeniceffect

nevirapine (NVP)

AZT(TDF)+3TC(FTC)+NVP

cotrimoxazoleprophylaxis

Pneumocystisjirovecii

drugsusceptibil-

ity testing (DST)

HIV

MDR-TB

HIV-positiveTBpatients

intermittentTBtherapyintensive

phaserelapsefailure

dailyintensivephase23

threetimesweekly

short-course intermittent regimen

acquiredrifampicinresistance

2HRZE/4HR

HIV positive HIV negative

rifampicin-containingregimen

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8relapse

6

anti-TB drugs,ART

cotrimoxazole

compliance

Supervision and patient support

(supervi-sion)

(directlyobservedtherapy,DOT)

(patient-centred care)

newsmear-positivecases

DOTS2006default5

Treatment of drug-resistant tuber-culosis standard treatment

MDR-TB

standard

empiricMDR-TB

(functionalequivalentofonlyonedrug

treatment)1

DST

4

cross-resistance

64smear

culturenegative

18culturenegative

24

MDR-TBsputumsmear

culture negative

smearculture3

sputumconversion

smearculturenegative2

30

MDR-TB5

Group 1: First-line oral agents pyrazinamide(Z),ethambutol(E),rifabutin

(Rfb)

DST

DST

rifabutin cross-resistance

rifampicin

Group 2: Injectable agents kana-mycin(Km),amikacin(Am),capreomycin(Cm),

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strepyomycin (S) MDR-TB

aminoglycosides

aminoglycosides

kanamycinamikacinstreptomy-cin

kanamycinamikacin

ototoxicitystreptomycin

kanamycin amikacin

cross-resistance

kanamycinamikacin

capreomycin

Group 3: Fluoroquinolones le-vofloxacin (Lfx),moxifloxacin (Mfx),ofloxacin

(Ofx)

MDR-TB levofloxacinmoxifloxacin

ofloxacin ciprofloxacin

drug-suscep-tibledrug-resistantTB

Group 4: Oral bacteriostatic second-line agents para-aminosclicylicacid(PAS),

cycloserine (Cs), terizidone (Trd), ethionamide

(Eto),protionamide(Pto)ethionamide

MDR-TB

para-

aminosalicylicacidenteric-coated

cross-

resistance 2

para-aminosalicylicacid

cycloserinepara-aminosalicylicacid

ethionamideGIside-effect

hypothyroidism

3

ethionamide,cycloserinepara-aminosalicylic

acidterizidonecycloserine

Group 5: Agents with unclear role in treatment of drug resistant-TBclofazimine

(Cfz), linezolid (Lzd), amoxicillin/clavulanate

(Amx/Clv),thioacetazone(Thz),imipenem/cilas-tatin(Ipm/Cln),high-doseisoniazid(16-20mg/kg/

day),clarithromycin(Clr)WHO

MDR-TB

1

4XDR-TB

Treatment of extrapulmonary TB and TB in special situations extrapulmonary TB

20 25

extrapulmonaryTB

HIV testing

extrapulmonaryTBex-trapulmonaryTBregimenpulmonary

TB2HRZE/4HR

912

disabil-itymortality9

corticosteroid

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streptomycin

ethambutol

latecomplication

hydrocephalus, obstructive uropathy,

constrictivepericarditis,neurologicalinvolve-mentPottsdisease

fluctuationaspiration

incisiondrainage

druginteractionsrifam-picinmetabolize

anti-infectives(proteaseinhibitor,

mefloquine,azoleantifungalagents,clarithromycin,

erythromycin,doxycycline,atovaquone,chloram-phenicol),hormonetherapy(ethinylestradiol,nore-hindrone,tamoxifen,levothyroxine),methadone,

warfarin,cyclosporine,corticosteroids,anticonvul-sants(phenytopn),cardiovascularagents(digoxin,

digitoxin, verapamil, nifedipine, diltiazem, pro-pranolol,metoprorol,enarapril,losartan,quinidine,

mexiletine,tocainide,propafenone),theophylline,

sulfonylureahypoglycemicdrug,hypolipidaemic

drugs(simvastatin,fluvastatin),nortriptyline,halo-peridol, quetiapine, benzodiazepines (diazepam,

triazolam), zolpidem, buspirone

rifampicin

higherdoseestrogen(50g)

rifampicinmetab-olism-inducingrifampicin2

rifampicin

rifampicin

2HRZE/4HR

first-line anti-TBdrugs

streptomycin

ototoxic

activeTBactiveTB

isoniazidprophylaxis6

BCGvaccination

isoniazid regimen

pyridoxine

supplement

LFTserum

alanineaminotransferaselevel3

LFT

regimen

- hepatotoxic drug 2

hepatotoxicdrugs3standard

regimen regimen 9HRE

2HRSE/6HR6-9RZE

-hepatotoxicdrugs1

regimen2HES/10HE

- hepatotoxicdrugsregimen

regimen18

24 streptomycin, ethambutol

fluoroquinolone

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2HRZE/4HR

isoniazidrifampicin

ethambutolpyrazinamide

3

pyrazinamide 25//

ethambutol 15//

3

isoniazid regimen

pyridoxine peripheral

neuropathy

streptomycinneph-rotoxicity ototoxicity

streptomycin 15/

/23

serumlevel

streptomycin

1. WorldHealthOrganization. Treatment of

tuberculosisguidelines.4thed.,2010.