5_Guidelines TB.doc

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guidelinesFourth edition

TreaTmenT of Tuberculosis


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Treatment of

tuberculosis

GuidelinesFourth edition

WHO Library Cataloguing-in-Publication Data:

Treatment of tuberculosis: guidelines – 4th ed

WHO!HT"!T#!$%%&4$%

'(ntitubercular agents – administration and dosage $Tuberculosis) Pulmonary

– drug thera*y +,ational health *rograms 4Patient com*liance


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.uidelines /World Health Organi0ation 1to* T# De*t

/1#, &23 &$ 4 '423+ + ,L" classification: W5 +6%7

© World Health Organization 2010

(ll rights reser8ed Publications of the World Health Organi0ation can be obtained from WHO Press)

World Health Organi0ation) $% (8enue (**ia) '$'' .ene8a $2) 19it0erland tel: 4' $$ 2&' 432; e-

mail: booe?uests for *ermission to re*roduce or translate WHO *ublications –

9hether for sale or for noncommercial distribution – should be addressed to WHO Press) at the abo8e

address fa@: 4' $$ 2&' 43%6; e-mail: *ermissions=9hoint7

The designations em*loyed and the *resentation of the material in this *ublication do not im*ly thee@*ression of any o*inion 9hatsoe8er on the *art of the World Health Organi0ation concerning the legal

status of any country) territory) city or area or of its authorities) or concerning the delimitation of its

frontiers or boundaries Dotted lines on ma*s re*resent a**ro@imate border lines for 9hich there may not

yet be full agreement

The mention of s*ecific com*anies or of certain manufacturersA *roducts does not im*ly that they are

endorsed or recommended by the World Health Organi0ation in *reference to others of a similar nature

that are not mentioned Brrors and omissions e@ce*ted) the names of *ro*rietary *roducts are

distinguished by initial ca*ital letters

(ll reasonable *recautions ha8e been ta


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Acknowledgements viii

Foreword ix

Executive summary 1

1. Introduction 15

1.1 Chapter objectives 1

1.! "urpose of the guidelines 1

1.# Target audience 1

1.$ scope 1

1. %h& a new edition' 1

1.( )ethodolog& 1*

1.+ international standards for Tuberculosis Care !1

1.* expir& date !1 2. Case definitions 23

!.1 Chapter objectives !#

!.! "urposes of defining a T, case !#

!.# Case definitions !#

!.$ Anatomical site of T, disease !$

!. ,acteriological results !

!.( -istor& of previous treatment patient registration group !(

!.+ -i/ status !*

3. Standard treatment regimens 29

#.1 Chapter objectives !0

#.! Aims of treatment !0

#.# essential antiT, drugs !0

#.$ standard regimens for defined patient groups #1

#. new patients #!

#.( "reviousl& treated patients and multidrug resistance #(

#.+ standard regimens for previousl& treated patients #*

#.* 2verall considerations in selecting a countr&3s standard

regimens $!

rEamEn of u!ErCu"oSIS: #uIdE"InES

$. monitoring during treatment 53

$.1 Chapter objectives #

$.! )onitoring the patient #

v


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$.# Assessing treatment response in new and previousl& treated

pulmonar&

T, patients4 and acting on the results #

$.$ extrapulmonar& T, +

$. 5ecording standardi6ed treatment outcomes +$.( Cohort anal&sis of treatment outcomes +

$.+ )anagement of treatment interruption 0

$.* "revention of adverse effects of drugs 0

$.0 )onitoring and recording adverse effects (7

$.17 s&mptombased approach to managing sideeffects of antiT,

drugs (7

5. Co%management of &I' and active ! disease (5

.1 Chapter objectives (

.! -i/ testing and counselling for all patients known or suspected

to have T, (

.# -i/ prevention in T, patients (+

.$ T, treatment in people living with -i/ (+

. Cotrimoxa6ole preventive therap& (0

.( Antiretroviral therap& (0

.+ drug susceptibilit& testing +1

.* "atient monitoring during T, treatment +1

.0 Considerations when T, is diagnosed in people living with -i/

who are

alread& receiving antiretroviral therap& +!

.17 -i/related prevention4 treatment4 care and support +!

(. Su)ervision and )atient su))ort *5

(.1 Chapter objectives +(.! 5oles of the patient4 T, programme staff4 the communit& and

other providers +

(.# supervised treatment ++

(.$ using a patientcentred approach to care and treatment deliver&

+*

(. "revention of treatment interruption *7

*. reatment of drug%resistant tu!ercu"osis +3

+.1 Chapter objectives *#

+.! Green light Committee initiative *#

+.# Groups of drugs to treat )d5T, *$

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+.$ General principles in designing an )d5T, treatment regimen

*(

ConEnS

+. "rogrammatic strategies for treatment of )d5T, *(

+.( selection of the countr&3s standard )d5T, treatment regimen

*0

+.+ selection of individuali6ed )d5T, regimens *0

+.* )onitoring the )d5T, patient 01

+.0 duration of treatment for )d5T, 01

+.17 Treating T, with resistance patterns other than )d5 0!

+.11 5ecording and reporting drugresistant T, cases4 evaluation of

outcomes 0!

+. reatment of extra)u"monary ! and of ! in s)ecia" situations

95

*.1 Chapter objectives 0

*.! Treatment of extrapulmonar& T, 0

*.# important drug interactions 0(

*.$ Treatment regimens in special situations 0+

annexes 1,1

1. essential firstline antituberculosis drugs 17#

!. summar& of evidence and considerations underl&ing the

recommendations 11

#. T, treatment outcomes 1#1

$. implementation and evaluation of the fourth edition 1##

. suggestions for future research 1$1

(. )embers of the Guidelines Group 1$

v


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Abbreviations

(5# acid-fast bacilli

(/D1 ac?uired immunodeficiency syndrome

(>T antiretro8iral thera*y

DOT directly obser8ed treatment

DOT1 the internationally agreed strategy for T# control

D>1 drug resistance sur8eillance

D1T drug susce*tibility testing

B ethambutol

BPT# e@tra*ulmonary tuberculosis

B( e@ternal ?uality assurance

5DC fi@ed-dose combination

.LC .reen Light Committee

H isonia0id

H/E human immunodeficiency 8irus

/1TC /nternational 1tandards for Tuberculosis Care

"D> multidrug resistance

"D>-T# multidrug-resistant tuberculosis

,,>T/ non-nucleoside re8erse transcri*tase inhibitor

,>T/ nucleoside re8erse transcri*tase inhibitor

,TP national tuberculosis control *rogramme

PT# *ulmonary tuberculosis> rifam*icin

1 stre*tomycin

T# tuberculosis

T#!H/E H/E-related T#

FD>-T# e@tensi8ely drug-resistant tuberculosis

G *yra0inamide

: :

i

x


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Acknowledgements

The 1to* T# De*artment of the World Health Organi0ation gratefully acGB!4H>7 9ill reduce the number of rela*ses and failures This 9ill

alle8iate *atient suffering resulting from a second e*isode of tuberculosis T#7 and

conser8e *atient and *rogramme resources

1econd) this fourth edition confirms *rior WHO recommendations for drug

susce*tibility testing D1T7 at the start of thera*y for all *re8iously treated *atients

5inding and treating multidrug-resistant T# "D>-T#7 in *re8iously treated

: :

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*atients 9ill hel* to im*ro8e the 8ery *oor outcomes in these *atients ,e9

recommendations for the *rom*t detection and a**ro*riate treatment of "D>-T#7

cases 9ill also im*ro8e access to life-sa8ing care The retreatment regimen 9ith

first-line drugs formerly called MCategory $N regimen7 is ineffecti8e in "D>-T#; it

is therefore critical to detect "D>-T# *rom*tly so that an effecti8e regimen can be

started Third) detecting "D>-T# 9ill re?uire e@*ansion of D1T ca*acity 9ithin the

conte@t of country-s*ecific) com*rehensi8e *lans for laboratory strengthening This

fourth edition *ro8ides guidance for treatment a**roaches in the light of ad8ances in

laboratory technology and the countryAs *rogress in building laboratory ca*acity /n

countries that use the ne9 ra*id molecular-based tests) D1T results for rifam*icin!

isonia0id 9ill be a8ailable 9ithin ' $ days and can be used in deciding 9hich ‒

regimen should be started for the indi8idual *atient >a*id tests eliminate the need to

treat Min the dar17 data or sur8eys 9ill be re?uired to identify subgrou*s of T#

*atients 9ith the highest *re8alence of "D>-T#) such as those 9hose *rior

treatment has failed /m*lementation of these recommendations 9ill re?uire e8erycountry to include an "D>-T# regimen in its standards for treatment in

collaboration 9ith the .reen Light Committee /nitiati8e

: :

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5ourth) diagnosing "D>-T# cases among *re8iously treated *atients and *ro8iding

effecti8e treatment 9ill greatly hel* in halting the spread of "D>-T# This edition

also addresses the *re8ention of acquired "D>-T#) es*ecially among ne9 T#

*atients 9ho already ha8e isonia0id-resistant Mycobacterium tuberculosis 9hen they

start treat ment The meta-analyses that form the e8idence base for this re8ision

re8ealed that ne9 *atients 9ith isonia0id-resistant T# ha8e a greatly increased ris


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T#!H/E and multidrug-resistant T# "D>-T#7 The 1to* T# 1trategy and the

.lobal Plan to im*lement the ne9 strategy maecommendations 9ere rated as MstrongN or MconditionalN

The e8idence and considerations underlying each recommendation are summari0ed

in (nne@ $

( strong recommendation is one for 9hich desirable effects of adherence to the

recommendation clearly out9eigh the undesirable effects The strong

recommendations in this edition use the 9ords MshouldN or Mshould notN ,o

alternati8es are listed

( conditional recommendation is one for 9hich the desirable effects of adherence to

the recommendation *robably out9eigh the undesirable effects but the trade-offs are

uncertain

>easons for uncertainty can include:

lac< of high-?uality e8idence to su**ort the recommendation;

limited benefits of im*lementing the recommendation;

costs not ustified by the benefits; im*recise

estimates of benefit

( weak recommendation is one for 9hich there is insufficient e8idence and it is

based on field a**lication and e@*ert o*inion >ecommendations for 9hich the

?uality of e8idence 9as not assessed in line 9ith the .>(DB methodology are not

rated

Conditional and 9ea< recommendations use the 9ords MmayN 5or se8eral of the

conditional recommendations) alternati8es are listed

The recommendations that address each of the se8en ?uestions are listed belo9) and

also a**ear in bold te@t in Cha*ter + 1tandard treatment regimens7) Cha*ter 4

"onitoring during treatment7 and Cha*ter Co-management of H/E and acti8e

T#7 (reas outside the sco*e of the se8en ?uestions) as 9ell as the remaining

cha*ters) ha8e been u*dated 9ith current WHO T# *olicies and recent references

but 9ere not the subect of systematic literature re8ie9s or of ne9 recommendations by the .uidelines .rou*

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-uestion 1. duration of rifam)icin in ne )atients

1hould ne9 *ulmonary T# *atients be treated 9ith the 6-month rifam*icin regimen

$H>GB!4H>7 or the $-month rifam*icin regimen $H>GB!6HB7

L Recommendation 1.1

New patients with pulmonary T should recei!e a regimen containing "months o# ri#ampicin$ 2HR%&'(HR

1trong!High grade of e8idence7

Remark a: >ecommendation '' also a**lies to e@tra*ulmonary T#) e@ce*t T# of

the central ner8ous system) bone or oint for 9hich some e@*ert grou*s suggest

longer thera*y see Cha*ter 37

Remark b: WHO recommends that national T# control *rogrammes ensure that

su*er8ision and su**ort are *ro8ided for all T# *atients in order to achie8e

com*letion of the full course of thera*y

Remark c: WHO recommends drug resistance sur8eys or sur8eillance7 for

monitoring the im*act of the treatment *rogramme as 9ell as for designing

standard regimens


The 2HR%&'"H& treatment regimen should )e phased out


-uestion 2. dosing fre/uency in ne )atients

When a country selects $H>GB!4H>) should *atients be treated 9ith a daily or three

times 9eeecommendation $':

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ExECuI'E Summary

L Recommendation 2.1,

New patients with pulmonary T may recei!e a daily intensi!e phase

#ollowed )y a three times wee-ly continuation phase 2HR%&'(/HR *

pro!ided that each dose is directly o)ser!ed

Conditional!High and moderate grade of e8idence7


Three times wee-ly dosing throughout therapy 2/HR%& '(/HR may )e

used as another alternati!e to Recommendation 2.1* pro!ided that e!ery

dose is directly o)ser!ed and the patient is NOT li!ing with H34 or li!ing

in an H345pre!alent setting


Remark a: Treatment regimens for T# *atients li8ing 9ith H/E or li8ing in

H/E-*re8alent settings are discussed in >ecommendation 4 and Cha*ter

Remark b: /n terms of dosing fre?uency for H/E-negati8e *atients) the

systematic re8ie9 found little e8idence of differences in failure or rela*se rates

9ith daily or three times 9ee


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L Recommendation

3n populations with -nown or suspected high le!els o# isoniazid resistance*

new T patients may recei!e HR& as therapy in the continuation phase as an

accepta)le alternati!e to HR

Wea

Remark a: While there is a *ressing need to *re8ent multidrug resistance "D>7)

the most effecti8e regimen for the treatment of isonia0id-resistant T# is not


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ExECuI'E Summary


L Recommendation (.

3# a daily continuation phase is not possi)le #or these patients* three times

wee-ly dosing during the continuation phase is an accepta)le alternati!e


L Recommendation (.(

/t is recommended that T# *atients 9ho are li8ing 9ith H/E should recei8e at

least the same duration of T# treatment as H/E-negati8e T# *atients


Remark a: 1ome e@*erts recommend *rolonging T# treatment in *ersons li8ing

9ith H/E see Cha*ter 7

Remark b: Pre8iously treated T# *atients 9ho are li8ing 9ith H/E should recei8e

the same retreatment regimens as H/E-negati8e T# *atients

>ecommendations '–4 as they relate to ne9 *atients7 are summari0ed in Table (

belo9) and sho9n in Tables +$ and ++ in Cha*ter +

Table A 8TAndArd regimen And do8ing fre9uenc& for new T, pATienT8

Intensive )hase Continuation

)hase

Comments

! months of -r:ea $ months of -r

! months of -r:e $ months of -re Applies onl& in countries with high levels

of isonia6id resistance in new T,

patients4 and where isonia6id drug

susceptibilit& testing in new patients is

not done ;or results are unavailable<

before the continuation phase beginsa w-o no longer recommends omission of ethambutol during the intensive phase of treatment

for patients with noncavitar&4 smearnegative pulmonar& T, or extrapulmonar& disease whoare known to be -i/negative.

dosing fre/uency

Comments

Intensive )hase Continuation )hase

dail& dail& optimal

dail& # times per week Acceptable alternative for an& new T,

patient receiving directl& observed

therap&

# times per week # times per week Acceptable alternative provided that thepatient is receiving directl& observed

therap& and is noT living with -i/ or

living in an -i/prevalent setting ;see

chapter <

9


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Note dail& ;rather than three times weekl&< intensivephase dosing ma& help to prevent

ac9uired drug resistance in T, patients starting treatment with isonia6id resistance ;see Annex

!


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ExECuI'E Summary

*ositi8e at the start of treatment Patients 9hose s*utum smears are *ositi8e at

month or 6 or 9ho are found to harbour "D>-T# strains at any time7 9ill be

re-registered as ha8ing failed treatment and be treated according to

>ecommendation 2 belo9

L Recommendation 8.(

3n pre!iously treated patients* i# the specimen o)tained at the end o# the

intensi!e phase /month is smear5positi!e* sputum culture and drug

suscepti)ility testing /9:T should )e per#ormed


-uestion (. reatment extension in ne )u"monary ! )atients

/n ne9 *ulmonary T# *atients) ho9 effecti8e is e@tension of treatment for *re8enting failure or rela*se

L Recommendation "

3n patients treated with the regimen containing ri#ampicin throughout

treatment* i# a positi!e sputum smear is #ound at completion o# the intensi!e

phase* the e6tension o# the intensi!e phase is not recommended


Remark: WHO recommends that a *ositi8e s*utum smear at com*letion of the

intensi8e *hase should trigger a careful re8ie9 of the ?uality of *atient su**ort

and su*er8ision) 9ith *rom*t inter8ention if needed see Cha*ter 47 /t should

also trigger additional s*utum monitoring) as *er >ecommendations $) + and

4

-uestion *. revious"y treated )atients

Which if any7 grou*s of *atients should recei8e a retreatment regimen 9ith first-

line drugs

Table + in Cha*ter + sho9s >ecommendations 2'–24

L Recommendation ;.1

:pecimens #or culture and drug suscepti)ility testing /9:T should )e

o)tained #rom all pre!iously treated T patients at or )e#ore the start o#

treatment. 9:T should )e per#ormed #or at least isoniazid and ri#ampicin

Remark a: D1T may be carried out by ra*id molecular-based methods or by

con8entional methods 1*utum should be obtained) as 9ell as a**ro*riate

s*ecimens for e@tra*ulmonary T#) de*ending on the site of disease

Remark b: Obtaining s*ecimens for culture and D1T should not delay the start of

treatment Bm*irical thera*y should be started *rom*tly) es*ecially if the *atient

is seriously ill or the disease is *rogressing ra*idly

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3n settings where rapid molecular5)ased 9:T is a!aila)le* the results should

guide the choice o# regimen

L Recommendation ;.3n settings where rapid molecular5)ased 9:T results are not routinely a!aila)le

to guide the management o# indi!idual patients* empirical 1 treatment should )e

started as #ollows$

L Recommendation ;..1

T patients whose treatment has failed 2 or other patient groups with high

li-elihood o# multidrug5resistant T /-T# are

those rela*sing or defaulting after their second or subse?uent course of

treatment 1ee also section +3$


T patients returning a#ter de#aulting or relapsing #rom their #irst

treatment course may recei!e the retreatment regimen containing #irst5

line drugs 2HR%&:'1HR%&'8HR& i# country5speci#ic data show low ormedium le!els o#


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ExECuI'E Summary

Table # belo9 lists


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S ( trial of broad-s*ectrum antibiotics is no longer recommended to be used

as a diagnostic aid for smear-negati8e *ulmonary T# in *ersons li8ing 9ith H/E

S 5or H/E-negati8e *atients) the fourth edition s*ecifies that) if broad-

s*ectrum antibiotics are used in the diagnosis of smear-negati8e *ulmonary T#)anti-T# drugs and fluoro?uinolones should be a8oided

S Pulmonary T# cases 9ithout smear results are no longer classified as

smear- negati8e /nstead) they are labelled Msmear not doneN on the T# register

and in the annual WHO sur8ey of countries

S Consistent 9ith 1tandard + of the /nternational 1tandards for T# Care)

culture and histo*athological e@amination are recommended for s*ecimens from

sus*ected e@tra*ulmonary sites of T# B@amination of s*utum and a chest

radiogra*h are also suggested) in case *atients ha8e concomitant *ulmonaryin8ol8ement

S The *atient registration grou* MOtherN no longer includes MchronicN

/nstead) *atients 9hose s*utum is smear-*ositi8e at the end of or returning from7

a second or subse?uent course of treatment are classified by the outcome of their

most recent retreatment course: rela*sed) defaulted or failed

Cha)ter 3. standard treatment regImens

S (dditional dosage information is *ro8ided for isonia0id ma@imum daily

dose for three times *er 9ee


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ExECuI'E Summary

le8els of isonia0id resistance This conditional recommendation a**lies 9here

isonia0id susce*tibility testing in ne9 *atients is not done or results are not

a8ailable7 before the continuation *hase begins

S D1T before or at the start of thera*y is strongly recommended for all *re8iously treated *atients

S Pre8iously treated *atients are defined by their li regimen is

recommended for *atients 9ith high li regimen is no9 recommended as one of each countryAs standard

regimens) for use in confirmed "D>-T# cases as 9ell as in *atients 9ith a high

li treatment is no longer an acce*table rationale for

*ro8iding a retreatment regimen of first-line drugs formerly called the MCategory

$ regimenN7 to *atients 9ith a high li-T# that are high enough to 9arrant an "D>

regimen 9hile a9aiting results of D1T

S WHO does not intend to establish thresholds for lo9) moderate) or high

li in s*ecific *atient grou*s) as 9ell asother factors such as "D> treatment resources a8ailable during scale-u*) and

fre?uency of concomitant conditions such as H/E7 that increase the short-term

ris< of dying from "D>-T#

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S Country drug resistance sur8eys) WHO estimates of "D> le8els) and other

data sources are recommended to inform decisions on each countryAs standard

treatment regimens for defined *atient grou*s

S /ntermittent dosing is no longer an o*tion for *re8iously treated *atientsrecei8ing the 3-month retreatment regimen 9ith first-line drugs

Cha)ter $. monItorIng durIng treatment

S The *erformance of s*utum smear microsco*y at the com*letion of the

intensi8e *hase of treatment is a conditional) rather than a strong)

recommendation) gi8en the e8idence that a *ositi8e smear at this stage has a 8ery

*oor ability to *redict rela*se or *retreatment isonia0id resistance (nne@ $7

Ho9e8er) its utility in detecting *roblems 9ith *atient su*er8ision and for

monitoring *rogramme *erformance is reaffirmed

S /n addition) this edition recommends that a *ositi8e s*utum smear at the

end of the intensi8e *hase in ne9 *atients should trigger s*utum smear

microsco*y at the end of the third month /f the latter is *ositi8e) culture and D1T

should be *erformed

S This edition no longer recommends e@tension of the intensi8e *hase for

*atients 9ho ha8e a *ositi8e s*utum smear at the end of the second month of

treatment

S /n *re8iously treated *atients) if the s*ecimen obtained at the end of the

intensi8e *hase month +7 is smear-*ositi8e) this edition recommends that s*utum

culture and D1T be *erformed then) rather than 9aiting until month 9hich 9as

recommended in the third edition7

S The outcome of cure no9 encom*asses culture results

S Patients found to harbour an "D>-T# strain at any *oint during treatment

are no9 classified as Mtreatment failureN They are re-registered and begin an

"D> regimen

S 5or "D>-T# *atients) this edition recommends the use of the "D>-T#

register and cohort analysis

S The sym*tom-based a**roach to side-effects of anti-T# drugs has been

re8ised

Cha)ter 5. Co%management of hI' and aCtI'e t dIsease

S Pro8ider-initiated H/E testing for all *atients 9ith


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ExECuI'E Summary

S Daily dosing is strongly recommended during the intensi8e *hase for T#

*atients 9ith


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S 1tre*tomycin: dosage adustments for the elderly and adults 9eighing less

than %


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introduction

1.1 Cha)ter o!ectives

This cha*ter defines the *ur*ose) target audience) sco*e and de8elo*ment of this

fourth edition of the guidelines /t also e@*lains 9hy a ne9 edition 9as needed and

*roects a date for the ne@t re8ision

1.2 ur)ose of the guide"ines

The *rinci*al *ur*ose of these guidelines is to hel* national T# control *rogrammes,TPs7 in setting T# treatment *olicy to o*timi0e *atient cure: curing *atients 9ill

*re8ent death) rela*se) ac?uired drug resistance) and the s*read of T# in the

community Their further *ur*ose is to guide clinicians 9or-T#7 The 1to* T# 1trategy and the .lobal Plan

1

1

5


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27 to im*lement the ne9 strategy made it necessary to re8ise the e@isting guidelines

7 and de8elo* this fourth edition

Historically) the greatest em*hasis of T# control acti8ities has been on the most

infectious *atients – those 9ho ha8e s*utum smear-*ositi8e *ulmonary tuberculosis

7 This changed 9ith the 1to* T# 1trategyAs em*hasis on uni8ersal access for all *ersons 9ith T# to high-?uality) *atient-centred treatment 17 Ho9e8er) highly

infectious) smear-*ositi8e *atients remain the *rimary focus for other as*ects of T#

control) including contact tracing and infection control The PatientsA Charter for T#

Care s*ecifies that all T# *atients ha8e Mthe right to free and e?uitable access to T#

care) from diagnosis through treatment com*letionN !7

This fourth edition of the guidelines has therefore abandoned Categories /–/E) 9hich

9ere used to *rioriti0e *atients for treatment' (ccording to this *rior categori0ation)

smear-negati8e T# *atients 9ere assigned third *riority and "D>-T# *atients

fourth *riority 5or treatment decisions it no longer maegistration

grou*s for *re8iously treated *atients are based on the outcome of their *rior

treatment course: failure) rela*se) and default

The fourth edition integrates detection and treatment of both H/E infection and

"D>-T#) and thus should contribute to9ards achie8ement of the 1to* T#

1trategyAs uni8ersal access to high-?uality "D>-T# and H/E care

With regard to H/E detection) this edition incor*orates recent WHOrecommendations for *ro8ider-initiated H/E testing of all *ersons 9ith diagnosed or

sus*ected T#) in all ty*es of H/E e*idemics lo9-le8el) concentrated or generali0ed7

%7 5or treatment of T# in *ersons li8ing 9ith H/E) ne9 recommendations on the

duration of thera*y and the role of intermittent regimens ha8e emerged from

systematic re8ie9s see Cha*ter 7 The ne9 edition also includes recent WHO

recommendations for D1T at the start of T# thera*y in all *eo*le li8ing 9ith H/E

&7) as 9ell as recommendations on the timing and ty*e of antiretro8iral thera*y

(>T7 regimens 1'7

' (lso) the original one-to-one corres*ondence bet9een *atient grou* and treatment regimens 9as lost

as Categories /–/E 9ere redefined o8er the years The same treatment regimen came to berecommended for *atients in Categories / and ///; after $%%4) different treatment regimens 9ere

recommended for *atients in Category // de*ending on factors such as *rogramme *erformance and

drug resistance

2

2


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1. InroduCIon

,e9 de8elo*ments in "D>-T# also contributed to the need for this re8ision

#uilding on the *rinci*le of uni8ersal access to "D>-T# diagnosis and care) T(e

MDR)T* and +DR)T* response plan 2''$,2''% 117 calls for the diagnosis and

treatment of "D>-T# in all countries by $%' B8en countries 9ith lo9 o8erall

le8els of multidrug resistance "D>7 are faced 9ith T# *atients 9ho ha8e been

*re8iously treated – a grou* that is fi8e times more li-T# diagnosis) this fourth edition

reaffirms e@isting WHO recommendations 27 that all *re8iously treated *atients

should ha8e access to culture and D1T at the beginning of treatment) in order to

identify "D>-T# as early as *ossible' /t also incor*orates the WHO

recommendation that treatment failure be confirmed by culture and D1T &7 /n

order to detect "D> sooner than the end of the fifth month of treatment) this edition

includes the e@isting WHO recommendation &7 for culture and D1T if *atients stillha8e smear-*ositi8e s*utum at the end of the third month of treatment

Cha*ters $– of this ne9 edition discuss the critical role of the identification of

Mycobacterium tuberculosis and of D1T This is in contrast to the *re8ious edition)

9hich relied almost e@clusi8ely on smear microsco*y for case definition) assignment

of standard regimens) and monitoring of treatment res*onse Line *robe assays can

identify "D>-T# 9ithin hours and li?uid media can do so 9ithin 9ee

regimen in its standard regimens This is essential 9hile a9aiting D1T results for

*atients 9ith a high li-T# treatment is no

longer an acce*table rationale for *ro8iding the 3-month retreatment regimen 9ith

first-line drugs formerly called the MCategory // regimenN7 to *atients 9ith a highli-T# and may result

in am*lification of drug resistance ") 17

Ise of ra*id D1T methods 9ill e8entually render the 3-month retreatment regimen

of first-line drugs obsolete /n the meantime) the regimen is retained in this fourth

edition in only t9o circumstances /n countries 9ith access to routine D1T using

con8entional methods) the 3-month retreatment regimen 9ith first-line drugs is

recommended 9hile a9aiting D1T results from *atients 9ho ha8e rela*sed or are

returning after default if country-s*ecific data sho9 they ha8e a medium li


30/161


of "D>-T#) or if such data are una8ailable7 /n countries that do not yet ha8e D1T

routinely a8ailable at the start of treatment for all *re8iously treated *atients see

section +2+7) the 3-month retreatment regimen 9ith first-line drugs 9ill be used for

the duration of treatment on an interim basis until laboratory ca*acity is a8ailable

/n *rinci*le) "D> treatment should be introduced only in 9ell-*erforming DOT1 *rogrammes #efore focusing on curing "D>-T# cases) it is critical to Mturn off the

ta*N) ie to strengthen *oor *rogrammes so that they sto* gi8ing rise to "D>-T#

5ollo9ing this *rinci*le) the $%%4 re8ision of the treatment cha*ter ' listed ade?uate

*erformance of a countryAs o8erall T# *rogramme as a re?uirement for the use of

"D> regimens in *atients 9ith a high li *ilot *roect that) once established)

can *ro8ide a model and an im*etus for the e@*ansion of basic DOT1 into more

areas /n most countries) ho9e8er) conditions for initiating an "D> com*onent inmost ,TPs are not met until the o8erall ,TP has the essential elements of DOT1

firmly in *lace

1.( methodo"ogy

De8elo*ment of the fourth edition of the guidelines follo9ed ne9 WHO *rocedures

WHO defined the sco*e of re8ision and con8ened a guidelines grou* of e@ternal

e@*erts (ll members of the grou* com*leted a Declaration for the Conflict of

/nterest; there 9ere no conflicts declared With in*ut from the .uidelines .rou*)

WHO identified se8en


31/161

1. InroduCIon

e8idence) 8alues) and costs) as 9ell as udgements about trade-offs bet9een benefits

and harm

The grou* graded the strength of each recommendation) reflecting the degree of

confidence that the desirable effects of adherence to a recommendation out9eigh the

undesirable effects (lthough the degree of confidence is necessarily a continuum)three categories are used – strong) conditional and 9ea(DB methodology 1!7

"oderate!lo9 ?uality of e8idence means that the estimate of effect of the

inter8ention is 8ery uncertain and further research is li


32/161


recommendation strength

Strong Conditiona"

hrasing of the

recommendation

>Shou"d? or >shou"d not?.

no alternatives are

presented

>o)tima" is?4 >may?4 or >it

is 6not7 recommended?.

Alternatives are often

listedfactors used to udge strength

9ualit& of evidence -igh9ualit& evidence low9ualit& evidence

,alance between

desirable and

undesirable effects on

patient and public

health

large4 certain net benefit

and@or difference between

benefits and harms or

burdens

8mall and@or uncertain

gradient

resource allocation low cost ;or little uncertaint&

about whether the

intervention represents a wise

use of resources<

-igh cost ;or high

uncertaint&<

uncertaint& in values

and preferences

variabilit& across

patients

8mall amount of uncertaint&

or variabilit&

large amount of

uncertaint& or variabilit&

Im)"ications

for )o"icy%ma8ers ;including nTp

managers<

The recommendation shouldune9uivocall& be used for

setting polic&

polic&making will re9uireextensive debate

for )atients most individuals would want

the recommended course of

action

The recommended

course of action can be

adjusted on the basis of

feasibilit& and

acceptabilit&for hea"th care

)roviders

most patients should be

treated according to the

recommended course of

action. Adherence to this

recommendation is areasonable measure of good

9ualit& care

The draft guidelines 9ere circulated to the e@ternal re8ie9 grou* 9hose members

are listed in (nne@ 67) made u* of ,TP managers from high-burden countries)

members of the WHO 1trategic) Technical and (d8isory .rou* on T# 1T(.-T#7)

si@ regional T# (d8isers and T# medical officers 9or


33/161

1. InroduCIon

1.* Internationa" Standards for u!ercu"osis Care

The -nternational tandards for Tuberculosis /are /1TC7 1"7 describe a 9idely

acce*ted le8el of T# care that all *ractitioners should see< to achie8e Cross-

referencing the a**licable /1TC standards in this ne9 edition should hel* *ro8iders

in both *ublic and *ri8ate sectors to ensure their im*lementation

1.+ Ex)iry date

The WHO 1to* T# De*artment 9ill re8ie9 and u*date these guidelines after +–

years or as needed 9hen ne9 e8idence) treatment regimens or diagnostic tests

become a8ailable

references' >a8iglione "C) I*le


34/161


'+ Bs*inal "( Time to abandon the standard retreatment regimen 9ith first-line

drugs for failures of standard treatment -nternational 4ournal of Tuberculosis and

0ung Disease) $%%+) 2:6%2–6%3

'4 .uyatt .H et al .>(DB: an emerging consensus on rating ?uality of e8idence

and strength of recommendations *ritis( Medical 4ournal ) $%%3) ++6:&$4–&$6

' -nternational tandards for Tuberculosis /are -T/;) $nd ed The Hague)Tuberculosis Coalition for Technical (ssistance) $%%&

2

2


35/161

Case definitions


This cha*ter describes

the *ur*ose of ha8ing case definitions for tuberculosis;

the definition of a case of T#) as 9ell as of sus*ected and confirmed cases;

additional features of T# cases im*ortant for the treatment of indi8idual

*atients) as 9ell as for e8aluating T# *rogrammes and monitoring the

e*idemic

The diagnosis of T# refers to the recognition by health 9or


36/161


2.3 Case definitions

The T# case definitions belo9 are based on the le8el of certainty of the diagnosis

and on 9hether or not laboratory confirmation is a8ailable

S Tu)erculosis suspect (ny *erson 9ho *resents 9ith sym*toms or signs

suggesti8e of T# The most common sym*tom of *ulmonary T# is a *roducti8ecough for more than $ 9ee


37/161

the lungs) constitutes a case of e=tra *ulmonary T# ( *atient 9ith both *ulmonary

and e@tra*ulmonary T# should be classified as a case of pulmonary T#

2. CaSE dEfInIIonS

&6trapulmonary tu)erculosis BPT#7 refers to a case of T# defined abo8e7in8ol8ing organs other than the lungs) eg *leura) lym*h nodes) abdomen)

genitourinary tract) s-T#

cases) see reference $

1tandard $ of the /1TC "7 states that all *atients sus*ected of ha8ing *ulmonary T#

should submit at least t9o s*utum s*ecimens for microsco*ic e@amination in a

?uality-assured laboratory When *ossible) at least one early-morning s*ecimen

should be obtained) as s*utum collected at this time has the highest yield /1TC

1tandard 4 states that all *ersons 9ith chest radiogra*hic findings suggesti8e of T#

should submit s*utum s*ecimens for microbiological e@amination "7

1mear-*ositi8e cases are the most infectious and most li


38/161


' /n countries 9ithout functional B() the definition from the third edition of these guidelines a**lies:

a smear-*ositi8e *ulmonary T# case 9as defined as one 9ith:

a t9o or more initial s*utum smear e@aminations *ositi8e for (5#) or

b one s*utum smear e@amination *ositi8e for (5# *lus radiogra*hic abnormalities consistent

9ith acti8e PT# as determined by a clinician) orc one s*utum smear *ositi8e for (5# *lus s*utum culture-*ositi8e for M. tuberculosis

mear)negative PT# cases should either:

( ha8e s*utum that is smear-negati8e but culture-*ositi8e for M. tuberculosis:

S a case of *ulmonary T# is considered to be smear)negative if at least t9o

s*utum s*ecimens at the start of treatment are negati8e for (5#' in countries

9ith a functional B( system) 9here the 9or


39/161

2.( &istory of )revious treatment: )atient registration grou)

(t the time of registration) each *atient meeting the case definition is also classified

according to 9hether or not he or she has *re8iously recei8ed T# treatment and) if

so) the outcome if


40/161


other B or All cases that do not fit the above

definitions4 such as patients

D for whom it is not known

whether the& have been

previousl& treated

D who were previousl& treated

but with unknown outcome of that

previous treatmentb ;34 8 other retreatment? in other w-o documents cited above.

2.* &I' status

Determining and recording the *atientAs H/E status is critical for treatment decisions

see Cha*ters + and 7 as 9ell as for monitoring trends and assessing *rogramme

*erformance WHOAs re8ised T# Treatment Card and T# >egister include dates of

H/E testing) starting co-trimo@a0ole) and starting (>T These im*ortant

inter8entions are discussed more fully in Cha*ter

references

' ?ngaging all (ealt( care providers in T* control: guidance on implementing

publicprivate mi= approac(es .ene8a) World Health Organi0ation) $%%6

WHO!HT"! T#!$%%6+6%7

$ @7> policy on T* infection control in (ealt( care facilities congregate

settings and (ouse(olds .ene8a) World Health Organi0ation) $%%&

WHO!HT"!T#!$%%&4'&7

+ -mplementing t(e @7> top T* trategy: a (andbook for national tuberculosis

control programmes .ene8a) World Health Organi0ation) $%%3

WHO!HT"!T#!$%%34%7

4 -mproving t(e diagnosis and treatment of smear)negative pulmonary and

e=trapulmonary tuberculosis among adults and adolescents: recommendations for

7-8)prevalent and resource)constrained settings .ene8a) World HealthOrgani0ation) $%%2 WHO! HT"!T#!$%%2+2&; WHO!H/E!$%%2'7

-nternational tandards for Tuberculosis /are -T/;) $nd ed The Hague)

Tuberculosis Coalition for Technical (ssistance) $%%&

6 Revised T* recording and reporting forms and registers , version 2''#

.ene8a) World Health Organi0ation) $%%6 WHO!HT"!T#!$%%6+2+; a8ailable at:

9999hoint! tb!dots!rUandUrUforms!en!inde@html7

2 6uidelines for t(e programmatic management of drug)resistant tuberculosis:

emergency update 2''% .ene8a) World Health Organi0ation) $%%3

WHO!HT"!T#! $%%34%$7

3 6lobal tuberculosis control 2''&: epidemiology strategy financing. @7>

report 2''& .ene8a) World Health Organi0ation) $%%& WHO!HT"!T#!$%%&4''7

3

3

0


41/161

standard treatment

regimens


This cha*ter describes:

the aims of treatment;

the recommended doses of first-line anti-T# drugs for adults;

regimens for ne9 and *re8iously treated *atients;

considerations in selecting regimens for defined *atient grou*s;

e8idence base for the selected regimens in defined *atient grou*sThe choice of T# regimens in s*ecial situations *regnancy) concurrent use of oral

contrace*ti8es) li8er disease) and renal failure7 is co8ered in Cha*ter 3; T# treatment

for *ersons li8ing 9ith H/E is discussed in Cha*ter

3.2 aims of treatment

The aims of treatment of tuberculosis are:

to cure the *atient and restore ?uality of life and *roducti8ity;

to *re8ent death from acti8e T# or its late effects; to *re8ent rela*se of T#;

to reduce transmission of T# to others;

to *re8ent the de8elo*ment and transmission of drug resistance

3.3 Essentia" antitu!ercu"osis drugs

Table +' sho9s the essential anti-T# drugs and their recommended dosages based

on the *atientAs 9eight

The WHO-recommended formulations of anti-T# drugs and fi@ed-dosecombinations 5DCs7 of drugs a**ear in the @7> Model 0ist of ?ssential

Medicines a8ailable at 9999hoint!medicines!*ublications!essentialmedicines!en7

The formulations and combinations of anti-T# drugs a8ailable in each country

should conform to this list 1ee also the WHO "odel 5ormulary at

9999hoint!selectionUmedicines!list! en7

To facilitate *rocurement) distribution and administration of treatment to *atients)

the daily dosage may be standardi0ed for three or four body 9eight bands – for

instance +%–+&


42/161


drug

recommended dose

dai"y 3 times )er ee8

dose and range

;mg@kg bod&weight<

maximum

;mg<

dose and range

;mg@kg bod&weight<

dai"y maximum

;mg<

isonia6id ;$(< #77 17 ;*1!< 077

rifampicin 17 ;*1!< (77 17 ;*1!< (77

p&ra6inamide ! ;!7#7< # ;#7$7<

ethambutol 1 ;1!7< #7 ;!#<

8treptom&cina 1 ;1!1*< 1 ;1!1*< 1777

a patients aged over (7 &ears ma& not be able to tolerate more than 77+7 mg dail&4 so some

guidelines recommend reduction of the dose to 17 mg@kg per da& in patients in this age group

;2


43/161

acce*tability and to@icity of a four-drug 5DC com*ared 9ith loose *ills gi8en in the

intensi8e *hase

3

1


44/161


of treatment has ust been com*leted and results should soon be a8ailable (nother

multicentre study including *harmaco

uality assurance is essential to ensure ade?uate bioa8ailability of the com*onentdrugs of 5DCs' Ising 5DCs does not ob8iate the need for se*arate drugs for

*atients 9ho de8elo* drug to@icity or intolerance or for those 9ith contraindications

to s*ecific com*onent drugs

#.#.! patient kits

( T# *atient


45/161

3. Sandard rEamEn rE#ImEnS

>ecommended regimens for different *atient registration grou*s are sho9n in Tables

+$) ++ and +4 "ore details on the e8idence and udgements underlying the

recommended regimens are described in (nne@ $

3.5 ne )atients

,e9 *atients are defined as those 9ho ha8e no history of *rior T# treatment or 9ho

recei8ed less than ' month of anti-T# drugs regardless of 9hether their smear or

culture results are *ositi8e or not7 see section $67

#..1 new patients presumed or known to have drugsusceptible T,

,e9 *atients are *resumed to ha8e drug-susce*tible T# 9ith t9o e@ce*tions:

S Where there is a high *re8alence of isonia0id resistance in ne9 *atientssee section +$7

or

S /f they ha8e de8elo*ed acti8e T# after GB!4H>7 $ 7 WHO therefore

recommends the follo9ing for ne9 *atients *resumed or


46/161



/n terms of dosing fre?uency for H/E-negati8e *atients) the systematic re8ie9 found

little e8idence of differences in failure or rela*se rates 9ith daily or three times

9ee


47/161


There is insufficient e8idence to su**ort the efficacy of t9ice 9ee


48/161


rifam*icin regimen $ 7 The global 9eighted mean of any isonia0id resistance

e@cluding "D>7 is 24R in ne9 *atients %7 Thus) a significant *ro*ortion of the

ne9 T# cases in many regions of the 9orld ha8e a ris< of *oor treatment outcomes

because of their *retreatment isonia0id resistance

The follo9ing 9ea< recommendation a**lies to countries 9here isonia0id

susce*tibility testing in ne9 *atients is not done or results are not a8ailable7 before

the continuation *hase begins

L Recommendation

3n populations with -nown or suspected high le!els o# isoniazid resistance*

new T patients may recei!e HR& as therapy in the continuation phase as an

accepta)le alternati!e to HR

Wea

.i8en the *otential benefit &7 and lo9 ris< of to@icity from ethambutol) the *ressing

need to *re8ent "D> 9arrants this recommendation Ho9e8er) the recommendation

is conditional) for the reasons e@*lained in more detail in (nne@ $ The most

effecti8e regimen for the treatment of isonia0id-resistant T# is not


49/161


3.( revious"y treated )atients and mu"tidrug resistance

Pre8ious T# treatment is a strong determinant of drug resistance 1'7) and

*re8iously treated *atients com*rise a significant *ro*ortion '+R7 of the global T#

notifications in $%%2Of all the forms of drug resistance) it is most critical to detect multidrug resistance

"D>7 because it ma treatment 9ith second-line drugs gi8es a better chance of cure and *re8ents

the de8elo*ment and s*read of further resistance #ecause of its clinical

significance) "D> rather than any drug resistance7 is used to describe the

retreatment *atient grou*s belo9

(t the global le8el) 'R of *re8iously treated *atients ha8e "D> %7) 9hich is fi8etimes higher than the global a8erage of +R in ne9 *atients 5igure +'7 B8en in

(frica) the WHO region thought to ha8e the lo9est le8el of "D> in retreatment

*atients) a significant *ro*ortion 6R7 of retreatment *atients ha8e "D>-T# %7' /f

their "D> is not detected and treated 9ith second-line drugs) these *atients 9ill

suffer *oor outcomes and s*read "D> in their communities

WHO sur8eillance data from '% countries found the le8el of "D> to be +$R in

*atients returning after defaulting or rela*sing and significantly higher 4&R7 in

*atients 9hose *rior treatment has failed 5igure +$7$ Other studies sho9 "D>

le8els of u* to 3%–&%R in *atients 9hose *rior treatment courses ha8e failed 1',

1# 7 "odelling described in (nne@ $ *redicts that) 9hen a first course of treatment

containing 6 months of rifam*icin fails) %–&4R of *atients ha8e "D>-T#

com*ared 9ith 4–6R of *atients u*on failure of a regimen containing $ months of

rifam*icin7

"any factors influence the le8el of "D> in *re8iously treated *atients) and le8els

are li


50/161


0! 7* casesb 1* *+# casesc

a 8ource Anti-tuberculosis

drug resistance in the orld! "ourthglobal re#ort . geneva4 world -ealth

organi6ation ;!77*< ;8


51/161


identify "D> as early as *ossible so that a**ro*riate treatment can be gi8en 1ee

also 1tandard '' of the /1TC 77


:pecimens #or culture and drug suscepti)ility testing /9:T should )eo)tained #rom all pre!iously treated T patients at or )e#ore the start o#

treatment. 9:T should )e per#ormed #or at least isoniazid and ri#ampicin

The a**roach to the initiation of retreatment de*ends on the countryAs laboratory

ca*acity) s*ecifically w(en or if7 D1T results are routinely a8ailable for the

indi8idual *atient Countries using ra*id molecular-based D1T 1%) 1&7 9ill ha8e

results for rifam*icin!isonia0id a8ailable 9ithin '–$ days; these results can be used

in deciding 9hich regimen to start for the indi8idual *atient section +2'7

Ising con8entional D1T methods yields results 9ithin 9ee

regimen Drug resistance sur8eillance or sur8eys often sho9 that those rela*sing or

returning after default ha8e a medium or lo9 li in

different *atient registration grou*s 8ary by setting'

/t must be noted) ho9e8er) that the retreatment regimen using first-line drugs is not

su**orted by e8idence deri8ing from clinical trials /t 9as designed *rimarily for usein settings 9ith lo9 *re8alence of initial drug resistance and in *atients *re8iously

treated 9ith a regimen that included rifam*icin for the first $ months 2'7

The assum*tion that *atients 9hose treatment has failed ha8e a high li7 may

need to be modified according to both the le8el of "D> found in these *atient

registration grou*s and the considerations discussed in section +3 belo97

' /f drug resistance sur8eys sho9 that *atients rela*sing or returning after default ha8e high le8els of "D>) they 9ill need an "D> regimen instead 1imilarly) if the country data sho9 that le8els of "D>

are lo9 in *atients 9ho failed their *re8ious treatment) the ,TP may decide to administer retreatment

regimens 9ith first-line drugs 1ee section +3 for further details

5

3


52/161


1e8eral other considerations also described in section +37 9ill ha8e an im*act on

the le8el of "D> the ,TP designates as MhighN in a gi8en country 1ee also

1tandard '$ of the /1TC 77

Countries 9ill need to use a mi@ of a**roaches if they are in transition) 9here someareas of the country do not yet ha8e D1T results routinely a8ailable and others do) or

some laboratories use ra*id and others con8entional D1T methods

#.+.1 previousl& treated patients in settings with rapid d8T

With line *robe assays) "D> can be essentially confirmed ' or e@cluded 9ithin '–$

days)$ 9hich allo9s the results to guide the regimen at the start of thera*y


3n settings where rapid molecular5)ased 9:T is a!aila)le* the results shouldguide the choice o# regimen

The use of ra*id molecular-based tests is discussed in more detail in section +3'

belo9

#.+.! previousl& treated patients in settings where conventional d8T results

are routinel& available for individual patients

Obtaining s*ecimens for con8entional culture and D1T should not delay the start of

thera*y Bm*irical regimens) often based on drug-resistance sur8eillance data) areused 9hile the results of con8entional D1T li?uid or solid media7 are a9aited) and

should be started *rom*tly+ This is es*ecially im*ortant if the *atient is seriously ill

or the disease is *rogressing ra*idly Placing a *atient on an em*iric regimen

*ending D1T is done to a8oid clinical deterioration (lso) once em*iric thera*y

begins to render the *atient less infectious) the ris< of transmission to contacts

decreases

While a9aiting the results of con8entional D1T) WHO recommends administering

an em*iric "D> regimen4 for *atient grou*s 9ith a high li Table +47

' Line *robe assays detect resistance to rifam*icin alone or in combination 9ith isonia0id resistance

O8erall high accuracy for detection of "D> is retained 9hen rifam*icin resistance alone is used as a

mar regimen is *ro8ided in Cha*ter 2 of this document)

and in Cha*ter 2 of 6uidelines for t(e programmatic management of drug)resistant T* # 7

5

2


53/161


L Recommendation ;.

3n settings where rapid molecular5)ased 9:T results are not routinely

a!aila)le to guide the management o# indi!idual patients* empiric treatment

should )e started as #ollows$


T patients whose treatment has failed 1 or other patient groups with high

li-elihood o# multidrug5resistant T /-T# are

those rela*sing or defaulting after their second or subse?uent course of treatment 1ee also section +3$


T patients returning a#ter defaulting or relapsing #rom their #irst

treatment course may recei!e the retreatment regimen containing #irst5

line drugs 2HR%&:'1HR%&'8HR& i# country5speci#ic data show low or

medium le!els o# -T# in *re8iously treated *atients) by using data from a drug resistance

sur8ey) from a national or su*ranational reference laboratory) or from a referral or

research centre see section +3$7 These data are critical for ascertaining the le8el

' 5ailures in a 9ell-run ,TP should be infre?uent in the absence of "D>-T# /f they do occur) they are

due either to "D>-T# or to *rogramme factors such as *oor DOT or *oor drug ?uality /f drugresistance data from failure *atients are a8ailable and these sho9 lo9 or medium le8els of "D>) *atients should recei8e the retreatment regimen outlined in 2+$) and e8ery effort should be made toaddress the underlying *rogrammatic issues

5

3


54/161


of "D> in retreatment *atients' 5or e@am*le) the results of re*resentati8e drug

resistance sur8eys may identify a grou* of *atients among 9hom a 8ery high

*ercentage ha8e "D>) 9hich could ustify the use of "D> regimens in all *atients

in the grou* e8en if indi8idual D1T is not a8ailable7 # 7 The ,TP manager is

encouraged to obtain technical assistance from the .reen Light Committee see

section +3+7

/f a 8ery high le8el of "D> is documented in a s*ecific grou* such as *atients 9ho

ha8e failed a retreatment regimen7) the ,TP manager should urgently see< means to

routinely obtain D1T on all such *atients at the start of treatment) in order to confirm

or e@clude "D> /f this cannot yet be achie8ed 9ith any in-country laboratory)

,TPs should ma-

T# regimen 9hile a9aiting confirmation of isonia0id and rifam*icin resistance last

ro9 of Table +47 # 7 This is a temporary measure that can be im*lemented only if

culture and D1T can be arranged in the first fe9 months of "D> treatment in each

enrolled *atient /t is essential to confirm the *resence of "D>) and to monitor theres*onse to treatment .rou*s of *atients 9hose li


55/161


Mne9 *atient regimenN: the regimen containing 6 months of rifam*icin:

$H>GB!4H> '

Mretreatment regimen 9ith first-line drugsN: $H>GB1!'H>GB!H>B$

M"D> regimenN

To im*lement these regimens in the country) the ,TP needs to consider the

follo9ing factors:

a8ailability of results of con8entional or ra*id molecular-based D1T to guide

management of indi8idual *atients;

le8el of drug resistance in the countryAs ne9 and *re8iously treated *atients;

number of "D>-T# *atients the *rogramme has the ca*acity to enrol and

treat;

the short-term ris< of dying from "D>-T# due to concomitant conditionses*ecially H/E) discussed in Cha*ter 7;

a8ailability of *atient su**ort and su*er8ision discussed in Cha*ter 67

"any of these factors de*end on a8ailable resources in the country) *articularly the

a8ailability of D1T and "D>-T# treatment #ecause these essential elements of the

1to* T# 1trategy are not yet fully in *lace throughout the 9orld) this cha*ter

*ro8ides guidance on interim a**roaches

Table +4 belo9 *resents suggestions for ho9 the ,TP manager can ta *re8alence /t is essential to detect

"D> as soon as *ossible in *ersons li8ing 9ith H/E) gi8en their high ris< of

mortality Table #.$ 8TAndArd regimen8 for pre/iou8l& TreATed

pATienT8 depending on the availabilit& of routine d8T to guide the

therap& of individual retreatment patients

' With or 9ithout ethambutol in the continuation *hase see section +$7

$ Countries 9ith ra*id molecular-based D1T 9ill not need this regimen

5

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dS "i8e"ihood of mdr 6)atient registration grou)a7

routinel& available for

previousl& treated

patients

-igh ;failureb< medium or low ;relapse4

default<

rapid molecularbased

method

d8T results available in 1! da&s confirm or exclude mdr

to guide the choice of regimen

conventional method while awaiting d8T resultsc

empirical mdr regimen !-r:e8@-r:e@-re

%egimen should be modi"ied %egimen should be

modi"ied once $*' results are a&ailable. once $*'

results are a&ailable.

none ;interim< empirical mdr regimen !-r:e8@-r:e@-re for full

%egimen should be modi"ied course of treatment.

once $*' results or $%* data %egimen should be

modi"ied

are a&ailable. once $*' results or $%* data

are a&ailable.a The assumption that failure patients have a high likelihood of mdr ;and relapse or defaulting

patients a medium likelihood< ma& need to be modified according to the level of mdr in these

patient registration groups4 as well considerations discussed in section #.*. b And other patients

in groups with high levels of mdr. one example is patients who develop active T, after known

contact with a patient with documented mdrT,. patients who are relapsing or returning after

defaulting from their second or subse9uent course of treatment probabl& also have a high

likelihood of mdr.c regimen ma& be modified once d8T results are available ;up to !# months after the start of

treatment-T#

S (ll ne9 *atients in countries 9here the le8el of "D>-T# in ne9 *atients is

+R

5

2


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27

/n addition to the indications listed abo8e for D1T at t(e start of treatment or

retreatment7) WHO recommends that D1T be *erforming during treatment in the

follo9ing situation:

S ,e9 and *re8iously treated *atients 9ho remain s*utum smear-*ositi8e at

the end of the intensi8e *hase should submit another s*ecimen for smear

microsco*y the follo9ing month /f that s*ecimen is also smear-*ositi8e) culture

and D1T should be undertaecommendation + in Cha*ter 47 This 9ill

allo9 a result to be a8ailable earlier than the fifth month of treatment

Com*rehensi8e systems for managing the ?uality of laboratory ser8ices) including

internal ?uality control and e@ternal ?uality assurance) are mandatory Laboratories

should follo9 standardi0ed *rotocols for good laboratory *ractice) technical *rocedures and biosafety) in com*liance 9ith international standards # 7

Documentary *roof of sustained technical *roficiency in D1T is essential) and lin and

am*lification of resistance to include ethambutol

S With em*irical use of "D> regimens) *atients 9hose D1T e8entually rules

out "D> 9ill ha8e been e@*osed to to@ic drugs they did not need 9hile a9aitingD1T results Conse?uences could include ad8erse drug effects and an increased

ris< of defaulting from treatment

' 1ee 9999hoint!tb!dots!laboratory!*olicy!en!inde@+html

5

3


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%a#id $*'

/n contrast to con8entional methods) molecular-am*lification assays such as line

*robe assays allo9 detection of rifam*icin resistance alone or in combination 9ith

isonia0id7 9ithin days of s*utum s*ecimens being obtained from the *atient and can

also be used on cultures obtained from ra*id li?uid culture systems7 Patients 9ith

"D>-T# can a8oid delays in starting an "D> regimen) and T# *atients 9ithout

"D> 9ill a8oid unnecessary second-line drug treatment WHO strongly encourages

the use of ra*id molecular and culture-based7 D1T in smear-*ositi8e *ersons li8ing

9ith H/E # 7

WHO recommends that ministries of health decide on line *robe assays for ra*id

detection of "D>-T# 9ithin the conte@t of country *lans for a**ro*riate

management of "D>-T# *atients; *lans should also include the de8elo*ment of

country-s*ecific screening algorithms and timely access to ?uality-assured second-line anti-T# drugs 2!7

Line *robe assays ha8e been ade?uately 8alidated in direct testing of s*utum

smear*ositi8e s*ecimens) as 9ell as on isolates of M. tuberculosis com*le@ gro9n

from smear-negati8e and smear-*ositi8e s*ecimens Direct use of line *robe assays

on smear-negati8e clinical s*ecimens is not recommended (do*tion of line *robe

assays does not eliminate the need for con8entional culture and D1T ca*ability;

culture remains necessary for definiti8e diagnosis of T# in smear-negati8e *atients)

9hile con8entional D1T is re?uired to determine drug susce*tibility to drugs other than rifam*icin and isonia0id (dditional guidance on selecting and im*lementing

ra*id drug susce*tibility tests can be found on the WHO 9eb site at:

9999hoint!tb! featuresUarchi8e!mdrtbUra*idUtests!en!inde@html

#.*.! level of drug resistance in the countr&3s new and previousl& treated

patients Countries re*orting a**ro@imately half the 9orldAs T# cases ha8e

conducted at least one drug resistance sur8ey since '&&4 %7 These results) together

9ith estimates of "D>-T# le8els in all countries) are a8ailable on the WHO 9eb

site at: 9999hoint! tb!featuresUarchi8e!drsre*ortUlaunchU$6feb%3!en!inde@html

Ne #atients

Drug resistance information is critical for managing ne9 *atients and selecting the

countryAs standard regimen for ne9 *atients:

S /f country data or WHO estimates7 sho9 that more than +R of ne9

*atients ha8e "D>) D1T should be obtained at the start of thera*y for all ne9

*atients see section +3'7

S "any countries ha8e a high le8el of isonia0id resistance in ne9 *atients butdo not ha8e drug susce*tibility results for isonia0id by the time of the

continuation *hase /n these countries) the ,TP may select an

5

2


59/161


isonia0id!rifam*icin!ethambutol continuation *hase for the standard regimen to be

used for all ne9 *atients) as discussed in section +$

,re&iously treated #atients(s discussed in section +6 abo8e) the ,TP needs to re8ie9 country-s*ecific data to

8erify) or modify) the assignment of failure *atients to high li #o@es +') +$ and ++ *ro8ide e@am*les of ho9 these data may

be used While WHO recommends that D1T be *erformed on all *re8iously treated

cases 227) systems that 9ill yield this critical information are not yet in *lace in

most countries Intil countries ha8e finished establishing the needed laboratory and

sur8eillance ca*acity) information on the le8el of "D> in *re8iously treated *atients

is a8ailable from a fe9 other sources

The .lobal Drug >esistance 1ur8eillance *roect includes actual and estimated

le8els of "D> in *re8iously treated *atients as a 9hole) although sam*le si0es 9ere

usually too small to yield 8ery *recise estimates %7 "oreo8er) only '% countries

ha8e measured "D> le8els in subgrou*s of *re8iously treated *atients since '&&4

5igure +$7

(lternati8e sources of data are in-country laboratories) su*ranational reference

laboratories) hos*itals) treatment centres and research *roects The results must be

inter*reted 9ith caution) as they re*resent only those *atients 9ho ha8e accessed thes*ecific ser8ices and those institutions 9here the testing is done 5or e@am*le) the

le8el of "D> found in a hos*ital-based sur8ey in a ca*ital city acce*ting referrals of

the most difficult cases is li


60/161


Note on other #atient-s#eci"ic ris "actors "or M$%

#y assigning registration grou*s of *re8iously treated *atients to high and medium

li-T# is *rior T# treatment 1)

1!7

Jno9n contact 9ith a *ro8en "D> case is another im*ortant determinant and can

be ascertained by T# *rogrammes at the time of *atient registration Other T#

*atients obser8ed to ha8e ele8ated "D> le8els in certain settings are those # 7:

treated in a *rogramme that o*erates *oorly;

9ith a history of using anti-T# drugs of *oor or un

such as certain *risons or mines7;

9ith co-morbid conditions associated 9ith malabsor*tion or ra*id-transit

diarrhoea;

li8ing 9ith H/E in some settings7;

9hose *rior course of thera*y included rifam*icin throughout (nne@ $7; ha8e ty*e $ diabetes mellitus 2"7

,TPs may be able to collect sam*les for D1T from some of the *atient grou*s listed

abo8e to determine their le8els of "D>

#.*.# number of mdrT, patients the programme has the capacit& to enrol

The .reen Light Committee .LC7 /nitiati8e hel*s countries to gain access to

?ualityassured second-line drugs' at considerably less than mar detection and treatment can a**ly to the .lobal 5und

to 5ight (/D1) Tuberculosis and "alaria or other donors for funding

' /f second-line drugs are used) the ,TP must ensure that they are ?uality-assured and can be *ro8ided by DOT throughout the entire '3–$4 months it ta


61/161


ox 3.2

5

3


62/161


An exAmple of A88igning T-e pATienT group wiT-

T-e -ig-e8T mdr le/el8 To recei/e empiricAl mdr TreATmenT4

And lATer Adding A pATienT group wiT- T-e nexT -ig-e8T mdr

le/el84 during 8cAleup of mdrT, TreATmenT,ased on a special surve& in one province4 countr& , finds an mdr level of 07I

in T, patients whose treatment failed after two or more prior courses. for

patients whose first treatment course failed4 the level is (7I. The T, patients in

this province are roughl& representative of the whole countr&3s T, patients. in

countr& ,4 d8T of isonia6id and rifampicin is done routinel& for individual

patients whose previous treatment has failed but results are t&picall& not

available for $ months.

countr& , has just begun a green light committee initiative project and has the

capacit& to treat a ver& limited number of mdrT, patients. it recommends thatpatients whose second or subse9uent course of treatment has failed be

managed as patients with a high likelihood of mdr ;as recommended in Table

#.$< and receive an empirical regimen for mdr while d8T results are awaited.

until the mdr programme is scaled up further4 patients whose first treatment

course has failed will be managed as those with a medium likelihood of mdr.

empiricall&4 the& all start the retreatment regimen with firstline drugs. when d8T

results are available $ months later4 those confirmed as having mdrT, are

changed to the mdr regimen.

Two &ears later4 another drug resistance surve& continues to show that (7I of patients whose first treatment failed have mdr4 and their outcomes have been

poor when treated empiricall& with the retreatment regimen of firstline drugs for

the $ months it takes to obtain d8T results. ,& contrast4 treatment with the

countr&3s standard mdr regimen is having good success in the patients in whom

two or more prior treatment courses have failed. The countr& applies for and

receives additional support from the global fund to now use empirical mdr

regimens ;while awaiting d8T results< for patients whose first treatment course

has failed.

(s sufficient funding becomes a8ailable) countries 9ill *ro8ide uni8ersal access to

"D>-T# treatment The stage of im*lementation has a bearing on the le8el of "D> that the country 9ill use to define MhighN) MmediumN and Mlo9N li *rogramme) 9hen the a8ailability of "D> treatment is

8ery limited) the ,TP may chose to include only the 8ery highest ris< *atients in the

Mhigh li treatment 9hile D1T results

are a9aited (s the *rogramme is scaled u*) the ,TP manager can include more

*atients 9ho need "D> treatment Thus) there are no absolute thresholds for lo9)

moderate) or high li-T# treatment

ox 3.3

5

2


63/161


An exAmple of weig-ing T-e -Arm8 And ,enefiT8 of empiricAl

mdr

TreATmenT in A 8eTTing of -ig- -i/ pre/Alence

in countr& c4 *7I of all T, patients are living with -i/4 and #7I of relapsepatients have mdr. while the countr& is planning to implement rapid d8T4 it takes

an average of ! months to obtain results using the current conventional

methods. The nTp is deciding which empirical regimen to include in the nTp

manual for relapse patients for the ! months it takes to obtain d8T results.

given the high level of -i/ and the attendant risks of earl& death from untreated

mdrT,4 the nTp decides to recommend that all relapse patients be treated with

the countr&3s empirical mdr regimen while d8T results are awaited. The benefit

of preventing earl& deaths in the #7I of relapse patients who do have mdr is

judged to be greater than the possible harmsa

of mdr treatment ;during the !months awaiting d8T results< in the +7I of relapse patients who will prove to

not have mdr.

a possible harms include drug toxicit&4 increased likelihood of patient default4 and burden

on patient and programme resources.

#.*.$ 8hortterm risk of death from mdrT,

Clinicians faced 9ith a 8ery ill T# *atient sus*ected of ha8ing "D>-T# 9ill initiate

an "D> regimen 9hile D1T results are *ending) e8en if the li regimen is out9eighed by the *ossible life-sa8ing benefit of the "D> regimen

1imilar udgements a**ly to regimen decisions at the le8el of the ,TP /f *re8iously

treated *atients as a grou* ha8e fre?uent concomitant conditions such as H/E7 that

increase the ris< of short-term death from "D>-T#) the ,TP 9ill 9ant to

recommend an em*irical "D> regimen for more retreatment *atients 9hile D1T

results are a9aited WHO also recommends the use of ra*id molecular-based tests

in smear-*ositi8e *ersons found to be li8ing 9ith H/E) as 9ell as culture-based D1T

to determine additional drug susce*tibility # 77

#.*. Availabilit& of patient support and supervision

The a8ailability of good ?uality *atient su**ort and su*er8ision is essential to

im*lementation of the regimens recommended in this cha*ter The im*ortance of the

ca*acity of T# *rogrammes to *ro8ide *atient-centred care is discussed in Cha*ter

6

references

' >ational Pharmaceutical "anagement Plus Program Managing

p(armaceuticals and commodities for tuberculosis: a guide for national tuberculosis

programs (rlington) E() "anagement 1ciences for Health) $%%

5

3


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$ (merican Thoracic 1ociety) CDC) /nfectious Diseases 1ociety of (merica

Treatment of tuberculosis Morbidity and Mortality @eekly Report:

Recommendations and Reports) $%%+) $>>-''7:'–22

+ -nternational tandards for Tuberculosis /are -T/;) $nd ed The Hague)

Tuberculosis Coalition for Technical (ssistance) $%%&4 Connor ) >after ,) >odgers ( Do fi@ed-dose combination *ills or unit-of-use

*acrganiAation) $%%4) 3$:&+–&+&

#artace< ( et al Com*arison of a four-drug fi@ed-dose combination regimen

9ith a single tablet regimen in smear-*ositi8e *ulmonary tuberculosis -nternational

4ournal of Tuberculosis and 0ung Disease) $%%&) '+:26%–266

6 6uidelines for t(e programmatic management of drug)resistant tuberculosis:

emergency update 2''% .ene8a) World Health Organi0ation) $%%3 WHO!HT"!

T#!$%%34%$72 "en0ies D et al Bffect of duration and intermittency of rifam*in on

tuberculosis treatment outcomes: a systematic re8ie9 and meta-analysis lo

Medicine) $%%&) 6:e'%%%'46

3 5nti)tuberculosis drug resistance in t(e world: fourt( global report .ene8a)

World Health Organi0ation) $%%3 WHO!HT"!T#!$%%3+&47

& "itchison D( #asic mechanisms of chemothera*y /(est ) '&2&) 266 1u**l7:

22'– 23'

'% Bs*inal "( et al Determinants of drug-resistant tuberculosis: analysis of ''

countries -nternational 4ournal of Tuberculosis and 0ung Disease ) $%%') :332–

3&+

'' Bs*inal "( et al 1tandard short-course chemothera*y for drug-resistant

tuberculosis: treatment outcomes in 6 countries 4ournal of t(e 5merican Medical

5ssociation) $%%%) $3+:$+2–$4

'$ uy HT et al Drug resistance among failure and rela*se cases of tuberculosis:

is the standard re-treatment regimen ade?uate -nternational 4ournal of

Tuberculosis and 0ung Disease) $%%+) 2:6+'–6+6

'+ 1ara8ia C et al >etreatment management strategies 9hen first-line

tuberculosis thera*y fails -nternational 4ournal of Tuberculosis and 0ung Disease)

$%%) &:4$'– 4$&'4 oshiyama T et al De8elo*ment of ac?uired drug resistance in recurrent

tuberculosis *atients 9ith 8arious *re8ious treatment outcomes -nternational

4ournal of Tuberculosis and 0ung Disease) $%%4) 3:+'–+3

' Drobnie9sussia 4ournal of t(e 5merican Medical

5ssociation) $%%) $&+:$2$6–$2+'

'6 5austini () Hall () Perucci C( >is< factors for multidrug resistant

tuberculosis in Buro*e: a systematic re8ie9 T(ora=) $%%6) 6':'3–'6+

'2 T(e 6lobal lan to top T* 2''#,2'1" .ene8a) World Health Organi0ation)

$%%6 WHO!HT"!1T#!$%%6+7

'3 #arnard " et al >a*id molecular screening for multidrug-resistant tuberculosis

in a high-8olume *ublic health laboratory in 1outh (frica 5merican 4ournal of

Respiratory and /ritical /are Medicine) $%%3) '22:232–2&$

5

2


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'& 1am /C et al "ycobacterium tuberculosis and rifam*in resistance) Inited

Jingdom ?merging -nfectious Diseases) $%%6) '$:2$–2&

$% "en0ies D et al 1tandardi0ed treatment of acti8e tuberculosis in *atients 9ith

*re8ious treatment and!or 9ith mono-resistance to isonia0id: a systematic re8ie9

and meta-analysis lo Medicine) $%%&) 6:e'%%%'%$' T(e global MDR)T* 9 +DR)T* response plan 2''$,2''% .ene8a) World

Health Organi0ation) $%%2 WHO!HT"!T#!$%%2+327

$$ 6uidelines for t(e surveillance of drug resistance in tuberculosis) 4th ed

.ene8a) World Health Organi0ation) $%%& WHO!HT"!T#!$%%&4$$7

$+ Bs*inal ") >a8iglione "C 5rom threat to reality: the real face of multidrug-

resistant tuberculosis 5merican 4ournal of Respiratory and /ritical /are Medicine)

$%%3) '23:$'6–$'2

$4 Molecular line probe assays for rapid screening of patients at risk of MDR T*:

policy statement .ene8a) World Health Organi0ation) $%%3 a8ailable at:9999hoint!tb! featuresUarchi8e!*olicyUstatement*df7

$ 5isher-Hoch 1P et al Ty*e $ diabetes and multidrug-resistant tuberculosis

candinavian 4ournal of -nfectious Diseases) $%%3) 4%:333–3&+

5

3


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67/161

)onitoring during

treatment

$.1 Cha)ter o!ectives

This cha*ter describes ho9 to:

monitor and record the res*onse to treatment) and decide on actions to ta


68/161


figure $.1 8puTum moniToring ,& 8meAr micro8cop& in new pulmonAr& T,

pATienT8Note if a patient is found to harbour a multidrugresistant strain of T, at an& time during

therap&4 treatment is declared a failure and the patient is reregistered and should be referred to

an mdrT, treatment programme.

months of treatment

1 2 3 $ 5 (

J K

D

J

D a if sm B4 obtain

culture4 d8Tb

K

D a if sm B4 obtain

culture4 d8Tb

if smearpositive at month !4 obtain sputum again at month #. if smearpositive at

month #4 obtain culture and d8T. J K J K

D D D D ;sm B< if sm B4 obtain if sm B4 obtain if sm B4 obtain culture4

d8T culture4 d8Tb culture4 d8Tb

=e&

JK intensive phase of treatment ;-r:e<

JK continuation phase ;-r<

D 8putum smear examination sm B 8mearpositive a omit if patient was

smearnegative at the start of treatment and at ! months.b

8mear or culturepositivit& at the fifth month or later ;or detection of mdrT, at an& point< is defined

as treatment failure and necessitates reregistration and change of treatment as

described in section #.+.

figure $.! 8puTum moniToring of pulmonAr& T, pATienT8 recei/ing T-e *

monT- reTreATmenT regimen wiT- fir8Tline drug8

months of treatment

1 2 3 $ 5 ( * +

J K

D if smB4

obtain

culture4

d8T

JD

if sm B4obtain

culture4

d8Ta

K

D if sm B4obtain

culture4

d8Ta

=e&

JK intensive phase ! months of -r:e8 followed b& 1 month of -r:e

JK continuation phase with months of -re

D 8putum smear examination

sm B 8mearpositivea 8mear or culturepositivit& at the fifth month or later ;or detection of mdrT, at an& point< is

defined as treatment failure and necessitates reregistration and change of treatment as

described in section #.+.

6

6


69/161

$. monIorIn# durIn# rEamEn

This recommendation a**lies both to ne9 *atients treated 9ith regimens containing

6 months of rifam*icin $H>GB!4H>7 and to *re8iously treated *atients recei8ing

the 3-month retreatment regimen 9ith first-line drugs $H>GB1!'H>GB!H>B7

1*utum should be collected 9hen the *atient is gi8en the last dose of the

intensi8e*hase treatment The end of the intensi8e *hase is at $ months in ne9

*atients and + months in *re8iously treated *atients recei8ing the 3-month regimen

of first-line drugs This recommendation also a**lies to smear-negati8e *atients

1*utum s*ecimens should be collected for smear e@amination at each follo9-u*

s*utum chec(DB tables are

a8ailable from WHO u*on re?uest

6

5


70/161



3n new patients* i# the specimen o)tained at the end o# the intensi!e phase

/month 2 is smear5positi!e* sputum smear microscopy should )e o)tained at

the end o# the third month

1trong!High grade of e8idence7L Recommendation 8.

3n new patients* i# the specimen o)tained at the end o# month is smear5

positi!e* sputum culture and drug suscepti)ility testing /9:T should )e

per#ormed 1trong!High grade of e8idence7

The main *ur*ose of obtaining cultures at this stage is to detect drug resistance

9ithout 9aiting until the fifth month to change to a**ro*riate thera*y ' ,ote that

treatment is declared a failure if a *atient is found to harbour "D>-T# at any *oint

in time during treatment; see Table 4'7

/f the country does not yet ha8e sufficient laboratory ca*acity for culture and D1T)

additional monitoring of *atients 9ho are still smear-*ositi8e at month + 9ill be only

by s*utum smear microsco*y during the fifth month and during the final month of

treatment /f either result is *ositi8e) treatment has failed) the *atient is reregistered

and treatment is changed as described in Cha*ter +

Ne #ulmonary '( #atients ith #ositi&e s#utum smears at the start o"

treatment These *atients should be monitored by s*utum smear microsco*y at the end of the

fifth and si@th months /f results at the fifth or si@th month are *ositi8e) a s*utum

s*ecimen should be obtained for culture and D1T Treatment has failed) the T#

Treatment Card is closed Outcome X treatment failure7 and a ne9 one is o*ened

Ty*e of *atient X treatment after failure7 Treatment should follo9 the

recommendations in Cha*ter + /f a *atient is found to harbour a multidrug-resistant

strain of T# at any *oint of time during thera*y) treatment is also declared a failure

1ee 5igure 4' for a monitoring scheme 9ith s*utum smear microsco*y

Ne #ulmonary '( #atients hose s#utum smear microsco#y as negati&e

or not done/ at the start o" treatment

/t is im*ortant to rechec< a s*utum s*ecimen at the end of the intensi8e *hase in case

of disease *rogression due to non-adherence or drug resistance7 or an error at the

time of initial diagnosis ie a true smear-*ositi8e *atient 9as misdiagnosed as

smear-negati8e7$ Pulmonary T# *atients 9hose s*utum smear microsco*y 9as

negati8e or not done7 before treatment and 9hose s*utum smears are negati8e at $

months need no further s*utum monitoring They should be monitored clinically;

body 9eight is a useful *rogress indicator

' B8en if there is e8entually full susce*tibility) a *ositi8e culture confirms *oor res*onse to treatment)

9hich necessitates in8estigation and inter8ention

$ /f the s*utum is found to be smear-*ositi8e) see >ecommendations $ and + abo8e

6

6


71/161

$. monIorIn# durIn# rEamEn

$.#.! previousl& treated sputum smearpositive pulmonar& T, patients

receiving firstline antiT, drugs

1*utum smear e@amination is *erformed at the end of the intensi8e *hase of

treatment the +rd month7) at the end of the fifth month and at the end of treatment

the eighth month7 /f the country has already de8elo*ed sufficient laboratory

ca*acity) culture and D1T should be *erformed

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