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gdFourth edition

TreaTmenT of Tuberculosis

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Tratmt o tbrco

GuidelinesForth to

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WHO Library Cataloguing-in-Publication Data:

reatment o tuberculosis: guidelines 4th ed.

WHO/HM/B/2009.420

1.Antitubercular agents administration and dosage. 2.uberculosis,

Pulmonary drug therapy. 3.National health programs. 4.Patient compliance.

5.Guidelines. I.World Health Organization. Stop B Dept.

ISBN 978 92 4 154783 3 (NLM classication: WF 360)

World Health Organization 2010

All rights reserved. Publications o the World Health Organization can be obtained rom WHO Press,

World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791 4857; e-mail:

[email protected]). Requests or permission to reproduce or translate WHO publications whether

or sale or or noncommercial distribution should be addressed to WHO Press, at the above address

(ax: +41 22 791 4806; e-mail: [email protected]).

Te designations employed and the presentation o the material in this publication do not imply the

expression o any opinion whatsoever on the part o the World Health Organization concerning thelegal status o any country, territory, city or area or o its authorities, or concerning the delimitation o

its rontiers or boundaries. Dotted lines on maps represent approximate border lines or which there may

not yet be ull agreement.

Te mention o specic companies or o certain manuacturers products does not imply that they are

endorsed or recommended by the World Health Organization in preerence to others o a similar nature

that are not mentioned. Errors and omissions excepted, the names o proprietary products are distin-

guished by initial capital letters.

All reasonable precautions have been taken by the World Health Organization to veriy the inormation

contained in this publication. However, the published material is being distributed without warranty o

any kind, either expressed or implied. Te responsibility or the interpretation and use o the materiallies with the reader. In no event shall the World Health Organization be liable or damages arising rom

its use.

Designed by minimum graphics

Printed in .

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iii

: :

Cott

Abbrvato v

Ackowgmt v

Forwor x

Eective s 1

1. Itcti 15

1.1 Chaptr objctv 15

1.2 Prpo o th g 15

1.3 Targt ac 15

1.4 scop 15

1.5 Why a w to? 15

1.6 Mthooogy 18

1.7 itratoa staar or Tbrco Car 21

1.8 expry at 21

2. Cse efitis 23


2.2 Prpo o fg a TB ca 23

2.3 Ca fto 23

2.4 Aatomca t o TB a 24

2.5 Bactroogca rt 25

2.6 Htory o prvo tratmt: patt rgtrato grop 262.7 HiV tat 28

3. St tetet egies 29


3.2 Am o tratmt 29

3.3 eta at-TB rg 29

3.4 staar rgm or f patt grop 31

3.5 nw patt 323.6 Prvoy trat patt a mtrg rtac 36

3.7 staar rgm or prvoy trat patt 38

3.8 Ovra corato ctg a cotry taar rgm 42

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iv

TrEaTmEnT o TubErCuloSIS: GuIdElInES

4. mitig ig tetet 53


4.2 Motorg th patt 53

4.3 Ag tratmt rpo w a prvoy trat pmoary

TB patt, a actg o th rt 53

4.4 extrapmoary TB 57

4.5 Rcorg taarz tratmt otcom 57

4.6 Cohort aay o tratmt otcom 57

4.7 Maagmt o tratmt trrpto 59

4.8 Prvto o avr ct o rg 59

4.9 Motorg a rcorg avr ct 604.10 symptom-ba approach to maagg -ct o at-TB rg 60

5. C-geet HIV ctive Tb isese 65


5.2 HiV ttg a cog or allpatt kow or pct to hav TB 65

5.3 HiV prvto TB patt 67

5.4 TB tratmt pop vg wth HiV 67

5.5 Co-trmoxazo prvtv thrapy 695.6 Atrtrovra thrapy 69

5.7 drg cptbty ttg 71

5.8 Patt motorg rg TB tratmt 71

5.9 Corato wh TB ago pop vg wth HiV who ar

aray rcvg atrtrovra thrapy 72

5.10 HiV-rat prvto, tratmt, car a pport 72

6. Spevisi ptiet sppt 75


6.2 Ro o th patt, TB programm ta , th commty a othr provr 75

6.3 sprv tratmt 77

6.4 ug a patt-ctr approach to car a tratmt vry 78

6.5 Prvto o tratmt trrpto 80

7. Tetet g-esistt tecsis 83


7.2 Gr lght Commtt itatv 83

7.3 Grop o rg to trat MdR-TB 84

7.4 Gra prcp gg a MdR-TB tratmt rgm 86

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v

7.5 Programmatc tratg or tratmt o MdR-TB 86

7.6 scto o th cotry taar MdR-TB tratmt rgm 89

7.7 scto o vaz MdR-TB rgm 89

7.8 Motorg th MdR-TB patt 91

7.9 drato o tratmt or MdR-TB 91

7.10 Tratg TB wth rtac pattr othr tha MdR 92

7.11 Rcorg a rportg rg-rtat TB ca, vaato o otcom 92

8. Tetet etp Tb Tb i speci sittis 95


8.2 Tratmt o xtrapmoary TB 95

8.3 importat rg tracto 96

8.4 Tratmt rgm pca tato 97

aees 101

1. eta frt- attbrco rg 103

2. smmary o vc a corato ryg th rcommato 115

3. TB tratmt otcom 131

4. impmtato a vaato o th orth to 1335. sggto or tr rarch 141

6. Mmbr o th G Grop 145

ConTEnTS

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vii

AFB acid-ast bacilli

AIDS acquired immunodeciency syndrome

AR antiretroviral therapy

DO directly observed treatment

DOS the internationally agreed strategy or B control

DRS drug resistance surveillance

DS drug susceptibility testing

E ethambutol

EPB extrapulmonary tuberculosis

EQA external quality assurance

FDC xed-dose combination

GLC Green Light Committee

H isoniazid

HIV human immunodeciency virus

ISC International Standards or uberculosis Care

MDR multidrug resistance

MDR-B multidrug-resistant tuberculosis

NNRI non-nucleoside reverse transcriptase inhibitor

NRI nucleoside reverse transcriptase inhibitor

NP national tuberculosis control programmePB pulmonary tuberculosis

R riampicin

S streptomycin

B tuberculosis

B/HIV HIV-related B

XDR-B extensively drug-resistant tuberculosis

Z pyrazinamide

: :

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viii

Te Stop B Department o the World Health Organization grateully acknowledges

the members o the Guidelines Group (listed in Annex 6), including Jeremiah Muh-

wa Chakaya, the Chairperson.

Richard Menzies (McGill University, Montreal, Canada), Karen Steingart and Phil-

lip Hopewell (University o Caliornia, San Francisco, USA) and Andrew Nunn and

Patrick Phillips (British Medical Research Council) led the teams that compiled, syn-thesized and evaluated the evidence underlying each recommendation.

Suzanne Hill and Holger Schnemann acilitated the meeting o the Guidelines

Group.

Useul eedback was obtained rom the External Review Group (also listed in An-

nex 6).

Additional eedback and support were provided by the Guidelines Review Commit-

tee (Chair, Suzanne Hill; Secretariat, Faith McLellan).

Publication o the guidelines was supported in part by a nancial contribution rom

the Global Fund to Fight AIDS, uberculosis and Malaria.

Te document was prepared by Sarah Royce and Malgorzata Grzemska.

Dorris Ortega provided secretarial support.

: :

Ackowgmt

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Forwor

Te World Health Organizations Stop B Department has prepared this ourth

edition oreatment o tuberculosis: guidelines, adhering ully to the new WHO proc-

ess or evidence-based guidelines. Several important recommendations are being

promoted in this new edition.

First, the recommendation to discontinue the regimen based on just 2 months o

riampicin (2HRZE/6HE) and change to the regimen based on a ull 6 months oriampicin (2HRZE/4HR) will reduce the number o relapses and ailures. Tis will

alleviate patient suering resulting rom a second episode o tuberculosis (B) and

conserve patient and programme resources.

Second, this ourth edition conrms prior WHO recommendations or drug suscep-

tibility testing (DS) at the start o therapy or all previously treated patients. Finding

and treating multidrug-resistant B (MDR-B) in previously treated patients will

help to improve the very poor outcomes in these patients. New recommendations

or the prompt detection and appropriate treatment o (MDR-B) cases will also

improve access to lie-saving care. Te retreatment regimen with rst-line drugs

(ormerly called Category 2 regimen) is ineective in MDR-B; it is thereore criti-

cal to detect MDR-B promptly so that an eective regimen can be started.

Tird, detecting MDR-B will require expansion o DS capacity within the context

o country-specic, comprehensive plans or laboratory strengthening. Tis ourth

edition provides guidance or treatment approaches in the light o advances in lab-

oratory technology and the countrys progress in building laboratory capacity. In

countries that use the new rapid molecular-based tests, DS results or riampicin/

isoniazid will be available within 12 days and can be used in deciding which regimenshould be started or the individual patient. Rapid tests eliminate the need to treat in

the dark during the long wait or results o DS by other methods (weeks or liquid

media methods or months or solid media methods).

Because o the delays in obtaining results, this new edition recommends that coun-

tries using conventional DS methods should start treatment with an empirical regi-

men. I there is a high likelihood o MDR-B, empirical treatment with an MDR

regimen is recommended until DS results are available. Drug resistance surveil-

lance (DRS) data or surveys will be required to identiy subgroups o B patientswith the highest prevalence o MDR-B, such as those whose prior treatment has

ailed. Implementation o these recommendations will require every country to in-

clude an MDR-B regimen in its standards or treatment in collaboration with the

Green Light Committee Initiative.

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Fourth, diagnosing MDR-B cases among previously treated patients and providing

eective treatment will greatly help in halting the spreado MDR-B. Tis edition

also addresses the prevention oacquiredMDR-B, especially among new B patients

who already have isoniazid-resistant Mycobacterium tuberculosis when they starttreatment. Te meta-analyses that orm the evidence base or this revision revealed

that new patients with isoniazid-resistant B have a greatly increased risk o acquiring

additional drug resistance. o prevent amplication o existing drug resistance, this

edition includes the option o adding ethambutol to the continuation phase o treat-

ment or new patients in populations with high prevalence o isoniazid resistance.

In addition, the daily dosing recommended or the intensive phase may also help in

reducing acquired drug resistance, especially in patients with pretreatment isoniazid

resistance.

Finally, this edition strongly rearms prior recommendations or supervised treat-

ment, as well as the use o xed-dose combinations o anti-B drugs and patient kits

as urther measures or preventing the acquisition o drug resistance.

Use o the new WHO process or evidence-based guidelines revealed many key un-

answered questions. What is the best way to treat isoniazid-resistant B and pre-

vent MDR? What is the optimal duration o B treatment in HIV-positive patients?

Which patients are most likely to relapse and how can they be detected and treated?

Identication o such crucial questions or the uture research agenda is an important

outcome o this revision and will require careul ollow-up to ensure that answerswill be provided to urther strengthen B care practices.

As new studies help to ll these gaps in knowledge, new laboratory technology is

introduced, and new drugs are discovered, these guidelines will be updated and

revised. In the meantime, WHO pledges its ull support to helping countries to im-

plement and evaluate this ourth edition oreatment o tuberculosis: guidelines and

to use the lessons learnt to improve access to high-quality, lie-saving B care.

Dr Mario Raviglione

DirectorStop B Department

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1

Major progress in global tuberculosis (B) control ollowed the widespread imple-

mentation o the DOS strategy. Te Stop B Strategy, launched in 2006, builds upon

and enhances the achievements o DOS. New objectives include universal access to

patient-centred treatment and protection o populations rom B/HIV and multi-

drug-resistant B (MDR-B). Te Stop B Strategy and the Global Plan to imple-

ment the new strategy make it necessary to revise the third edition oreatment o

tuberculosis: guidelines or national programmes, published in 2003.

Creation o the ourth edition ollows new WHO procedures or guidelines develop-

ment. With input rom a group o external experts the Guidelines Group WHO

identied seven key questions, and systematic reviews were conducted or each ques-

tion. Te Guidelines Group based its recommendations on the quality o the evidence

(assessed according to the GRADE methodology), patient values, and costs, as well

judgements about trade-os between benets and harms. Recommendations were

rated as strong or conditional.

Te evidence and considerations underlying each recommendation are summarized

in Annex 2.

A strong recommendation is one or which desirable eects o adherence to the rec-

ommendation clearly outweigh the undesirable eects. Te strong recommendations

in this edition use the words should or should not. No alternatives are listed.

A conditional recommendation is one or which the desirable eects o adherence to

the recommendation probably outweigh the undesirable eects but the trade-os are

uncertain.

Reasons or uncertainty can include:

lack o high-quality evidence to support the recommendation;

limited benets o implementing the recommendation;

costs not justied by the benets;

imprecise estimates o benet.

A weak recommendation is one or which there is insucient evidence and it is based

on eld application and expert opinion. Recommendations or which the quality o

evidence was not assessed in line with the GRADE methodology are not rated.

Conditional and weak recommendations use the words may. For several o the con-

ditional recommendations, alternatives are listed.

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exctv mmary

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2


Te recommendations that address each o the seven questions are listed below,

and also appear in bold text in Chapter 3 (Standard treatment regimens), Chapter 4

(Monitoring during treatment) and Chapter 5 (Co-management o HIV and active

B). Areas outside the scope o the seven questions, as well as the remaining chapters,have been updated with current WHO B policies and recent reerences but were

not the subject o systematic literature reviews or o new recommendations by the

Guidelines Group.

Qesti 1. dti ipici i ew ptiets

Should new pulmonary B patients be treated with the 6-month riampicin regimen

(2HRZE/4HR) or the 2-month riampicin regimen (2HRZE/6HE)?

L

Recommendation 1.1New patients with pulmonary B should receive a regimen containing 6 months

o riampicin: 2HRZE/4HR

(Strong/High grade o evidence)

Remark a: Recommendation 1.1 also applies to extrapulmonary B, except B o

the central nervous system, bone or joint or which some expert groups suggest

longer therapy (see Chapter 8).

Remark b: WHO recommends that national B control programmes ensure that

supervision and support are provided or all B patients in order to achieve com-

pletion o the ull course o therapy.

Remark c: WHO recommends drug resistance surveys (or surveillance) or moni-

toring the impact o the treatment programme as well as or designing standard

regimens.

L Recommendation 1.2

Te 2HRZE/6HE treatment regimen should be phased out


Qesti 2. dsig eqec i ew ptiets

When a country selects 2HRZE/4HR, should patients be treated with a daily or three

times weekly intensive phase?


Wherever easible, the optimal dosing requency or new patients with pulmo-

nary B is daily throughout the course o therapy


Tere are two alternatives to Recommendation 2.1:

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3

ExECuTIVE Summary

L Recommendation 2.1A

New patients with pulmonary B may receive a daily intensive phase

ollowed by a three times weekly continuation phase [2HRZE/4(HR)3], pro-

vided that each dose is directly observed(Conditional/High and moderate grade o evidence)

L Recommendation 2.1B

Tree times weekly dosing throughout therapy [2(HRZE)3/4(HR)

3] may be

used as another alternative to Recommendation 2.1, provided that every

dose is directly observed and the patient is NO living with HIV or living in

an HIV-prevalent setting

(Conditional/High and moderate grade o evidence)

Remark a: reatment regimens or B patients living with HIV or living in

HIV-prevalent settings are discussed in Recommendation 4 and Chapter 5.

Remark b: In terms o dosing requency or HIV-negative patients, the system-

atic review ound little evidence o dierences in ailure or relapse rates with

daily or three times weekly regimens (see Annex 2). However, rates o acquired

drug resistance were higher among patients receiving three times weekly dosing

throughout therapy than among patients who received daily drug administra-

tion throughout treatment. Moreover, in patients with pretreatment isoniazid

resistance, three times weekly dosing during the intensive phase was associ-

ated with signicantly higher risks o ailure and acquired drug resistance than

daily dosing during the intensive phase.


New patients with B should not receive twice weekly dosing or the ull course

o treatment unless this is done in the context o ormal research


Remark: Te available evidence showed equivalent ecacy o daily intensive-phase dosing ollowed by two times weekly continuation phase. However, twice

weekly dosing is not recommended on operational grounds, since missing one

dose means the patient receives only hal the regimen.

Qesti 3. Iiti egie i cties with high eves isiziesistce

In countries with high levels o isoniazid resistance in new B patients, should the

continuation phase (containing isoniazid and riampicin) be changed in the stan-dard treatment o all new patients, in order to prevent the development o multidrug

resistance?1

1 Tis question applies to countries where isoniazid susceptibility testing in new patients is not done (orresults are not avai lable) beore the continuation phase begins.

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L Recommendation 3

In populations with known or suspected high levels o isoniazid resistance, new

B patients may receive HRE as therapy in the continuation phase as an accept-

able alternative to HR(Weak/Insucient evidence, expert opinion)

Remark a: While there is a pressing need to prevent multidrug resistance (MDR),

the most eective regimen or the treatment o isoniazid-resistant B is not known.

Tere is inadequate evidence to quantiy the ability o ethambutol to protect

riampicin in patients with pretreatment isoniazid resistance. Te evidence or

ocular toxicity rom ethambutol was not systematically reviewed or this revision,

but the risk o permanent blindness exists. Tus, urther research (see Annex 5) is

urgently needed to dene the level o isoniazid resistance that would warrant theaddition o ethambutol (or other drugs) to the continuation phase o the standard

new patient regimen in B programmes where isoniazid drug susceptibility test-

ing is not done (or results are unavailable) beore the continuation phase begins.

Remark b: Daily (rather than three times weekly) intensive-phase dosing may also

help prevent acquired drug resistance in B patients starting treatment with iso-

niazid resistance. Te systematic review (Annex 2) ound that patients with isoni-

azid resistance treated with a three times weekly intensive phase had signicantly

higher risks o ailure and acquired drug resistance than those treated with daily

dosing during the intensive phase.

Qesti 4. Tb tetet i pess ivig with HIV

Should intermittent regimens be used or persons living with HIV? What should be

the duration o B treatment in people living with HIV?

Remark: Current WHO recommendations promoting the use o antiretroviral thera-

py in B patients living with HIV should be put rapidly into practice.

L Recommendation 4.1B patients with known positive HIV status and all B patients living in HIV-

prevalent settings should receive daily B treatment at least during the inten-

sive phase


Remark: HIV-prevalent settings are dened as countries, subnational administra-

tive units, or selected acilities where the HIV prevalence among adult pregnant

women is 1% or among B patients is 5%.


For the continuation phase, the optimal dosing requency is also daily or these

patients


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5


I a daily continuation phase is not possible or these patients, three times

weekly dosing during the continuation phase is an acceptable alternative



It is recommended that B patients who are living with HIV should receive at least

the same duration o B treatment as HIV-negative B patients


Remark a: Some experts recommend prolonging B treatment in persons living

with HIV (see Chapter 5).

Remark b: Previously treated B patients who are living with HIV should receivethe same retreatment regimens as HIV-negative B patients.

Recommendations 14 (as they relate to new patients) are summarized in able A

below, and shown in ables 3.2 and 3.3 in Chapter 3.

Tab A STAndArd regimen And doSing requency or new TB pATienTS

Itesive phse Ctiti phse Cets

2 ths HrZea 4 ths Hr

2 ths HrZe 4 ths Hre As ts th hh vs saz ssta TB atts, a

h saz sstbt tst atts s t ( sts a

avaab) b th tat hasbs

a wHo s ss thabt th tsv has tatt

atts th -avta, sa-atv a TB taa sas h a k

t b HiV-atv.

dsig eqecCets

Itesive phse Ctiti phse

da da ota

da 3 ts k Atab atatv a TB att

v t bsv tha

3 ts k 3 ts k Atab atatv v that th

att s v t bsv thaa s noT v th HiV v a HiV-

vat stt (schat 5)

Note: da (ath tha th ts k) tsv-has s a h t vt a

ssta TB atts stat tatt th saz ssta (s A 2).

ExECuTIVE Summary

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6


Qesti 5. Spt itig ig Tb tetet se-psitivep Tb ptiets

In pulmonary B patients who are initially smear positive, how eective is moni-

toring sputum specimens or predicting relapse, ailure and pretreatment isoniazidresistance?

Figures 4.1 and 4.2 in Chapter 4 illustrate Recommendations 5.15.3.


For smear-positive pulmonary B patients treated with rst-line drugs, sputum

smear microscopy may be perormed at completion o the intensive phase o

treatment


Remark a: Tis recommendation applies both to new patients treated with regimens

containing 6 months o riampicin, and to patients returning aer deault or relapse

and now receiving the 8-month retreatment regimen (2HRZES/1HRZE/5HRE).

Note that the end o the intensive phase may be at 2 months or 3 months, depend-

ing on the regimen.

Remark b: Available evidence showed that smear status at the end o the intensive

phase is a poor predictor o relapse, ailure and pretreatment isoniazid resistance.

Nonetheless, WHO continues to recommend perorming smear microscopy atthis stage because a positive smear should trigger an assessment o the patient,

as well as additional sputum monitoring (see Recommendations 5.2 and 5.3).

Sputum smear conversion at the end o the intensive phase is also an indicator o

B programme perormance.


In new patients, i the specimen obtained at the end o the intensive phase

(month 2) is smear-positive, sputum smear microscopy should be obtained at

the end o the third month



In new patients, i the specimen obtained at the end o month 3 is smear-positive,

sputum culture and drug susceptibility testing (DS) should be perormed


Remark: National B control programmes (NPs) should continue to ollow

the current WHO recommendation to obtain sputum specimens or smear mi-

croscopy at the end o months 5 and 6 or all new pulmonary B patients who

were smear-positive at the start o treatment. Patients whose sputum smears are

positive at month 5 or 6 (or who are ound to harbour MDR-B strains at any

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7

time) will be re-registered as having ailed treatment and be treated according to

Recommendation 7 below.


In previously treated patients, i the specimen obtained at the end o the inten-sive phase (month 3) is smear-positive, sputum culture and drug susceptibility

testing (DS) should be perormed


Qesti 6. Tetet etesi i ew p Tb ptiets

In new pulmonary B patients, how eective is extension o treatment or preventing

ailure or relapse?

L Recommendation 6

In patients treated with the regimen containing riampicin throughout treat-

ment, i a positive sputum smear is ound at completion o the intensive phase,

the extension o the intensive phase is not recommended


Remark: WHO recommends that a positive sputum smear at completion o the

intensive phase should trigger a careul review o the quality o patient support

and supervision, with prompt intervention i needed (see Chapter 4). It should alsotrigger additional sputum monitoring, as per Recommendations 5.2, 5.3 and 5.4.

Qesti 7. Pevis tete ptiets

Which (i any) groups o patients should receive a retreatment regimen with rst-line

drugs?

able 3.5 in Chapter 3 shows Recommendations 7.17.4.


Specimens or culture and drug susceptibility testing (DS) should be obtainedrom all previously treated B patients at or beore the start o treatment. DS

should be perormed or at least isoniazid and riampicin

Remark a: DS may be carried out by rapid molecular-based methods or by con-

ventional methods. Sputum should be obtained, as well as appropriate specimens

or extrapulmonary B, depending on the site o disease.

Remark b: Obtaining specimens or culture and DS should not delay the start o

treatment. Empirical therapy should be started promptly, especially i the patient

is seriously ill or the disease is progressing rapidly.

ExECuTIVE Summary

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8



In settings where rapid molecular-based DS is available, the results should

guide the choice o regimen

L Recommendation 7.3In settings where rapid molecular-based DS results are not routinely available

to guide the management o individual patients, empirical1 treatment should be

started as ollows:

L Recommendation 7.3.1

B patients whose treatment has failed2 or other patient groups with high

likelihood o multidrug-resistant B (MDR-B) should be started on an em-

pirical MDR regimen

Remark a: In the absence o culture and DS results, the patient should be clini-

cally evaluated beore the MDR regimen is administered.

Remark b: Other examples o patients with high likelihood o MDR-B are

those relapsing or deaulting aer their second or subsequent course o treat-

ment. See also section 3.8.2.

L Recommendation 7.3.2

B patients returning afer deaulting or relapsing rom their rst treat-

ment course may receive the retreatment regimen containing rst-line drugs

2HRZES/1HRZE/5HRE i country-specic data show low or medium levels

o MDR in these patients or i such data are unavailable

Remark: When DS results become available, regimens should be adjusted

appropriately.


In settings where DS results are not yet routinely available to guide the man-

agement o individual patients, the empirical regimens will continue through-

out the course o treatmentL Recommendation 7.5

National B control programmes should obtain and use their country-specic

drug resistance data on ailure, relapse and deault patient groups to determine

the levels o MDR.

1 In these guidelines, empirical means providing treatment beore (or without) knowing whether the

patients B organisms are MDR or not.2 Failures in a well-run NP should be inrequent in the absence o MDR-B. I they do occur, they are

due either to MDR-B or to programme actors such as poor DO or poor drug quality. I drug resis-tance data rom ailure patients are avai lable and show low or medium levels o MDR, patients shouldreceive the retreatment regimen outlined in section 7.3.2., and every eort should be made to addressthe underlying programmatic issues.

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9

Remark: Country-specic drug resistance data should include data stratied by

type o regimen given or the patients rst course o B treatment (i.e. 2 vs 6

months o riampicin).

able B below lists key changes in this ourth edition, compared to the 2004 updateo the third edition.1

Tab B Key cHAngeS Since THe THird ediTion

Chapter 1. IntroduCtIon

Te scope is now limited to treatment o B in adults. Te ourth edition no longer

covers:

B case detection and diagnosis;

diagnosis and treatment o B in children (WHO has published a separateguideline on management o childhood B);

drug supply management.

Instead o Diagnostic categories IIV, this edition uses the same patient regis-

tration groups used or recording and reporting, which dierentiate new patients

rom those with prior treatment and speciy reasons or retreatment.

Each applicable standard rom the International Standards or B Care is cross-

reerenced.

An expiry date is provided.

Chapter 2. Case defInItIons

Te recent WHO case denition or sputum smear-positive pulmonary B2 has

been applied to a denite case o B, so that now a patient with one positive AFB

smear is considered a denite case in countries with a unctional external quality

assurance (EQA) system. (In the third edition, two positive smears were required

beore a patient could be considered a denite case.)

Bacteriology now includes culture and new methods or identication oM. tuber-culosis.

New WHO data elements or recording and reporting, such as HIV status and

MDR-B, are included.

Severity o disease is no longer included as a eature o the case denition.

In the denition or smear-negative B, this edition incorporates WHO policy

reducing the number o specimens rom three to two or screening patients sus-

pected to have B. Tis policy applies only in settings where a well-unctioning

EQA system exists, the workload is very high, and human resources are limited.3

1 http://www.who.int/tb/publications/cds_tb_2003_313/en/index.html2 http://www.who.int/tb/dots/laboratory/policy/en/index1.html3 http://www.who.int/tb/dots/laboratory/policy/en/index2.html

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In settings with an HIV prevalence >1% in pregnant women or 5% in B patients,

sputum culture or Mycobacterium tuberculosis should be perormed in patients

who are sputum smear-negative to conrm the diagnosis o B.

A trial o broad-spectrum antibiotics is no longer recommended to be used as adiagnostic aid or smear-negative pulmonary B in persons living with HIV.

For HIV-negative patients, the ourth edition species that, i broad-spectrum

antibiotics are used in the diagnosis o smear-negative pulmonary B, anti-B

drugs and fuoroquinolones should be avoided.

Pulmonary B cases without smear results are no longer classied as smear-

negative. Instead, they are labelled smear not done on the B register and in the

annual WHO survey o countries.

Consistent with Standard 3 o the International Standards or B Care, culture and

histopathological examination are recommended or specimens rom suspected

extrapulmonary sites o B. Examination o sputum and a chest radiograph are

also suggested, in case patients have concomitant pulmonary involvement.

Te patient registration group Other no longer includes chronic. Instead,

patients whose sputum is smear-positive at the end o (or returning rom) a sec-

ond or subsequent course o treatment are classied by the outcome o their most

recent retreatment course: relapsed, deaulted or ailed.

Chapter 3. standard treatment regImens

Additional dosage inormation is provided or isoniazid (maximum daily dose or

three times per week) and streptomycin (maximum dose, and adjustments in per-

sons aged over 60 years or weighing less than 50 kg). Tioacetazone is no longer

included among the rst-line drugs.

A new section on B patient kits has been added.

Te recommended new patient regimen contains 6 months o riampicin; the

regimen with 2 months o riampicin (with the 6-month continuation phase oisoniazid and ethambutol) is no longer an option.

In this edition, three times weekly dosing throughout therapy is an alternative only

or patients who are receiving directly observed therapy o every dose and who are

not HIV-positive or living in an HIV-prevalent setting. Tree times weekly dosing

during the intensive phase is no longer an option or HIV-positive B patients or

B patients living in HIV-prevalent settings.

WHO now recommends against twice weekly dosing or the ull course o treat-

ment or new patients (unless done in the context o ormal research).Te third

edition included the option to omit ethambutol during the intensive phase o

treatment or patients with non-cavitary, smear-negative pulmonary B or extra-

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pulmonary disease who are known to be HIV-negative. In the ourth edition, the

omission o ethambutol is no longer recommended.

Tis ourth edition includes an alternative continuation phase o ethambutol,

riampicin, and isoniazid or new patients in populations with high levels o isoni-azid resistance. Tis conditional recommendation applies where isoniazid suscep-

tibility testing in new patients is not done (or results are not available) beore the

continuation phase begins.

DS beore or at the start o therapy is strongly recommended or all previously

treated patients.

Previously treated patients are dened by their likelihood o MDR-B, and rec-

ommendations or treatment regimen depend on reason or retreatment (ailure,

versus relapse and deault).

Laboratory tests (liquid media, line probe assays) to meet the needs or the prompt

identication oM. tuberculosis and DS are discussed, based on country-specic,

comprehensive plans or laboratory strengthening.

Guidance or starting therapy is provided or previously treated patients, based

on whether the country has access to new rapid molecular-based tests, access to

conventional DS, or no routine access to DS results to guide management o

individual patients.

In countries using conventional DS, a standard empirical MDR regimen is rec-

ommended or patients with high likelihood o MDR, while awaiting DS results.

When DS results become available, regimens should be adjusted appropriately.

An MDR regimen is now recommended as one o each countrys standard regi-

mens, or use in conrmed MDR-B cases as well as in patients with a high likeli-

hood o MDR while awaiting DS results. Tis edition also gives interim guidance

to countries where DS is not yet routinely available or individual retreatment

patients.

Given the availability o unding rom international nancial mechanisms, lack o

resources or MDR treatment is no longer an acceptable rationale or providing a

retreatment regimen o rst-line drugs (ormerly called the Category 2 regimen)

to patients with a high likelihood o MDR.

Te previous edition recommended the 8-month retreatment regimen with rst-

line drugs or all B patients returning aer deaulting or relapsing. By contrast,

this edition allows or the possibility that, in some countries, these patients may

have levels o MDR-B that are high enough to warrant an MDR regimen whileawaiting results o DS.

WHO does not intend to establish thresholds or low, moderate, or high likeli-

hoods or levels o MDR. NPs will dene low, moderate and high or their

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own countries, based on levels o MDR in specic patient groups, as well as other

actors such as MDR treatment resources available during scale-up, and requency

o concomitant conditions (such as HIV) that increase the short-term risk o dying

rom MDR-B. Country drug resistance surveys, WHO estimates o MDR levels, and other data

sources are recommended to inorm decisions on each countrys standard treat-

ment regimens or dened patient groups.

Intermittent dosing is no longer an option or previously treated patients receiving

the 8-month retreatment regimen with rst-line drugs.

Chapter 4. monItorIng durIng treatment

Te perormance o sputum smear microscopy at the completion o the inten-

sive phase o treatment is a conditional, rather than a strong, recommendation,

given the evidence that a positive smear at this stage has a very poor ability to pre-

dict relapse or pretreatment isoniazid resistance (Annex 2). However, its utility in

detecting problems with patient supervision and or monitoring programme per-

ormance is rearmed.

In addition, this edition recommends that a positive sputum smear at the end o

the intensive phase in new patients should trigger sputum smear microscopy at

the end o the third month. I the latter is positive, culture and DS should be

perormed.

Tis edition no longer recommends extension o the intensive phase or patients

who have a positive sputum smear at the end o the second month o treatment.

In previously treated patients, i the specimen obtained at the end o the intensive

phase (month 3) is smear-positive, this edition recommends that sputum culture

and DS be perormed then, rather than waiting until month 5 (which was recom-

mended in the third edition).

Te outcome o cure now encompasses culture results. Patients ound to harbour an MDR-B strain at any point during treatment are

now classied as treatment ailure. Tey are re-registered and begin an MDR

regimen.

For MDR-B patients, this edition recommends the use o the MDR-B register

and cohort analysis.

Te symptom-based approach to side-eects o anti-B drugs has been revised.

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Chapter 5. Co-management of hIV and aCtIVe tB dIsease

Provider-initiated HIV testing or all patients with known or suspected B is now

recommended, regardless o the stage o the countrys HIV epidemic.

Tis edition includes current WHO recommendations to start co-trimoxazole as

soon as possible when a person living with HIV is diagnosed with B.

Daily dosing is strongly recommended during the intensive phase or B patients

with known positive HIV status, and all new patients living in HIV-prevalent

settings. Tree times per week dosing during the intensive phase is no longer an

acceptable alternative.

Current WHO recommendations or antiretroviral therapy and timing o initia-

tion are incorporated. Drug susceptibility testing is now recommended at the start o B therapy in all

people living with HIV.

Chapter 6. superVIsIon and patIent support

Roles o the patient, B programme sta, the community, and other providers

are described in assuring adherence to treatment. A treatment supporter must be

identied or each B patient, which may be a health worker, or a trained and

supervised member o the community or amily.

reatment supervision is dened in the context o a larger support package to

address patients needs.

Chapter 7. treatment of drug-resIstant tB

Tis chapter has been extensively revised to refect recent WHO recommendations

or the programmatic management o drug-resistant B.

Chapter 8. tB treatment of extrapulmonary dIsease and of tB In

speCIal sItuatIons

While WHO continues to recommend the same regimens or extrapulmonaryand pulmonary disease, this ourth edition reerences other guidelines suggesting

longer treatment or B meningitis and or bone or joint B.

For B patients with pre-existing liver disease, this ourth edition includes regi-

mens with one, two and no hepatotoxic drugs. A 9-month regimen o riampicin

and ethambutol is no longer included as an option.

For B patients with renal ailure, this edition recommends the 6-month regimen

with isoniazid, riampicin, ethambutol and pyrazinamide, whereas the prior edi-

tion omitted pyrazinamide. Tis edition recommends administering ethambutol(15 mg/kg) and pyrazinamide (25 mg/kg) three times per week. Tis edition now

discourages the use o streptomycin in patients with renal ailure; however, i it

must be used, 15 mg/kg should be administered two to three times per week, with

monitoring o drug levels.

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annexes

ae 1

Riampicin: includes a list o drugs which interact with riampicin. Streptomycin: dosage adjustments or the elderly and adults weighing less than

50 kg are provided.

Ethambutol: creatinine clearance

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1

itrocto

1.1 Chpte jectives

Tis chapter denes the purpose, target audience, scope and development o this

ourth edition o the guidelines. It also explains why a new edition was needed and

projects a date or the next revision.

1.2 Ppse the gieiesTe principal purpose o these guidelines is to help national B control programmes

(NPs) in setting B treatment policy to optimize patient cure: curing patients will

prevent death, relapse, acquired drug resistance, and the spread o B in the commu-

nity. Teir urther purpose is to guide clinicians working in both public and private

sectors.

1.3 Tget iece

Te primary target audience or the guidelines is the managers and sta o NPs,

together with other B service providers working in public and private health care

acilities at the central and peripheral levels.

Use o the term NP manager in these guidelines reers to the ocial within, or

designated by, the ministry o health who is responsible or the B programme or to

that ocials designee.

1.4 Scpe

Tese guidelines address the treatment o active B disease in adults. Tey exclude

many related topics that have already been covered in detail in other publications:

diagnosis, laboratory standards or smear microscopy, protocols or use o rapid drug

susceptibility tests, paediatric B, drug procurement and supply management, in-

ection control, intensied case-nding in persons living with HIV, and isoniazid

preventive therapy.

1.5 Wh ew eiti?

Major progress in global B control ollowed the widespread implementation o the

DOS strategy. Te Stop B Strategy, launched in 2006, builds upon and enhancesthe achievements o DOS (1): new objectives include universal access to patient-

centred treatment, and protection o populations rom B/HIV coinection and

multidrug-resistant B (MDR-B). Te Stop B Strategy and the Global Plan (2) to

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implement the new strategy made it necessary to revise the existing guidelines (3)

and develop this ourth edition.

Historically, the greatest emphasis o B control activities has been on the most in-

ectious patients those who have sputum smear-positive pulmonary tuberculosis(3). Tis changed with the Stop B Strategys emphasis on universal access or all

persons with B to high-quality, patient-centred treatment (1). However, highly in-

ectious, smear-positive patients remain the primary ocus or other aspects o B

control, including contact tracing and inection control. Te Patients Charter or B

Care species that all B patients have the right to ree and equitable access to B

care, rom diagnosis through treatment completion (4).

Tis ourth edition o the guidelines has thereore abandoned Categories IIV, which

were used to prioritize patients or treatment.1

According to this prior categorization,smear-negative B patients were assigned third priority and MDR-B patients ourth

priority. For treatment decisions it no longer makes sense to assign third priority

to smear-negative patients given their high mortality i they are living with HIV.

Equally, MDR-B patients should not be assigned ourth priority, given their high

mortality and the urgent need to prevent the spread o these deadliest B strains.

o replace Categories IIV, this ourth edition groups patients (and standard regi-

mens recommended or each group) according to the likelihood o their having

drug resistance. Drug resistance is a critical determinant o treatment success, and

prior B treatment coners an increased risk (5, 6). Tis edition uses the same patient

registration groups as those used or recording and reporting, which dierentiate

new patients rom those who have had prior treatment (7). Registration groups or

previously treated patients are based on the outcome o their prior treatment course:

ailure, relapse, and deault.

Te ourth edition integrates detection and treatment o both HIV inection and

MDR-B, and thus should contribute towards achievement o the Stop B Strategys

universal access to high-quality MDR-B and HIV care.

With regard to HIV detection, this edition incorporates recent WHO recommenda-

tions or provider-initiated HIV testing o all persons with diagnosed or suspected

B, in all types o HIV epidemics (low-level, concentrated or generalized) (8). For

treatment o B in persons living with HIV, new recommendations on the dura-

tion o therapy and the role o intermittent regimens have emerged rom systematic

reviews (see Chapter 5). Te new edition also includes recent WHO recommenda-

tions or DS at the start o B therapy in all people living with HIV (9), as well as

recommendations on the timing and type o antiretroviral therapy (AR) regimens

(10).1 Also, the original one-to-one correspondence between patient group and treatment regimens was lost

as Categories IIV were redened over the years. Te same treatment regimen came to be recommend-ed or patients in Categories I and III; aer 2004, dierent treatment regimens were recommended orpatients in Category II depending on actors such as programme perormance and drug resistance.

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New developments in MDR-B also contributed to the need or this revision. Build-

ing on the principle o universal access to MDR-B diagnosis and care, Te MDR-B

and XDR-B response plan 20072008 (11) calls or the diagnosis and treatment o

MDR-B in all countries by 2015. Even countries with low overall levels o multidrugresistance (MDR) are aced with B patients who have been previously treated a

group that is ve times more likely to have MDR-B than new patients (see section

3.6).

In terms o ensuring universal access to MDR-B diagnosis, this ourth edition rea-

rms existing WHO recommendations (2) that all previously treated patients should

have access to culture and DS at the beginning o treatment, in order to identiy

MDR-B as early as possible.1 It also incorporates the WHO recommendation that

treatment ailure be conrmed by culture and DS (9). In order to detect MDR soon-

er than the end o the h month o treatment, this edition includes the existing

WHO recommendation (9) or culture and DS i patients still have smear-positive

sputum at the end o the third month o treatment.

Chapters 25 o this new edition discuss the critical role o the identication oMyco-

bacterium tuberculosis and o DS. Tis is in contrast to the previous edition, which

relied almost exclusively on smear microscopy or case denition, assignment o stand-

ard regimens, and monitoring o treatment response. Line probe assays can identiy

MDR-B within hours and liquid media can do so within weeks (rather than months

when solid media are used) (12). Tese techniques should be introduced in line withcomprehensive, country-specic plans or laboratory capacity strengthening.

o move towards universal access to MDR-B treatment, the ourth edition includes

a new recommendation or every country to include an MDR regimen in its stand-

ard regimens. Tis is essential while awaiting DS results or patients with a high

likelihood o MDR (such as those whose prior treatment with a 6-month riampicin

regimen has ailed), and or patients in whom resistance to isoniazid and riampicin is

conrmed. With the availability o unding rom international nancial partners,2 lack

o resources or MDR-B treatment is no longer an acceptable rationale or providingthe 8-month retreatment regimen with rst-line drugs (ormerly called the Category

II regimen) to patients with a high likelihood o MDR; this regimen is ineective in

treating MDR-B and may result in amplication o drug resistance (5, 13).

Use o rapid DS methods will eventually render the 8-month retreatment regimen

o rst-line drugs obsolete. In the meantime, the regimen is retained in this ourth

edition in only two circumstances. In countries with access to routine DS using

conventional methods, the 8-month retreatment regimen with rst-line drugs is

recommended while awaiting DS results rom patients who have relapsed or are

returning aer deault (i country-specic data show they have a medium likelihood

1 Tis recommendation is consistent with the International Standards or uberculosis Care and resolu-tions endorsed by the World Health Assembly in 2007 which call or universal access to DS by 2015.

2 Such as UNIAID and the Global Fund to Fight AIDS, uberculosis and Malaria.

1. InTroduCTIon

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o MDR-B, or i such data are unavailable). In countries that do not yet have DS

routinely available at the start o treatment or all previously treated patients (see sec-

tion 3.7.3), the 8-month retreatment regimen with rst-line drugs will be used or the

duration o treatment on an interim basis until laboratory capacity is available.In principle, MDR treatment should be introduced only in well-perorming DOS

programmes. Beore ocusing on curing MDR-B cases, it is critical to turn o the

tap, i.e. to strengthen poor programmes so that they stop giving rise to MDR-B.

Following this principle, the 2004 revision o the treatment chapter1 listed adequate

perormance o a countrys overall B programme as a requirement or the use o

MDR regimens in patients with a high likelihood o MDR. Tis is no longer a pre-

requisite in the ourth edition. In some countries with limited DOS coverage, there

may be an appropriate setting or an MDR pilot project that, once established, can

provide a model and an impetus or the expansion o basic DOS into more areas.

In most countries, however, conditions or initiating an MDR component in most

NPs are not met until the overall NP has the essential elements o DOS rmly

in place.

1.6 methg

Development o the ourth edition o the guidelines ollowed new WHO procedures.

WHO dened the scope o revision and convened a guidelines group o external

experts. All members o the group completed a Declaration or the Confict o Inter-est; there were no conficts declared. With input rom the Guidelines Group, WHO

identied seven key questions on the treatment o B (see Annex 2) covering the

ollowing topics:

duration o riampicin in new patients;

dosing requency in new patients;

initial regimen or new B patients in countries with high levels o isoniazid

resistance;

B treatment in persons living with HIV; sputum monitoring during B treatment;

treatment extension;

retreatment.

Systematic literature reviews were conducted or each question and the evidence was

synthesized2 (see Annex 2).

Input rom the Guidelines Group to the revision o guidelines was made by e-mail, in

conerence calls and at a 3-day meeting (2123 October 2008) during which the nal

treatment recommendations were established once consensus had been reached by1 reatment o tuberculosis: guidelines or national programmes, 3rd ed. Chapter 4, Standard treatment

regimens, was revised in June 2004 and the new version was posted on the WHO web site.2 At the time o publication o this ourth edition, evidence gathered through some o the systematic

reviews had not been published.

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the Guidelines Group. Te recommendations are based on the quality o the evidence,

values, and costs, as well as judgements about trade-os between benets and harm.

Te group graded the strength o each recommendation, refecting the degree o con-

dence that the desirable eects o adherence to a recommendation outweigh theundesirable eects. Although the degree o condence is necessarily a continuum,

three categories are used strong, conditional and weak. Te quality o the evidence

was assessed according to the GRADE methodology (14).

Moderate/low quality o evidence means that the estimate o eect o the interven-

tion is very uncertain and urther research is likely to have an important impact on

condence in the estimate. For high-quality evidence, by contrast, urther research

is unlikely to change condence in the estimate o eect.

A strong recommendation means that the desirable eects o adherence to the rec-ommendation clearly outweigh the undesirable eects. Strong recommendations use

the words should or should not. No alternatives are listed.

A conditional recommendation means that the desirable eects o adherence to the

recommendation probably outweigh the undesirable eects, but the trade-os are

uncertain. Reasons or lack o certainty include:

high-quality evidence to support the recommendation is lacking;

benets o implementing the recommendation are small;

benets may not justiy the costs;

it was not possible to arrive at precise estimates o benet.

A weak recommendation means that there is insucient evidence; the recommenda-

tion is thereore based on eld application and expert opinion.

Conditional and weak recommendations use the word may. Alternatives are listed

or several o the conditional recommendations.

able 1.1 shows how strong and conditional recommendations dier in terms both

o wording and o the actors used to judge their strength. Strong and conditionalrecommendations also have dierent implications or policy-makers, patients, and

health care providers; these are summarized in the table.

A plan or implementing and evaluating the strong recommendations is outlined in

Annex 4. o address the gaps in the evidence critical or decision-making, the Guide-

lines Group developed a series o questions as a basis or uture research; these are

detailed in Annex 5. Members o the Guidelines Group are listed in Annex 6.

Te recommendations that address the seven key questions appear in the context

o guidance on standard treatment (Chapter 3), monitoring (Chapter 4) and HIV(Chapter 5). Areas outside the scope o those questions have been updated with cur-

rent reerences and WHO B policies but were not the subject o systematic literature

reviews or o new recommendations by the Guidelines Group.

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Tab 1.1 STrong VerSuS condiTionAl recommendATionS

receti s tegth

Stg Citi

Phsig theeceti

Sh sh t.n atatvs a st

opti is, , itis (t) ecee.Atatvs a t st

cts se t jge stegth

qat v Hh-at v l-at v

Baa btsab a sab

ts att ab hath

la, ta t bt a/ bt bts a

has bs

Sa a/ taat

rs aat l st ( t t tatabt hth th tvtsts a s s

ss)

Hh st ( hhtat)

utat vas a

s; vaabtass atts

Sa at tat

vaabt

la at tat

vaabt

Ipictis

pic-kes

( nTpaas)

Th at sh

va b s stt

p-ak

tsv bat

ptiets mst vas at th s at

Th s at a b ajst th bass asbt a

atabt heth ce

pviesmst atts sh b tat

a t th s at. Ah

t ths at s aasab as

at a

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21

Te dra guidelines were circulated to the external review group (whose members

are listed in Annex 6), made up o NP managers rom high-burden countries, mem-

bers o the WHO Strategic, echnical and Advisory Group on B (SAG-B), six

regional B Advisers and B medical ocers working in high-burden countries.Comments received rom the external review group were appropriately addressed

and the ew disagreements between the external reviewers and the Guidelines Group

were resolved by e-mail consultation.

1.7 Iteti Sts Tecsis Ce

Te International Standards or uberculosis Care (ISC) (15) describe a widely ac-

cepted level o B care that all practitioners should seek to achieve. Cross-reerencing

the applicable ISC standards in this new edition should help providers in both pub-lic and private sectors to ensure their implementation.

1.8 Epi te

Te WHO Stop B Department will review and update these guidelines aer 35

years or as needed when new evidence, treatment regimens or diagnostic tests

become available.

reeecesRaviglione MC, Uplekar MW. WHOs new stop B strategy.1. Lancet, 2006, 367:952

955.

Te global plan to stop B, 200620152. . Geneva, World Health Organization, 2006

(WHO/HM/SB/2006.35).

reatment o tuberculosis: guidelines or national programmes3. , 3rd ed. Geneva, World

Health Organization, 2003 (WHO/CDS/B/2003.313).

Patients charter or tuberculosis care: patients rights and responsibilities4. . Geneva,

World Care Council, 2006 (available at: www.who.int/tb/publications/2006/patients_

charter.pd).

Espinal MA et al. Standard short-course chemotherapy or drug-resistant tuberculo-5.sis: treatment outcomes in 6 countries.Journal o the American Medical Association,

2000, 283:25372545.

Aziz MA et al. Epidemiology o antituberculosis drug resistance (the Global Project6.

on Anti-tuberculosis Drug Resistance Surveillance): an updated analysis. Lancet,

2006, 368:21422154.

Revised B recording and reporting orms and registers version 20067. . Geneva, World

Health Organization, 2006 (WHO/HM/B/2006.373; available at: www.who.int/

tb/dots/r_and_r_orms/en/index.html).

Guidance on provider-initiated HIV testing and counselling in health acilities8. .Geneva, World Health Organization, 2007.

Guidelines or the programmatic management o drug-resistant tuberculosis: emer-9.

gency update 2008. Geneva, World Health Organization, 2008 (WHO/HM/B/

2008.402).

1. InTroduCTIon

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Antiretroviral therapy or HIV inection in adults and adolescents in resource-limited10.

settings: recommendations or a public health approach. Geneva, World Health Or-

ganization, 2006.

Te global MDR-B & XDR-B response plan 2007200811. . Geneva, World Health Or-

ganization, 2007 (WHO/HM/B/2007.387).

Molecular line probe assays or rapid screening o patients at risk o MDR B: policy12.

statement. Geneva, World Health Organization, 2008 (available at: www.who.int/tb/

eatures_archive/policy_statement.pd).

Espinal MA. ime to abandon the standard retreatment regimen with rst-line13.

drugs or ailures o standard treatment. International Journal o uberculosis and

Lung Disease, 2003, 7:607608.

Guyatt GH et al. GRADE: an emerging consensus on rating quality o evidence and14.

strength o recommendations. British Medical Journal, 2008, 336:924926.

International Standards or uberculosis Care (ISC)15. , 2nd ed. Te Hague, uberculo-sis Coalition or echnical Assistance, 2009.

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23

2

Ca fto

2.1 Chpte jectives

Tis chapter describes

the purpose o having case denitions or tuberculosis;

the denition o a case o B, as well as o suspected and conrmed cases;

additional eatures o B cases important or the treatment o individual pa-

tients, as well as or evaluating B programmes and monitoring the epidemic.Te diagnosis o B reers to the recognition by health workers (medical ocer,

nurse, paramedic or other) o an active case, i.e. a patient with current disease due to

M. tuberculosis. Te role o NPs is dierent: they are responsible or ensuring that

diagnosed cases are notied (1), meet the denition or case or denite case, and are

treated appropriately, and that outcomes are evaluated.1

All providers must report both new and retreatment B cases and their treatment

outcomes to local public health authorities, in conormance with applicable legal re-

quirements (Standard 21 o the ISC (5)). NPs ensure that critical eatures o the Bcase are recorded and reported so that treatment is appropriate and eedback is pro-

vided to the treating clinician (6). Analysis o these reports also helps the NP man-

ager to monitor trends and evaluate the eectiveness o B activities at all levels.

2.2 Ppses efig Tb cse

Uniorm criteria to dene a B case are needed or:

proper patient registration and case notication;

selecting appropriate standard treatment regimens (see Chapter 3); standardizing the process o data collection or B control;

evaluating the proportion o cases according to site, bacteriology and treat-

ment history;

cohort analysis o treatment outcomes;

accurate monitoring o trends and evaluation o the eectiveness o B pro-

grammes within and across districts, countries and global regions.

2.3 Cse efitis

Te B case denitions below are based on the level o certainty o the diagnosis and

on whether or not laboratory conrmation is available.

1 NP programmes also acilitate the detection o cases via sputum screening o suspects with coughattending health acilities (2), as well as screening o contacts (3) and screening o persons living withHIV/AIDS (4).

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uberculosis suspect. Any person who presents with symptoms or signs sugges-

tive o B. Te most common symptom o pulmonary B is a productive cough or

more than 2 weeks,1 which may be accompanied by other respiratory symptoms

(shortness o breath, chest pains, haemoptysis) and/or constitutional symptoms(loss o appetite, weight loss, ever, night sweats, and atigue).2

Case o tuberculosis. A denite case o B (dened below) or one in which a

health worker (clinician or other medical practitioner) has diagnosed B and has

decided to treat the patient with a ull course o B treatment.

Note. Any person given treatment or B should be recorded as a case. Incomplete

trial B treatment should not be given as a method or diagnosis.

Denite case o tuberculosis. A patient withMycobacterium tuberculosis complex

identied rom a clinical specimen, either by culture or by a newer method suchas molecular line probe assay. In countries that lack the laboratory capacity to

routinely identiyM. tuberculosis, a pulmonary case with one or more initial spu-

tum smear examinations positive or acid-ast bacilli (AFB) is also considered to

be a denite case, provided that there is a unctional external quality assurance

(EQA) system with blind rechecking.3

Cases o B are also classied according to the:

anatomical site o disease;

bacteriological results (including drug resistance);

history o previous treatment;

HIV status o the patient.

Each o these key eatures o B cases is discussed below.

2.4 atic site Tb isese

In general, recommended treatment regimens are similar, irrespective o site (see sec-

tion 8.2). Dening the site is important or recording and reporting purposes and to

identiy the more inectious patients those with pulmonary involvement (who will

be urther subdivided by smear status see section 2.5 below).

Pulmonary tuberculosis (PB) reers to a case o B (dened above) involving the

lung parenchyma. Miliary tuberculosis is classied as pulmonary B because there

are lesions in the lungs. uberculous intrathoracic lymphadenopathy (mediastinal

and/or hilar) or tuberculous pleural eusion, without radiographic abnormalities in

the lungs, constitutes a case oextrapulmonary B. A patient with both pulmonary

and extrapulmonary B should be classied as a case opulmonary B.

1 Standard 1 o the International Standards or B Care (5) states that all persons with otherwise unex-plained productive cough lasting 23 weeks or more should be evaluated or B.

2 Te denition o a B suspect depends on other local actors, including the patients age and HIVstatus, HIV prevalence in the population, B prevalence in the population, etc.

3 See: www.who.int/tb/dots/laboratory/policy/en/index1.html.

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Smear-negative PB cases should either:

A. have sputum that is smear-negative but culture-positive orM. tuberculosis:

a case o pulmonary B is considered to be smear-negative i at least two

sputum specimens at the start o treatment are negative or AFB1 in countries

with a unctional EQA system, where the workload is very high and human

resources are limited (see http:///www.who.int/tb/dots/laboratory/policy/en/

index2.html);

in all settings with an HIV prevalence o >1% in pregnant women or 5% in B

patients, sputum culture or M. tuberculosis should be perormed in patients

who are sputum smear-negative to conrm the diagnosis o B (4).

ORB. meet the ollowing diagnostic criteria: (68)

decision by a clinician to treat with a ull course o anti-B therapy; and

radiographic abnormalities consistent with active pulmonary B and

either:

laboratory or strong clinical evidence o HIV inection

or:

i HIV-negative (or unknown HIV status living in an area o low HIV preva-lence), no improvement in response to a course o broad-spectrum antibiot-

ics (excluding anti-B drugs and fuoroquinolones and aminoglycosides).

Pulmonary B cases without smear results are no longer classied as smear-negative

(4); instead, they are recorded as smear not done on the B register (6) and on the

annual WHO survey o countries.

For patients suspected o having EPB, specimens should be obtained rom the sus-

pected sites o involvement (Standard 3 o the ISC (5)). Where available, culture

and histopathological examination should also be carried out. Additionally, a chest

X-ray and examination o sputum may be useul, especially in persons with HIV

inection.

2.6 Hist pevis tetet: ptiet egistti gp

At the time o registration, each patient meeting the case denition is also classied

according to whether or not he or she has previously received B treatment and, i so,

the outcome (i known). It is important to identiy previously treated patients because

they are at increased risk o drug resistance, including MDR-B (see section 3.6).At the start o therapy, specimens should be obtained or culture and DS rom all

previously treated patients. reatment depends on whether the patient has relapsed

1 And no specimen is smear-positive.

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or is returning aer deault or aer prior treatment has ailed (see section 3.7). Te

distinctions between new and previously treated patients, and among the subgroups

o previously treated patients, are also essential or monitoring the B epidemic and

programme perormance.New patients have never had treatment or B, or have taken anti-B drugs or less

than 1 month. New patients may have positive or negative bacteriology and may have

disease at any anatomical site.

Previously treated patients have received 1 month or more o anti-B drugs in the

past, may have positive or negative bacteriology and may have disease at any ana-

tomical site. Tey are urther classied by the outcome o their most recent course o

treatment as shown in able 2.1 below.

Patients whose sputum is smear-positive at the end o (or returning rom) a secondor subsequent course o treatment are no longer dened as chronic. Instead, they

should be classied by the outcome o their most recent retreatment course: relapsed,

deaulted or ailed.

2. CaSE dEInITIonS

Tab 2.1 regiSTrATion group By ouTcome o moST recenT

TB TreATmenT

registti gp(a st sas)

bcteig otce st ecet pi tetet(efe i Te 4.1)

new +

Pevis tete repse + c

Tatt t

ie + Tatt a

det + dat

Tse i: A att h hasb tas ath TB

st t t tatt

+ St tatt

othe + A ass that t t th abvts, sh as atts

h t s t k hthth hav b vs tat;

h vs tat bt th

k t that vstattb (3, 8); a/

h hav t t tattth sa-atv pTB bata atv epTBb (3)

a + ats stv sa, t th as t M. tuberculosis

ats that a ss tst atv.b d as th tatt th wHo ts t abv.

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2.7 HIV stts

Determining and recording the patients HIV status is critical or treatment decisions

(see Chapters 3 and 5) as well as or monitoring trends and assessing programme

perormance. WHOs revised B reatment Card and B Register include dates oHIV testing, starting co-trimoxazole, and starting AR. Tese important interven-

tions are discussed more ully in Chapter 5.

reeeces

Engaging all health care providers in B control: guidance on implementing public-1.

private mix approaches. Geneva, World Health Organization, 2006 (WHO/HM/

B/2006.360).

WHO policy on B inection control in health care acilities, congregate settings and2.

households. Geneva, World Health Organization, 2009 (WHO/HM/B/2009.419).Implementing the WHO Stop B Strategy: a handbook or national tuberculosis control3.

programmes. Geneva, World Health Organization, 2008 (WHO/HM/B/2008.40).

Improving the diagnosis and treatment o smear-negative pulmonary and extrapulmo-4.

nary tuberculosis among adults and adolescents: recommendations or HIV-prevalent

and resource-constrained settings. Geneva, World Health Organization, 2007 (WHO/

HM/B/2007.379; WHO/HIV/2007.1).

International Standards or uberculosis Care (ISC)5. , 2nd ed. Te Hague, uberculo-

sis Coalition or echnical Assistance, 2009.

Revised B recording and reporting orms and registers version 20066. . Geneva, WorldHealth Organization, 2006 (WHO/HM/B/2006.373; available at: www.who.int/

tb/dots/r_and_r_orms/en/index.html).

Guidelines or the programmatic management o drug-resistant tuberculosis: emer-7.

gency update 2008. Geneva, World Health Organization, 2008 (WHO/HM/B/

2008.402).

Global tuberculosis control 2009: epidemiology, strategy, nancing. WHO report 20098. .

Geneva, World Health Organization, 2009 (WHO/HM/B/2009.411).

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3

staar tratmt rgm

3.1 Chpte jectives

Tis chapter describes:

the aims o treatment;

the recommended doses o rst-line anti-B drugs or adults;

regimens or new and previously treated patients;

considerations in selecting regimens or dened patient groups; evidence base or the selected regimens in dened patient groups.

Te choice o B regimens in special situations (pregnancy, concurrent use o oral

contraceptives, liver disease, and renal ailure) is covered in Chapter 8; B treatment

or persons living with HIV is discussed in Chapter 5.

3.2 ais tetet

Te aims o treatment o tuberculosis are:

to cure the patient and restore quality o lie and productivity;

to prevent death rom active B or its late eects;

to prevent relapse o B;

to reduce transmission o B to others;

to prevent the development and transmission o drug resistance.

3.3 Esseti titecsis gs

able 3.1 shows the essential anti-B drugs and their recommended dosages based

on the patients weight.

Te WHO-recommended ormulations o anti-B drugs and xed-dose combina-

tions (FDCs) o drugs appear in the WHO Model List o Essential Medicines (available

at www.who.int/medicines/publications/essentialmedicines/en). Te ormulations

and combinations o anti-B drugs available in each country should conorm to this

list. (See also the WHO Model Formulary at www.who.int/selection_medicines/list/

en.)

o acilitate procurement, distribution and administration o treatment to patients,

the daily dosage may be standardized or three or our body weight bands orinstance 3039 kg, 4054 kg, 5570 kg and over 70 kg, as is done with the Global

Drug Facility patient kits. (See also reerence 1.)

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All anti-B drugs should be quality-assured, and management o anti-B drugs

should be incorporated into the management o other essential medicines by the

ministry o health.Annex 1 provides additional inormation on the essential anti-B drugs, including

contraindications, precautions, use in pregnancy, adverse eects, and drug inter-

actions. Intermittent dosing schedules are discussed in section 3.5.1 below.

3.3.1 -s bats at-TB s

While evidence on xed-dose combinations (FDCs) o anti-B drugs was not system-

atically reviewed or this ourth edition, WHO continues to recommend their use,

as does Standard 8 o the ISC (3). FDCs are thought to prevent acquisition o drugresistance due to monotherapy, which may occur with separate (loose) drugs. With

FDCs, patients cannot be selective in the choice o drugs to ingest. Prescription errors

are likely to be less requent because dosage recommendations are more straightor-

ward, and adjustment o dosage according to patient weight is easier. Te number o

tablets to ingest is smaller and may thus encourage patient adherence.

While there is ecological evidence o the benets o FDCs in relation to drug re-

sistance in early studies o DOS programmes, there is limited direct evidence o

improved adherence with FDCs (4). A recent multicentre trial ound FDCs to have

equivalent ecacy to single pills and to be more acceptable to patients (5). However,

assessment o cure and relapses was based on smear microscopy and not on culture.

A multicentre trial (Te Union Study C) evaluating the ecacy, acceptability and

toxicity o a our-drug FDC compared with loose pills given in the intensive phase

Tab 3.1 recommended doSeS o irST-line AnTiTuBerculoSiS drugS

or AdulTS

dg

recee se

di 3 ties pe week

dse ge(/k b

ht)

mi()

dse ge(/k b

ht)

di i()

isaz 5 (46) 300 10 (812) 900

ra 10 (812) 600 10 (812) 600

paza 25 (2030) 35 (3040)

ethabt 15 (1520) 30 (2535)

Stta

15 (1218) 15 (1218) 1000a patts a v 60 as a t b ab t tat tha 500750 a, s s -

s t th s t 10 /k a atts ths a (2). patts

h ss tha 50 k a t tat ss abv 500750 a (WHO Model Formulary 2008,

.h.t/st_s/st//).

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3. STandard TrEaTmEnT rEGImEnS

o treatment has just been completed and results should soon be available. Another

multicentre study including pharmacokinetic assessment is soon to be completed by

WHO/DR.

Quality assurance is essential to ensure adequate bioavailability o the compo-nent drugs o FDCs.1 Using FDCs does not obviate the need or separate drugs or

patients who develop drug toxicity or intolerance or or those with contraindications

to specic component drugs.

3.3.2 patt kts

A B patient kit contains the ull course o treatment or a single patient and thus as-

sures the B patient that his or her medicines will be available throughout treatment.

Te kit provides health workers with a container that has all required medicines inthe necessary strengths and quantities. Tis helps limit conusion and wastage, and

makes it easier to monitor the regularity o treatment; avoiding stock-outs also helps

to maintain patient condence in the health system. In addition, the patient may eel

a sense o ownership o the patient kit and enhanced motivation to complete the

ull course o treatment during visits to the health centre he or she can actually see

the quantity o medicines that must be taken to achieve cure (1).

It should be noted that the B patient kit does not eliminate the need or directly

observed treatment (DO).

3.4 St egies efe ptiet gps

Standardized treatment means that all patients in a dened group receive the same

treatment regimen. Standard regimens have the ollowing advantages over individu-

alized prescription o drugs:

errors in prescription and thus the risk o development o drug resistance

are reduced;

estimating drug needs, purchasing, distribution and monitoring are acilitat-

ed;

sta training is acilitated;

costs are reduced;

maintaining a regular drug supply when patients move rom one area to an-

other is made easier;

outcome evaluation is convenient and results are comparable.

For assigning standard regimens, patients are grouped by the same patient regis-

tration groups used or recording and reporting, which dierentiate new patients

rom those who have had prior treatment. Registration groups or previously treatedpatients are based on the outcome o their prior treatment course: ailure, relapse and

deault (seeChapter 2).

1 See Global Drug Facil ity, www.stoptb.org/gd/drugsupply/quality_sourcing_process.asp.

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Recommended regimens or dierent patient registration groups are shown in ables

3.2, 3.3 and 3.4. More details on the evidence and judgements underlying the recom-

mended regimens are described in Annex 2.

3.5 new ptiets

New patients are dened as those who have no history o prior B treatment or who

received less than 1 month o anti-B drugs (regardless o whether their smear or

culture results are positive or not) (see section 2.6).

3.5.1 n atts s k t hav -sstb TB

New patients are presumed to have drug-susceptible B with two exceptions:

Where there is a high prevalence o isoniazid resistance in new patients (see sec-tion 3.5.2).

or

I they have developed active B aer known contact with a patient documented

to have drug-resistant B; they are likely to have a similar drug resistance pattern

to the source case (6), and DS should be carried out at the start o treatment.

While DS results o the patient are awaited, a regimen based on the DS o the

presumed source case should be started.

Te 2-month riampicin regimen (2HRZE/6HE) is associated with more relapses anddeaths than the 6-month riampicin regimen (2HRZE/4HR) (7). WHO thereore rec-

ommends the ollowing or new patients presumed or known to have drug-suscepti-

ble B. (See also Standard 8 o the ISC (3).)


New patients with pulmonary B should receive a regimen containing 6 months

o riampicin: 2HRZE/4HR


Remark a: Recommendation 1.1 also applies to extrapulmonary B except B o

the central nervous system, bone or joint or which some expert groups suggest

longer therapy (see Chapter 8).

Remark b: WHO recommends that national B control programmes provide su-

pervision and support or all B patients in order to ensure completion o the ull

course o therapy.

Remark c: WHO recommends drug resistance surveys (or surveillance) or moni-

toring the impact o the treatment programme, as well as or designing standardregimens.

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Te 2HRZE/6HE treatment regimen should be phased out


In terms o dosing requency or HIV-negative patients, the systematic review ound

little evidence o dierences in ailure or relapse rates with daily or three times week-

ly regimens (7). However, patients receiving three times weekly dosing throughout

therapy had higher rates o acquired drug resistance than patients who received

drugs daily throughout treatment. In patients with pre-treatment isoniazid resist-

ance, three times weekly dosing during the intensive phase was associated with

signicantly higher risks o ailure and acquired drug resistance than daily dosing

during the intensive phase. (reatment regimens or B patients living with HIV are

discussed in detail in Chapter 5.)


Wherever easible, the optimal dosing requency or new patients with pulmo-

nary B is daily throughout the course o therapy


Tere are two alternatives to Recommendation 2.1:

L Recommendation 2.1A

New patients with pulmonary B may receive a daily intensive phase ol-lowed by three times weekly continuation phase [2HRZE/4(HR)

3] provided

that each dose is directly observed

(Conditional/High or moderate grade o evidence))

L Recommendation 2.1B

Tree times weekly dosing throughout therapy [2(HRZE)3/4(HR)

3] is anoth-

er alternative to Recommendation 2.1, provided that every dose is directly

observed and the patient is NO living with HIV or living in an HIV-prev-

alent setting

(Conditional/High or moderate grade o evidence))

Remark a: reatment regimens or B patients living with HIV or living in

HIV-prevalent settings are discussed in Recommendation 4 and Chapter 5.

Remark b: In terms o dosing requency or HIV-negative patients, the sys-

tematic review ound little evidence o dierences in ailure or relapse rates

with daily or three times weekly regimens (7). However, rates o acquired drug

resistance were higher among patients receiving three times weekly dosingthroughout therapy than among patients who received daily drug administra-

tion throughout treatment. Moreover, in patients with pretreatment isoniazid

resistance, three times weekly dosing during the intensive phase was associ-

3. STandard TrEaTmEnT rEGImEnS

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ated with signicantly higher risks o ailure and acquired drug resistance than

daily dosing during the intensive phase.

Tere is insucient evidence to support the ecacy o twice weekly dosing through-

out therapy (7).


New patients with B should not receive twice weekly dosing or the ull course

o treatment unless this is done in the context o ormal research


Remark: Te available evidence showed equivalent ecacy o daily intensive-

phase dosing ollowed by two times weekly continuation phase (7). However, twice

weekly dosing is not recommended on operational grounds, since missing onedose means the patient receives only hal the regimen.

ables 3.2a and 3.2b present standard treatment regimen and dosing requency or

new B patients.

Tab 3.2a STAndArd regimenS or new TB pATienTS

(s, k, t hav -sstb TB)

Itesive phse tetet Ctiti phse

2 ths HrZea 4 ths Hr

a wHo s ss thabt th tsv has tatt

atts th -avta, sa-atv pTB epTB h a k t b HiV-atv. i tb-

s ts, thabt sh b a b stt.

H = saz, r = a, Z = aza, e = thabt, S = stt

Tab 3.2b doSing requency or new TB pATienTS

Documents

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