Management of MDR-TB

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Guidelines for theprogrammatic management of

drug-resistant tuberculosisEmErgEncy updatE 2008

ISBn 978 92 4 154758 1

guidelinesfortheprorammaticmanaementofdru-resis

tanttuberculosis

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tuberculosis: emergency updated edition 2008 eles evios

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Guidelies or te

rogrammatic maagemeto drug-resistat

tuberculosis


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WHO Library Cataloguing-in-Publication Data

Guidelines or the programmatic management o drug-resistant tuberculosis. WHO/HTM/TB/2008.402 .

1.Tuberculosis, Multidrug-resistant drug therapy. 2.Tuberculosis, Multidrug-resistant prevention and control. 3.Antitubercular agents administration anddosage. 4.HIV inections drug therapy. 5.Antiretroviral therapy, Highly active.6.Guidelines. I.World Health Organization.

ISBN 978 92 4 154758 1 (NLM classication: WF 310)

The 2006 edition was unded by the Bill & Melinda Gates Foundation and the Unit-ed States Agency or International Development to the Green Light Committee sub-

group o the Stop TB Partnership Working Group on MDR-TB.The 2008 emergency update was unded by the UK Department or International

Development and the United States Agency or International Development. Theirnancial contribution was essential or WHO and partners to produce and analysemost o the evidence supporting these guidelines.

Emergency update, 2008

Expiry date: 2010

World Health Organization 2008

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

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The designations employed and the presentation o the material in this publication do not imply theexpression o any opinion whatsoever on the part o the World Health Organization concerning the

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Cotets

Acknowledgements v

Abbreviations viii

Executive summary xi

Foreword to the 2008 emergency updated edition xvii

Chapter 1 Background inormation on DR-TB 1

Chapter 2 Framework or eective control o DR-TB 8

Chapter 3 Political commitment and coordination 14

Chapter 4 Denitions: case registration, bacteriology and

treatment outcomes 19

Chapter 5 Case-nding strategies 26

Chapter 6 Laboratory aspects 36

Chapter 7 Treatment strategies or MDR-TB and XDR-TB 50

Chapter 8 Mono-resistant and poly-resistant strains (DR-TB other

than MDR-TB) 75

Chapter 9 Treatment o DR-TB in special conditions and situations 79

Chapter 10 HIV inection and MDR-TB 89

Chapter 11 Initial evaluation, monitoring o treatment andmanagement o adverse eects 107

Chapter 12 Treatment delivery and community-based DR-TB support 120

Chapter 13 Management o patients ater MDR-TB treatment ailure 130

Chapter 14 Management o contacts o MDR-TB patients 135

Chapter 15 Drug resistance and inection control 140

Chapter 16 Human resources: training and stang 145

Chapter 17 Management o second-line antituberculosis drugs 150

Chapter 18 Category IV recording and reporting system 154

Chapter 19 Managing DR-TB through patient-centred care 165


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iv

GUIDELINES FOR THE PROGRAMMATIC MANAGEMENT OF DRUG-RESISTANT TUBERCULOSIS

Aees

Annex 1 Drug inormation sheets 173

Annex 2 Weight-based dosing o drugs or adults 193

Annex 3 Suggestions or urther reading 195

Annex 4 Legislation, human rights and patients rights in

tuberculosis prevention and control 198

Annex 5 Use o experimental drugs outside o clinical trials

(compassionate use) 208

Annex 6 Methodology 213

Forms 217


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v

Ackoledgemets

WHO grateully acknowledges the contributions o the ollowing individuals

to the 2006 edition and the 2008 emergency edition.

2006 editio

Writing Committee

Jaime Bayona

Karin Bergstrm

Kai Blndal

Jos Caminero

Peter Cegielski

Manred Danilovits

Jennier Furin

Victoria Gammino

Malgorzata Grzemska

Einar Heldal

Myriam Henkens

Vahur Hollo

Ernesto Jaramillo

Fabienne Jouberton

Boris Kazenniy

Michael Kimerling

Hans Kluge

Kitty Lambregts

Kayla Laserson

Vaira Leimane

Andrey Mariandyshev

Fuad Mirzayev

Carole Mitnick

Joia Mukherjee

Edward Nardell

Eva Nathanson

Lisa Nelson

Paul Nunn

Michael Rich

Kwonjune Seung

Alexander Sloutsky

Tamara Tonkel

Arnaud Trbucq

Thelma Tupasi

Francis Varaine

Irina Vasilieva

Fraser Wares

Karin Weyer

Abigail Wright

Matteo Zignol

Expert Reiew Committee

Marcos Espinal

Paul Farmer

Mario Raviglione

Wang Xie Xiu

2008 emergec udate

Steering Group

Ernesto JaramilloSalmaan Kevshavjee

Kitty Lambregts

Michael Rich

Karen Weyer (Chair)


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Guidelines Reerence Group

Jaime Bayona, Socios En Salud, Sucursal Peru, Lima, Peru

Jose Caminero, International Union Against Tuberculosis and Lung Disease,

Paris, FranceRichard Coker, London School o Hygiene and Tropical Medicine, London,

UK

Charles Daley, National Jewish Medical and Research Center, Denver, CO,

USA

Hamish Fraser, Partners In Health, USA

Jennier Furin, Partners In Health, Boston, MA, USA

Giuliano Gargioni, WHO Stop TB Department, Geneva, Switzerland

Haileyesus Getahun, WHO Stop TB Department, Geneva, Switzerland

Charles Gilks, WHO HIV Department, Geneva, Switzerland

Case Gordon, World Care Council, Geneva, Switzerland

Reuben Granich, WHO HIV Department, Geneva, Switzerland

Diane Havlir, University o Caliornia, San Francisco, CA, USA

Einar Heldal, Independent consultant

Tim Holtz, United States Centers or Disease Control and Prevention, At-

lanta, GA, USA

Phil Hopewell, University o Caliornia, San Francisco, CA, USA

Ernesto Jaramillo, WHO Stop TB Department, Geneva, SwitzerlandSalmaan Kevshavjee, Partners In Health, Harvard Medical School, Boston,

MA, USA

Catharina (Kitty) Lambregts van Weezenbeek, KNCV Tuberculosis Founda-

tion, Netherlands

Vaira Leimane, State Agency o Tuberculosis and Lung Diseases, Latvia

Reloe Matji, University Research Corporation, South Arica

Fuad Mirzayev, WHO Stop TB Department, Geneva, Switzerland

Carole Mitnick, Harvard Medical School, Boston, MA, USA

Christo van Niekerk, Global Alliance or TB Drug DevelopmentDomingo Palmero, Hospital Muniz, Buenos Aires, Argentina

Genevive Pinet, WHO Legal Department, Geneva, Switzerland

Mamel Quelapio, Tropical Disease Foundation, Philippines

Michael Rich, Partners In Health/Division o Social Medicine and Health

Inequalities, Brigham and Womens Hospital, Boston, MA, USA

Vija Riekstina, State Agency o Tuberculosis and Lung Diseases, Latvia

Irina Sahakyan, WHO Stop TB Department, Geneva, Switzerland

Fabio Scano, WHO Stop TB Department, Geneva, Switzerland

Adrienne Socci, Partners In Health, Boston, MA, USAKathrin Thomas, WHO Stop TB Department, Geneva, Switzerland

Arnaud Trbucq, International Union Against Tuberculosis and Lung Dis-

ease, Paris, France


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Francis Varaine, Mdecins Sans Frontires, France

Marco Vitoria, WHO HIV Department, Geneva, Switzerland

Fraser Wares, WHO Regional Oce or South-East Asia, New Delhi

Karin Weyer, WHO Stop TB Department, Geneva, SwitzerlandAbigail Wright, WHO Stop TB Department, Geneva, Switzerland

Matteo Zignol, WHO Stop TB Department, Geneva, Switzerland

Declaratio o iterests

All o the above contributors completed a WHO Declaration o Interest orm.

The ollowing interests were declared:

Case Gordon declared that he is an unpaid advocate or patients with anti-

TB drug resistance and or improved access to high-quality care. Hedeclared that he has himsel survived XDR-TB.

Tim Holtz declared that he is an unpaid technical adviser and member o

the Scientic Advisory Board o a manuacturer o anti-TB products, to

advise on the development o a new anti-TB compound that will be tested

in clinical trials o MDR-TB regimens.

Salmaan Keshavjee declared that his employer received unding rom a oun-

dation associated with a manuacturer o anti-TB products to support the

research and training unit that he is heading.

Carole Mitnick declared that she is serving as a paid member o theScientic Advisory Board o a manuacturer o anti-TB products, to ad-

vise on the development o a new anti-TB compound that will be tested in

clinical trials o MDR-TB regimens.

Michael Rich declared that his employer received unding rom a manuac-

turer o anti-TB products, in support o his salary.

ACkNOWLEDGEMENTS


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Abbreiatios

ACSM advocacy, communication and social mobilization

AFB acid-ast bacilli

AIDS acquired immunodeciency syndromeART antiretroviral therapy

CDC United States Centers or Disease Control and Prevention

CHW community health worker

CMV cytomegalovirus

CPT co-trimoxazole preventive therapy

CXR chest X-ray

DOT directly observed therapy

DOTS The internationally recommended strategy or TB control

until 2005, and the oundation o the new Stop TB Strategy

introduced in 2006

DRS drug resistance surveillance

DR-TB drug-resistant tuberculosis

DST drug susceptibility testing

FDC xed-dose combination

FIND Foundation or Innovative New Diagnostics

GLC Green Light Committee

Global Fund Global Fund to Fight AIDS, Tuberculosis and MalariaHAART highly active antiretroviral therapy

HIV human immunodeciency virus

HPF high-power eld

HRD human resource development

IHR International Health Regulations

IRIS immune reconstitution infammatory syndrome

LFT liver unction test

MDR-TB multidrug-resistant tuberculosis

MIC minimum inhibitory concentrationNNRTI non-nucleoside reverse transcriptase inhibitor

NRTI nucleoside reverse transcriptase inhibitor

NTM non-tuberculous mycobacteria

NTP national TB control programme


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PI protease inhibitor

PIH Partners In Health

PPD puried protein derivative

PPM publicprivate mixR&R recording and reporting

SCC short-course chemotherapy

SMX sulamethoxazole

SRL supranational reerence laboratories

STB WHO Stop TB Department

TB tuberculosis

TB/HIV HIV-related TB

TMP trimethroprim

TSH thyroid-stimulating hormone

UNAIDS Joint United Nations Programme on HIV/AIDS

Union International Union Against Tuberculosis and Lung Disease

UVGI ultraviolet germicidal irradiation

WHO World Health Organization

XDR-TB extensively drug-resistant tuberculosis

Antituberculosis drug abbreiations

Group Description DruG AbbreviAtion

1 First-line oral isoniazid H

antituberculosis drugs riampicin R

ethambutol E

prazinamide Z

riabutin Rb

2 Injectable antituberculosis anamcin km

drugs amiacin Am

capreomcin Cm

streptomcin S

3 Fluoroquinolones leooxacin Lx

moxioxacin Mx

ooxacin Ox

4 Oral bacteriostatic second-line ethionamide Eto

antituberculosis drugs protionamide Pto

ccloserine Cs

terizidone Trd

p-aminosaliclic acid PAS

5 Antituberculosis drugs with cloazimine Cz

unclear efcac or unclear role linezolid Lzd

in MDR-TB treatment (not amoxicillin/claulanate Amx/Cl

recommended b WHO or thioacetazone Thz

routine use in MDR-TB patients) clarithromcin Clr

imipenem Ipm

ABBREvIATION


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Antiretroiral drug abbreiations

DruG clAss nAme AbbreviAtion

Non-nucleoside reerse transcriptase inhibitors eairenz EFvneirapine NvP

Nucleoside reerse transcriptase inhibitors zidoudine AZT

lamiudine 3TC

staudine D4T

didanosine ddI

zalcitabine ddC

abacair ABC

tenooir TDFa

Protease inhibitors indinair IDv

ritonair RTv

saquinair SQv

nelfnair NFv

lopinair/ritonair LPv/RTv

a TDF is a nucleotide reerse transcriptase inhibitor but is tpicall grouped with this class o

drugs.


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Eecutie summar

Multidrug-resistant tuberculosis (MDR-TB), dened as TB caused by

organisms that are resistant to isoniazid and riampicin, two rst-line anti-

TB drugs, continues to threaten the progress made in controlling the dis-ease. The emergence o extensively drug-resistant TB (XDR-TB), dened

as MDR-TB that is resistant as well to any one o the fuoroquinolones and

to at least one o three injectable second-line drugs (amikacin, capreomycin

or kanamycin), has heightened this threat. XDR-TB has been identied in

all regions o the world since 2006. Treatment outcomes are signicantly

worse in XDR-TB patients than in MDR-TB patients. Outbreaks o XDR-

TB in populations with high prevalence o HIV have caused alarmingly high

mortality rates. The emergence o XDR-TB as a new threat to global public

health demands that health ocials and health-care providers respond with

a coordinated strategy drawing on the Stop TB Strategy.1

Guidelines or the programmatic management o drug-resistant tuberculosis:emergency update 2008provides updated guidelines and recommendationson how to manage drug-resistant TB (DR-TB) based on a rapid assessment o

the best available evidence by a group o experts. A ully revised second edi-

tion will be published in 2010, ollowing WHO guidance on retrieval, syn-

thesis and grading o evidence. Until that time, the emergency update serves

as interim guidance or TB control programmes and medical practitionerson all aspects o the management o DR-TB, including XDR-TB. It contains

19 chapters based on the original 18 chapters rom the rst edition published

by the World Health Organization in 20062 plus an additional chapter on

patient-centered care.

1 The Stop TB Strategy launched by the World Health Organization in 2006 describes the recom-mended interventions that should be implemented to achieve the targets or global TB controlthat have been established within the context o the Millennium Development Goals. See Rav-iglione MC, Uplekar MW. WHOs new Stop TB Strategy. Lancet, 2006, 367:952955.

2 Guidelines or the programmatic management o drug-resistant tuberculosis. Geneva, World HealthOrganization, 2006 (WHO/HTM/TB/2006.361).


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The key changes or the emergency update 2008 are summarized below.

chApter Key recommenDAtions Key chAnGes(* da dad da)

Cater 1 Not applicable Target audience is defned.

Bacground Deelopment o guidelines is

inormation on described.

drug-resistant Stop TB Strateg is

tuberculosis summarized.

New data are proided rom

the WHO/IUATLD Global

Project on Antituberculosis

Drug Resistance

Sureillance.

Updated inormation isproided rom a sure o the

networ o supranational

reerence laboratories to

determine the prealence o

XDR-TB among strains sent

or drug susceptibilit testing

(DST).

Cater 4 Not applicable Defnition o XDR-TB is

Defnitions: case introduced.

registration, Concise instructions or

bacteriolog and registration o new cases otreatment XDR-TB are proided.

outcomes

Cater 5 All patients at increased ris Stronger emphasis is placed

Case-fnding or MDR-TB should be screened on the recommendation that

strategies or drug resistance.* all patients at increased ris

Patients inected with HIv or MDR-TB should receie

should receie DST at the start DST, with the goal o

o anti-TB therap to aoid uniersal access to DST or

mortalit caused b all that need it.

unrecognized MDR-TB.* The use o rapid DST in all

Rapid DST should be used or HIv-inected patients who arethe initial screening o MDR-TB smear-positie is highl

wheneer possible. encouraged, and it is

Patients at increased ris or recommended that all

XDR-TB should receie DST o HIv-inected patients at

isoniazid, riampicin, second- moderate to high ris be

line injectable agents and a screened or resistance in

uoroquinolone.* order to aoid the high

mortalit associated with

unrecognized MDR-TB.

An algorithm or the use o

rapid drug-resistance testing

is introduced.

The use o DST or second-

line drugs in case-fnding or

XDR-TB is introduced, and

ris actors or XDR-TB are

described.


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EXECUTIvE SUMMARy

chApter Key recommenDAtions Key chAnGes(* da dad da)

Cater 6 All patients with suspected Defnitions o common terms

Laborator MDR-TB or XDR-TB need access used in laborator issues areaspects to laborator serices or proided at the start o the

adequate and timel diagnosis. chapter.

Laboratories should be tested New recommendations or

or profcienc and qualit DST to second-line drugs are

assured externall to perorm proposed based on recent

DST.* WHO polic guidance;

Laboratories should perorm Reerences or regulations on

DST or the uoroquinolones how to transport inectious

and second-line injectable specimens internationall are

agents where adequate capacit proided.

and expertise exists.* DR-TB strains can be

transported sael across

international borders i inter-

national procedures and guide-

lines are ollowed.*

Laboratories must ollow all

standardized protocols or

inection control and biosaet.

Qualit control and qualit

assurance should be in place

or microscop, culture and DST.

Lins with supranational

reerence laboratories are

strongl encouraged.

Cater 7 Design regimens with a The fe groups o anti-TB

Treatment consistent approach based on drugs are re-defned.

strategies or the hierarch o the fe groups Thioacetazone is placed in

MDR-TB o anti-TB drugs. Group 5. High-dose isoniazid

Promptl diagnose MDR-TB and and imipenem are added to

initiate appropriate therap. Group 5.

Use at least our drugs with Ciprooxacin is remoed as

either certain, or almost certain, an anti-TB agent because o

eectieness. its wea efcac compared

DST should generall be used to with other uoroquinolones.

guide therap; howeer, do not Strong caution is warranted

depend on DST o ethambutol or an programme that uses

or prazinamide in indiidual gatioxacin gien the rare but

regimen design, prazinamide, dangerous aderse eects o

Group 4 and 5 drugs. dsglcaemia associated

Do not use ciprooxacin as an with this drug.

anti-TB agent in management A new reiew o DST o

o DR-TB.** second-line drugs has

Design a programme strateg resulted in strong caution

that taes into consideration against basing the design oaccess to qualit-assured DST, indiidual regimens on

rates o DR-TB, HIv prealence, results o DST o ethambutol,

technical capacit and fnancial prazinamide, or Group 4 and

resources. 5 drugs.


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Foreord to te 2008emergec udated editio

The emergence o resistance to antituberculosis drugs, and particularly o multi-

drug-resistant TB (MDR-TB),1 has become a major public health problem in a

number o countries and an obstacle to eective global TB control. Nearly hala million cases o MDR-TB emerge every year as a result o under-investment

in basic activities to control TB, poor management o the supply and quality o

antituberculosis drugs, improper treatment o TB patients and transmission o

the disease in congregate settings. However, in many areas such as Arica, the

extent o drug resistance is unknown and in most resource-constrained coun-

tries the treatment o patients with MDR-TB is absent or inadequate.

As with other inectious diseases, rom staphylococcal inections to ma-

laria, pathogens have almost invariably developed resistance to the drugs used

to treat them. Tuberculosis is no exception: strains resistant to streptomycin

were identied within months o the start o use, in the mid 1940s, o this

rst antituberculosis drug. Indeed, the emergence o drug resistance was the

primary reason that therapy or TB evolved to include treatment with more

than one drug or up to 18 to 24 months the standard o care or over two

decades. The advent o riampicin in the early 1970s permitted a drastic reduc-

tion in the duration o therapy to six months while the ecacy o treatment

improved. But those amiliar with drug resistance in general would have pre-

dicted the emergence o resistance to what are now termed these rst-linedrugs, and by the mid-1990s, most countries participating in a global survey

o anti-TB drug resistance registered cases o MDR-TB. The worse was yet to

come: in 2006, extensively drug-resistant TB (XDR-TB) emerged. This is de-

ned as resistance to rst- and second-line drugs2 and was rapidly announced

by the World Health Organization (WHO) as a serious emerging threat to

global public health, especially in countries with a high prevalence o human

immunodeciency virus (HIV). In act, reports have identied XDR-TB in

all regions o the world and, to date, treatment outcomes have been shown to

1 MDR-TB is dened as TB caused byMycobacterium tuberculosisresistant in vitro to the eects oisoniazid and riampicin, with or without resistance to any other drugs. Resistance is dened byspecic laboratory criteria (see Chapter 6).

2 XDR-TB is dened as TB resistant to multiple rst-line drugs as well as to any one o the fuo-roquinolones and to at least one o three injectable second-line drugs (amikacin, capreomycin orkanamycin).


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lished in June 2000 as a partnership among ve categories o participants:

governments o resource-limited countries; academic institutions; civil-society

organizations; bilateral donors; and WHO. The GLC has successully negoti-

ated prices o drugs with producers; solicited creation o, and adopted soundpolicies or, proper management o DR-TB; established strict criteria to review

proposals or DR-TB management programmes; assisted countries in develop-

ing such proposals and ensured their proper implementation; and, nally, has

provided access to quality-assured second-line drugs at concessionary prices

to those management programmes considered technically and scientically

sound and not at risk o producing additional drug resistance. In brie, the

GLC rapidly became a model o good practice which, by providing access to

previously unaordable drugs, ensured that their use was as sae and ratio-

nal as possible. Demand or technical assistance rom the GLC grew rapidly

and in 2002, the GLC was adopted by the newly established Global Fund to

Fight AIDS, Tuberculosis and Malaria (the Global Fund) as its mechanism or

screening proposals or DR-TB programme nancing. This was a major his-

toric milestone, and today the Global Fund is the leading nancial mechanism

supporting the management o MDR-TB in resource-constrained settings.

Today, a new threat that linked to XDR-TB now requires even more in-

novative thinking (7). In October 2006, the WHO Stop TB and HIV depart-

ments organized a meeting o the Global Task Force on XDR-TB at WHOheadquarters in Geneva, Switzerland, in response to the XDR-TB emergency.

During this meeting, eight recommendations were put orward to the inter-

national TB community, outlining key areas o response, beginning with

strengthening o basic TB and HIV/AIDS control and proper management o

MDR-TB (8). The eight recommendations are:

strengthening basic activities to control TB and HIV/AIDS, as detailed in

the Stop TB Strategy and the Global Plan, to avoid additional emergence

o MDR-TB and XDR-TB;

scaling-up the programmatic management o MDR-TB and XDR-TB to

reach the targets set orth in the Global Plan;

strengthening laboratory services or adequate and timely diagnosis o

MDR-TB and XDR-TB;

expanding surveillance o MDR-TB and XDR-TB to better understand the

magnitude and trends o drug resistance and the links with HIV;

ostering sound inection-control measures to avoid MDR-TB and XDR-

TB transmission to protect patients, health workers, others working in

congregate settings and the broader community, especially in high HIVprevalence settings;

strengthening advocacy, communication and social mobilization or sus-

tained political commitment and a patient-centered approach to treat-

ment;

FOREWORD TO THE 2008 EMERGENCy UPDATED EDITION


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pursuing resource mobilization at global, regional and country levels to en-

sure that necessary resources are available;

promoting research and development into new diagnostics, drugs, vaccines,

and operational research on MDR-TB management to shorten the lengtho treatment.

The ongoing changes in the eld combined with new evidence and recom-

mendations mandate a revision o the previous guidelines. This publication

aims to underpin these recommendations with new or updated guidelines

that might provide the guidance on programmatic management necessary to

achieve many o the eight recommendations rom the Global Task Force. We

are condent that these new guidelines represent the best current knowledge

regarding the management o DR-TB and MDR-TB and oer programmesand providers options or tailoring diagnosis and care to the needs evinced

in dierent epidemiological and programmatic contexts. The recommenda-

tions, compiled by leading experts, should be ollowed by all national TB con-

trol programmes and their partners. With nearly hal a million new cases o

MDR-TB emerging every year, and an estimated global prevalence that may

be as high as one million cases, the challenge is huge. At the same time, it is

imperative to stress that the ve elements o the DOTS strategy remain the

cornerstone o TB control and the most eective tool or preventing the onset

and dissemination o drug resistance. Without the essential elements o TBcontrol ully in place, management o MDR-TB will undoubtedly ail in the

long term, as one cannot control it i the tap is not turned o. These updated

guidelines ocus on care or DR-TB patients, in the hope that the occurrence

o massive numbers o new cases can be prevented through sound TB-

control practices. While urther scientic advances are clearly needed in the

ght against DR-TB, these guidelines outline the tools we have at our disposal

to make an immediate impact on this destructive and grave epidemic.

Dr Mario Raviglione

Director

Stop TB DepartmentWorld Health Organization


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Reereces

1. Gandhi NR et al. Extensively drug-resistant tuberculosis as a cause o

death in patients co-inected with tuberculosis and HIV in a rural area

o South Arica. Lancet, 2006, 368(9547):15751580.2. Shah NS et al. Worldwide emergence o extensively drug-resistant tuber-

culosis. Emerging Inectious Diseases, 2007, 13(3):380387.3. Migliori GB et al. Extensively drug-resistant tuberculosis, Italy and Ger-

many. Emerging Inectious Diseases, 2007, 13(5):780782.4. Kim HR et al. Impact o extensive drug resistance on treatment outcomes

in non-HIV-inected patients with multidrug-resistant tuberculosis. Clin-ical Inectious Diseases, 2007, 45(10):12901295.

5. Guidelines or the programmatic management o drug-resistant tuberculo-sis. Geneva, World Health Organization, 2006 (WHO/HTM/TB/2006.361).

6. Treatment o tuberculosis: guidelines or national programmes, 3rd ed. Ge-neva, World Health Organization, 2003 (WHO/CDS/TB/2003.313).

7. Raviglione MC, Smith IM. XDR tuberculosis Implications or global

public health. New England Journal o Medicine, 2007, 356(7):656659.8. The Global MDR-TB & XDR-TB Response Plan 20072008. Geneva,

World Health Organization, 2007 (WHO/HTM/TB/2007.387).

FOREWORD TO THE 2008 EMERGENCy UPDATED EDITION


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1

CHAPTER 1

Backgroud iormatioo DR-TB

1.1 Chapter objecties 1

1.2 The Stop TB Strateg 1

1.2.1 Pursuing high-qualit DOTS expansion and enhancement 2

1.2.2 MDR-TB, XDR-TB and other challenges 2

1.2.3 Contributing to health sstem strengthening 2

1.2.4 Engaging all care proiders 2

1.2.5 Empowering people with TB, and communities 2

1.2.6 Enabling and promoting research 2

1.3 Integration o diagnostic and treatment serices to control TB 2

1.4 Causes o DR-TB 3

1.5 Addressing the sources o DR-TB 3

1.6 Magnitude o the DR-TB problem 4

1.7 Management o DR-TB, the Green Light Committee and

the global response to DR-TB 6

Table 1.1 Causes o inadequate antituberculosis treatment 3

1.1 Cater objecties

This chapter summarizes key inormation on the emergence o drug-resistantTB (DR-TB), its public health impact, experience gained in the management

o patients and strategies or addressing drug resistance within national TB

control programmes (NTPs).

1.2 Te Sto TB Strateg

The goals o the Stop TB Strategy are to reduce dramatically the burden o

TB by 2015 in line with the Millennium Development Goals and the Stop TB

Partnership targets and to achieve major progress in the research and devel-

opment needed or TB elimination. The Stop TB Strategy continues to em-phasize the basic components o the DOTS strategy (See Chapter 2 or how

the basic DOTS strategy applies to DR-TB) while addressing additional con-

straints and challenges to TB control. The Stop TB Strategy has six principal

components:


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1.2.1 Pursuing high-qualit DOTS expansion and enhancement

a. Political commitment with increased and sustained nancing

b. Case detection through quality-assured bacteriology

c. Standardized treatment with supervision and patient supportd. Eective drug supply and management system

e. Monitoring and evaluation system and impact measurement

1.2.2 Addressing TB/HIv, MDR-TB, XDR-TB and other challenges by

implementing collaborative TB/HIV activities, preventing and controlling

DR-TB, including XDR-TB, and addressing prisoners, reugees and other

high-risk groups and situations.

1.2.3 Contributing to health sstem strengthening by collaboratingwith other health-care programmes and general services, e.g. by mobilizing

the necessary human and nancial resources or implementation and im-

pact evaluation, and by sharing and applying achievements o TB control

as well as innovations rom other elds.

1.2.4 Engaging all care proiders, including public, nongovernmental

and private providers, by scaling up publicprivate mix (PPM) approaches

to ensure adherence to international standards o TB care, with a ocus on

providers or the poorest and most vulnerable groups.

1.2.5 Empowering people with TB, and communities by scaling up

community TB care and creating demand through context-specic advo-

cacy, communication and social mobilization.

1.2.6 Enabling and promoting research to improve programme per-

ormance and to develop new drugs, diagnostics and vaccines.

Emphasis on expanding laboratory capacity (sputum smear microscopy rst,then culture and drug susceptibility testing (DST)) and the use o quality-

assured drugs across all programmes are important aspects o this comprehen-

sive approach to TB control.

1.3 Itegratio o diagostic ad treatmet serices to

cotrol TB

Detection and treatment o all orms o TB, including drug-resistant orms,

should be integrated within NTPs. In the past, many public health authorities

reasoned that scarce resources should be used or new patients with drug-sus-ceptible TB because the cost o detecting and treating the disease was 10- to

100-old lower than or MDR-TB. However, it has now proved easible and

cost eective to treat all orms o TB, even in middle- and low-income coun-

tries. Untreated or improperly treated patients with DR-TB are a source o


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3

1. BACkGROUND INFORMATION ON DRUG-RESISTANT TUBERCULOSIS

ongoing transmission o resistant strains, resulting in uture added costs and

mortality. The ramework or the management o DR-TB presented in these

guidelines can be adapted to all NTPs and integrated within the basic DOTS

strategy.

1.4 Causes o DR-TB

Although its causes are microbial, clinical and programmatic, DR-TB is essen-

tially a man-made phenomenon. From a microbiological perspective, resist-

ance is caused by a genetic mutation that makes a drug ineective against the

mutant bacilli. From a clinical and programmatic perspective, it is an inad-

equate or poorly administered treatment regimen that allows a drug-resistant

strain to become the dominant strain in a patient inected with TB. Table 1.1

summarizes the common causes o inadequate treatment.Short-course chemotherapy (SCC) or patients inected with drug-resistant

strains may create even more resistance to the drugs in use. This has been

termed the amplier eect o SCC.

Ongoing transmission o established drug-resistant strains in a population

is also a signicant source o new drug-resistant cases.

TABLE 1.1 Causes o iadequate atituberculosis treatmet (1)

heAlth-cAre proviDers: DruGs: inADequAte supply pAtients: inADequAteinADequAte reGimens or quAlity DruG intAKe

Inappropriate guidelines Poor qualit Poor adherence (or poor

Noncompliance with Unaailabilit o certain DOT)

guidelines drugs (stoc-outs or Lac o inormation

Absence o guidelines delier disruptions) Lac o mone (no treatment

Poor training Poor storage conditions aailable ree o charge)

No monitoring o Wrong dose or Lac o transportation

treatment combination Aderse eects

Poorl organized or unded Social barriers

TB control programmes Malabsorption

Substance dependenc

disorders

1.5 Addressig te sources o DR-TB

Any ongoing production o DR-TB should be addressed urgently beore em-

barking on any programme designed or its control. The ramework approach

described in these guidelines can help to identiy and curtail possible sources

o DR-TB. Recent outbreaks o highly resistant TB underscore the impor-

tance o preventing the development o resistance, as mortality or patientsinected with highly resistant strains is alarmingly high.

The possible contributing actors to the development o new drug-resistant

cases should be reviewed (see Table 1.1 or a list o possible actors). Well-

administered rst-line treatment or susceptible cases is the best way to pre-


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vent acquisition o resistance. Timely identication o DR-TB and adequate

treatment regimens (Category IV regimens) administered early in the course

o the disease are essential to stop primary transmission. Integration o DOTS

with treatment o DR-TB works synergistically to eliminate all the potentialsources o TB transmission.

1.6 Magitude o te DR-TB roblem

The incidence o drug resistance has increased since the rst drug treatment or

TB was introduced in 1943. The emergence o MDR-TB ollowing the wide-

spread use o riampicin beginning in the 1970s led to the use o second-line

drugs. Improper use o these drugs has uelled the generation and subsequent

transmission o highly resistant strains o TB termed extensively DR-TB, or

XDR-TB. These strains are resistant to at least one o the fuoroquinolonedrugs and an injectable agent in addition to isoniazid and riampicin.

The WHO/IUATLD Global Project on Antituberculosis Drug Resistance

Surveillance gathers data on drug resistance using a standard methodology in

order to determine the global magnitude o resistance to our rst-line antitu-

berculosis drugs: isoniazid, riampicin, ethambutol and streptomycin (2). Thestandard methodology includes representative sampling o patients with ad-

equate sample sizes, standardized data collection distinguishing between new

and previously treated patients and quality-assured laboratory DST supported

by a network o supranational TB reerence laboratories (SRLs).

Based on available inormation rom the duration o the Global Project (3),the most recent data available rom 116 countries and settings were weighted

by the population in areas surveyed, representing 2 509 545 TB cases, with the

ollowing results: global population weighted proportion o resistance among

new cases: any resistance 17.0% (95% condence limits (CLs), 13.620.4),

isoniazid resistance 10.3% (95% CLs, 8.412.1) and MDR-TB 2.9% (95%

CLs, 2.23.6). Global population weighted proportion o resistance among

previously treated cases: any resistance 35.0% (95% CLs, 24.145.8), isoni-azid resistance 27.7% (95% CLs, 18.736.7), MDR-TB 15.3% (95% CLs,

9.621.1). Global population weighted proportion o resistance among all TB

cases: any resistance 20.0% (95% CLs, 16.123.9), isoniazid resistance 13.3%

(95% CLs, 10.915.8) and MDR-TB 5.3% (95% CLs, 3.96.6). Based on

drug resistance inormation rom these 116 countries and settings reporting

to this project, as well as nine other epidemiological actors, it is estimated

that 489 139 (95% CLs, 455 093614 215) cases emerged in 2006. China and

India carry approximately 50% o the global burden o MDR-TB and the

Russian Federation a urther 7%.Data rom the most recent collection period showed ar greater proportions

o resistance among new cases than ound in previous reports, ranging all the

way to 16% MDR-TB among new cases in Donetsk, Ukraine, 19.4% in the

Republic o Moldova and 22.3% in Baku, Azerbaijan. Trends in MDR-TB


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7

6. Global tuberculosis control: surveillance, planning, fnancing. WHOreport 2008. Geneva, World Health Organization, 2008 (WHO/HTM/TB/2008.393).

7. The Global MDR-TB and XDR-TB Response Plan 20072008. Geneva,World Health Organization, 2007 (WHO/HTM/TB/2007.387).

8. Emergence o Mycobacterium tuberculosis with extensive resistance to

second-line drugs worldwide, 20002004. Morbidity and MortalityWeekly Report, 2006, 55(11):301305.

9. Gandhi NR et al. Extensively drug-resistant tuberculosis as a cause o

death in patients co-inected with tuberculosis and HIV in a rural area o

South Arica. Lancet, 2006, 368(9547):15751580.10. Kim JY et al. From multidrug-resistant tuberculosis to DOTS expansion

and beyond: making the most o a paradigm shit. Tuberculosis, 2003,83:5965.

1. BACkGROUND INFORMATION ON DRUG-RESISTANT TUBERCULOSIS


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CHAPTER 2

Frameork or eectiecotrol o DR-TB


2.2 DOTS ramewor applied to the management o DR-TB 8

2.2.1 Sustained political commitment 9

2.2.2 A rational case-fnding strateg including accurate, timel

diagnosis through qualit-assured culture and DST 9

2.2.3 Appropriate treatment strategies that use second-line

drugs under proper case management conditions 9

2.2.4 Uninterrupted suppl o qualit-assured antituberculosis drugs 10

2.2.5 Standardized recording and reporting sstem 10

2.3 A plan or tailored integration o management o DR-TB into

national programmes 112.4 Summar 11

Box 2.1 ke steps or integrating management o DR-TB into

national TB control programmes 12

Box 2.2 List o ariables to consider when assessing needs or

integrating management o DR-TB into national TB control

programmes 12

Box 2.3 Fie components o DOTS as applied to DR-TB 13

2.1 Cater objecties

This chapter describes the ve essential components o the DOTS ramework

as they apply to the management o DR-TB. It also introduces a systematic ap-

proach or tailoring these components to the local situation, with integration

into a DOTS-based NTP.

2.2 DOTS rameork as alied to te maagemet o DR-TB

The ramework or DR-TB is organized around the ve components o the

DOTS strategy because the underlying principles are the same (12):a. Sustained political commitment

b. A rational case-nding strategy including accurate, timely diagnosis

through quality-assured culture and DST


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2. FRAMEWORk FOR EFFECTIvE CONTROL OF DRUG-RESISTANT TUBERCULOSIS

c. Appropriate treatment strategies that use second-line drugs under proper

case management conditions

d. Uninterrupted supply o quality-assured antituberculosis drugs

e. Standardized recording and reporting system

Each o these components involves more complex and costly operations than

those or controlling drug-susceptible TB. However, addressing DR-TB usu-

ally strengthens the NTP.

2.2.1 Sustained political commitment

Sustained political commitment is essential to establish and maintain the

other our components. It requires both long-term investment and leader-

ship to ensure an appropriate environment or integrating the managemento DR-TB into NTPs. An appropriate environment includes adequate inra-

structure, development and retention o human resources, interagency cooper-

ation, enactment o necessary legislation, TB control policies enabling rational

implementation o the programme and acilitation o the procurement o qual-

ity-assured second-line drugs. In addition, the NTP must be strengthened to

prevent the emergence o more MDR-TB and XDR-TB cases.

2.2.2 A rational case-fnding strateg including accurate, timel

diagnosis through qualit-assured culture and DSTAccurate, timely diagnosis is the backbone o a sound NTP. DR-TB must be

diagnosed correctly beore it can be treated eectively. Case-nding strate-

gies may vary depending on the epidemiological situation and local capacity.

In some settings, all TB patients are tested with culture and DST. However,

in most settings, only patients with an increased risk o DR-TB are tested

(strategies on which risk groups to test are discussed in Chapter 5). In areas

where XDR-TB threatens TB control, laboratories should develop the capac-

ity or DST to second-line injectable agents and the fuoroquinolones in order

to diagnose XDR-TB.Quality-assured culture and DST are indispensable. Non-viable cultures,

culture contamination and unreliable DST results have major consequences

or both individual patients and the NTP as a whole. Internal quality control

and external quality assurance should thereore be in place, including a link

or prociency testing with a recognized reerence laboratory such as one o

the WHO-recognized SRLs.

2.2.3 Appropriate treatment strategies that use second-line drugs

under proper case management conditions

An appropriate treatment strategy consists o a rational method or designing

the optimal treatment regimen, a patient-centered approach or delivering this

regimen with direct observation, and a plan or monitoring and managing


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adverse drug reactions. Designing an optimal regimen requires proessional

expertise to consider several actors together, including:

representative data on drug resistance surveillance (DRS) o well-dened

local groups o TB patients, distinguishing new cases and dierent types o

re-treatment cases;

history o drug use in the country and in the individual;

specic array o available second-line drugs;

availability o DST to rst- and selected second-line drugs;

reliable options or delivering directly observed therapy (DOT) or up to

two years;

addressing patients coinected with HIV;

proper inection control policies implemented.A standardized regimen or certain groups o patients may be more appropri-

ate than an individualized regimen in some countries, while in others the con-

verse may be best.

The choice between hospitalization and ambulatory treatment depends on

several actors in addition to the severity o the disease. Such actors include

the availability o hospital beds with adequate inection control measures to

prevent nosocomial transmission; the availability o trained personnel at hos-

pitals and clinics to administer treatment and manage adverse drug reactions;

the availability o a social support network to acilitate adherence to ambu-

latory treatment; and the presence o other clinical or social conditions in

patients.

2.2.4 Uninterrupted suppl o qualit-assured

antituberculosis drugs

Management o second-line drugs is complex, especially when individualized

treatment regimens are used. Drugs are requently changed as a result o ad-

verse eects, delayed DST results and poor response to treatment. In addition,most second-line drugs have a short shel-lie, global production o quality-

assured drugs is limited, and drug registration may be a lengthy and costly

process that is not always attractive to drug manuacturers. Steps to ensure an

uninterrupted drug supply must begin six months or more in advance o the

anticipated need, and drug needs must be estimated as accurately as possible.

Countries should use only drugs that have been quality-assured by a stringent

drug regulatory authority recognized by WHO, a WHO prequalication pro-

gramme or that meet WHO GMP standards.

2.2.5 Standardized recording and reporting sstem

The specic characteristics o a DR-TB control programme include a record-

ing system with dierently dened categories or patient registration, culture

and DST results, and monitoring o treatment delivery and response or 24


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months. Cohort analysis includes interim indicators and treatment outcomes

ater two or more years, as well as treatment outcomes by treatment regimen

and DST results. The set o case registration groups and treatment outcome

denitions or MDR-TB used in these guidelines (Chapter 4) were developedthrough a process that involved the Stop TB Working Group on DOTS-Plus

or MDR-TB (3). They can be used or conducting cohort analyses in DR-TB control programmes. The redesigned recording and reporting system (see

Chapter 18) is essential or evaluating programme perormance and treatment

eectiveness.

2.3 A la or tailored itegratio o maagemet o DR-TB

ito atioal rogrammes

Management o DR-TB should be ully integrated into the NTP. The chal-lenge involved in this integration should not be underestimated. However, the

complexity o the process should not deter programmes rom taking the steps

necessary to allow all patients with DR-TB access to lie-saving treatment. I

many o the patients with DR-TB are treated in the private sector, integra-

tion can be acilitated through PPM approaches. Box 2.1 depicts the three key

steps o a plan or integrating the management o DR-TB into NTPs.

The most important consideration is the political will to deliver rational

treatment to patients with DR-TB as part o a sound NTP. Following conr-

mation o political will, a needs assessment should be carried out. Box 2.2 lists

the most relevant variables to consider.

The needs assessment will acilitate the design and implementation o a

plan to meet the gaps identied, in terms o both inrastructure and unction-

ing o the health-care system. Once the inrastructure is in place and the key

unctions such as a quality-assured TB laboratory are operating, a stepwise

integration o activities to control DR-TB can proceed within the NTP. Step-

wise integration means that those districts or administrative areas where the

integration is more likely to succeed should be prioritized.The design and implementation o a DR-TB control programme may vary

between and within countries, depending on the local needs and resources

available. Despite a wide range o acceptable strategies, essential requirements

such as quality-assured laboratories or diagnosis and monitoring o treat-

ment response, delivery o DOT and use o quality-assured second-line drugs

should be met under all conditions to ensure proper case management and

prevent the emergence o resistance to second-line drugs.

2.4 SummarThe DOTS ramework approach to management o DR-TB, summarized in

Box 2.3, includes ve essential components that orm the basis or every NTP

that includes detection and treatment o DR-TB.



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Reereces

1. Treatment o tuberculosis: guidelines or national programmes, 3rd ed.Geneva, World Health Organization, 2003 (WHO/CDS/TB/2003.

313).

2. An expanded DOTS ramework or eective tuberculosis control. Geneva,World Health Organization, 2002 (WHO/CDS/TB/2002.297).

3. Laserson KF et al. Speaking the same language: treatment outcome

denitions or multidrug-resistant tuberculosis. International Journal o Tuberculosis and Lung Disease, 2005, 9(6):640645.

BOx 2.1

Ke stes or itegratig maagemet o DR-TB ito atioal TB

cotrol rogrammes

1. Assessment o political will to delier rational treatment to patients with

drug-resistant TB.

2. Needs assessment or drug-resistant TB control actiities.

3. Design and implementation o a plan or management o drug-resistant TB

and its stepwise integration into the national TB control programme.

BOx 2.2

List o ariables to cosider e assessig eeds or itegratig

maagemet o DR-TB ito atioal TB cotrol rogrammes

Magnitude and distribution o DR-TB

Magnitude o HIv

Preailing patterns o drug resistance

Options or case-fnding

Existing inrastructure o the health-care sstem

Aailable laborator capacit

Resources aailable or DOT oer a prolonged period

Inection control polic in place and adequate unding aailable or control

measures

Qualit standards o the laborator networ

Aailabilit o human resources

Training needs Existing legal ramewor or management o second-line drugs

Needs or external technical assistance


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BOx 2.3 FIvE COMpOnEnTS OF DOTS AS AppLIED TO DR-TB

1. Sustaied olitical commitmet

Addressing the actors leading to the emergence o MDR-TB

Long-term inestment o sta and resources

Coordination o eorts between communities, local goernments and inter-

national agencies

A well-unctioning DOTS programme

2. Aroriate case-dig strateg icludig qualit-assured culture

ad DST

Rational triage o patients into DST and the DR-TB control programme

Relationship with supranational TB reerence laborator

3. Aroriate treatmet strategies tat use secod-lie drugs uder

roer case maagemet coditios Rational treatment design (eidence-based)

DOT

Monitoring and management o aderse eects

Properl trained human resources

4. Uiterruted sul o qualit-assured secod-lie atituberculosis

drugs

5. Recordig ad reortig sstem desiged or DR-TB cotrol

rogrammes tat eables moitorig o erormace ad ealuatio o

treatmet outcomes


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14

CHAPTER 3

political commitmet adcoordiatio


3.2 General considerations 14

3.3 Political commitment 14

3.3.1 Sufcient economic support 15

3.3.2 Regulator and operational documents 15

3.4 Coordination 16

3.5 Proposed checlist 17

Box 3.1 Proposed elements o the DR-TB control programme manual 16

Box 3.2 Summar checlist or DR-TB control programme managers 18

3.1 Cater objecties

Sustained political commitment is a prerequisite or control o DR-TB. This

chapter considers how political commitment can be translated into practical

measures to support all aspects o the ramework or control o DR-TB, and

the practical implications or NTPs. The main elements are described and a

checklist or programme managers is provided.

3.2 Geeral cosideratios

Sustained political commitment and leadership are the oundation or any

sound programme to control TB. The legal and regulatory context denes

the potential as well as the structure and policies o NTPs and DR-TB control

programmes. Political commitment is expressed through adequate nancial

support and appropriate inrastructure, including acilities and trained sta.

Coordination among the dierent components o public and private health-

care programmes and organizations is essential or successul programme im-

plementation. Sucient training and retention o medical and public health

personnel depend on long-term government planning and support.

3.3 political commitmet

Political commitment must be expressed at all stages o the health intervention

process, rom planning and implementation to monitoring and evaluation.


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15

3. POLITICAL COMMITMENT AND COORDINATION

Political support needs to be garnered rom sources including government

ministries and regional departments responsible or TB control, nongovern-

mental organizations and the private sector, the pharmaceutical industry,

academic and research institutions, proessional medical societies and thedonor community. This commitment takes the orm o nancial and human

resources, training, legal and regulatory documents, inrastructure and coor-

dination o all stakeholders involved in all aspects o the ramework or control

o DR-TB.

3.3.1 Sufcient economic support

The NTP budget must be sucient to develop and retain an adequate work-

orce with interest and expertise in DR-TB without weakening the workorce

o the national programme as a whole. The nancial resources needed to sup-

port the ramework should be provided. There should be no nancial barriers

to patients accessing appropriate care or DR-TB. Human resource needs are

discussed in Chapter 16.

3.3.2 Regulator and operational documents

Beore embarking on a DR-TB control programme, national and regional au-

thorities need to develop policies as a oundation or any subsequent legal,

administrative and technical support necessary or the initiation, implementa-tion and monitoring o the programme. Regulatory document(s) should con-

sider how the programme will be integrated into the NTP. The ollowing are

examples o the use o regulatory and operational documents:

Legislation can be drated to ensure proper registration, availability, qual-

ity, saety and distribution o second-line drugs. (Oten, strict control o

second-line drugs is possible only ater establishment o the programme to

provide quality-assured drugs ree o charge to patients.)

A local steering committee or expert committee can be ormed to meetperiodically to consult on individual patients and to address programmatic

problems.

A memorandum o understanding delineating responsibilities and unding

is oten necessary i multiple organizations are involved. In settings where

programmes involve dierent ministries or departments (including, or ex-

ample, the prison system or the social security system), an interministerial

or interdepartmental agreement should be signed that codies the mecha-

nism or coordinating services or diagnosis o TB and treatment o patients

between all authorities.

A programme manual can be the vehicle or disseminating operational and

clinical protocols to ensure consistency. It should be ocially endorsed by

the relevant authorities. The manual describes treatment protocols, denes


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16


responsibilities or dierent health-care providers and delineates the hu-

man resources that will be needed. It specically denes how disease will be

diagnosed and how patients will be registered, reported, treated and ol-

lowed up, in addition to programme monitoring and evaluation. Items tobe included in the programme manual are proposed in Box 3.1.

BOx 3.1 pROpOSED ELEMEnTS OF ThE DR-TB COnTROL

pROGRAMME MAnUAL

Bacground inormation on the DOTS programme and its integration with

treatment o patients with DR-TB

Organization and management o the DR-TB control programme

Case detection, diagnosis, classifcation o and reporting requirements or

drug-resistant TB

Organization o the laborator networ, including qualit control proceduresor laboratories proiding culture and DST

Treatment regimens or drug-resistant TB

Management o aderse eects caused b antituberculosis drugs

Management o drug-resistant TB in special populations and situations (in-

cluding children; pregnant or lactating women; diabetes mellitus; HIv; renal

or hepatic insufcienc; the elderl; alcohol and drug-dependent patients;

prisoners)

Case management sstem including DOT, transition to ambulator care,

patient assistance and deaulter tracing

Standards or ealuation and monitoring o treatment and o oerall project

perormance Plan or inection control in health acilities and other methods to preent

drug-resistant TB

3.4 Coordiatio

Coordination needs to include the contributions o all the key stakeholders,

organizations and external partners, as considered below.

National TB control programme. The NTP is the central coordinating

body or the activities described in the strategic ramework. Commitmento the necessary resources, particularly or a strong central management

team, ensures that all elements are in place, rom the procurement o sec-

ond-line drugs to the appropriate implementation and monitoring o the

DR-TB control programme. As needed, the national programme may build

partnerships with all relevant health-care providers.

Local health system. DR-TB control programmes should be tailored to

t the local inrastructure. The precise organizational structure o the pro-

gramme may vary greatly between dierent settings depending on how

the local health care is provided. Transer rom hospitals to outpatient set-

tings or between DOT centres requires care, advance planning and good

communication. Given the type o care required during the treatment o

DR-TB patients, a team o health workers including physicians, nurses and

social workers is oten used.


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17

Community level. Community involvement and communication with

community leaders can greatly acilitate implementation o treatment and

respond to needs that cannot be met by medical services alone. Commu-

nity education, involvement and organization around TB issues can ostercommunity ownership o control programmes and reduce stigma. In some

circumstances, communities have helped to address the interim needs o

patients, including the provision o DOT, ood and/or housing. Commu-

nity health workers oten play a critical role in ambulatory care o DR-TB

patients.

Coordination with prisons (1). Transmission in prisons is an importantsource o spread o DR-TB in some countries, and inection control meas-

ures can reduce incidence substantially. In many cases, inmates are releasedrom prison beore they nish treatment. Close coordination and commu-

nication with the civilian TB control programme, advance planning, tar-

geted social support and specic procedures or transerring care will help

ensure that patients complete treatment ater release rom prison.

All health-care providers (both public and private) (2). In some coun-tries, private practitioners manage most cases o DR-TB. In these settings,

it is important to involve the private sector in the design and technical as-

pects o the programme. Many PPM programmes have demonstrated eec-

tive and mutually benecial cooperation (3). In PPM systems, patients andinormation move in both directions. For example, private providers can be

compensated airly through negotiated systems o reimbursement, and the

public health system may provide clinic- or community-based DOT as well

as registering patients and their treatment outcomes. Similar PPM mixes

can be established or treatment o patients with DR-TB, but they require

exceptional coordination. The public health system may also get involved

in training on national guidelines or DR-TB.

International level. International technical support through WHO, theGLC, SRLs and other technical agencies is recommended. The NTP

should set up and lead an interagency body that ensures clear division o

tasks and responsibilities.

3.5 proosed cecklist

From the earliest planning phase, the ull range o issues encompassed in po-

litical commitment needs to be addressed. These include adequate nancial

support, an enabling regulatory environment, sucient human resources, ad-

equate physical inrastructure and good coordination. In addition, a communi-

cation strategy should be established to ensure that inormation is disseminated

eectively rom the central level to the periphery and that reports rom the peri-

pheral level are received centrally. Box 3.2 provides a checklist or programme

managers, summarizing the key aspects o a DR-TB control programme.

3. POLITICAL COMMITMENT AND COORDINATION


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Reereces

1. Bone A et al. Tuberculosis control in prisons: a manual or programmemanagers. Geneva, World Health Organization, 2000 (WHO/CDS/TB/2000.281).

2. Involving private practitioners in tuberculosis control: issues, interventions

and emerging policy ramework. Geneva, World Health Organization,2001 (WHO/CDS/TB/2001.285).

3. Towards scaling up. Report o the Third Meeting o the PPM Subgroup orDOTS Expansion. Geneva, World Health Organization, 2005 (WHO/CDS/TB/2005.356).

BOx 3.2 SUMMARy ChECKLIST FOR DR-TB COnTROL pROGRAMME MAnAGERS

preetio Sound implementation o DOTS programme

Inection control measures taen where all DR-TB patients will be treated

Contact tracing or MDR-TB cases in place

Laborator

Testing and maintenance o equipment

Biosaet measures in place

Reagents suppl

Superision and qualit assurance sstem (relationship with SRL estab-

lished)

Sstem or reporting laborator results to the treatment centre

Laborator or monitoring o electroltes, creatinine, lipase, throid unc-

tion, lier enzmes, and hematocrit in place Point-o-care HIv testing, with counselling and reerral aailable

Pregnanc testing

patiet care Council o experts or steering committee set up

Adequate capacit and trained sta at the health centre or DOT and

patient support

DOT in place and plan to ensure case holding

Sstem to detect and treat aderse eects, including suppl o appropriate

medications

Patient and amil support to increase adherence to treatment, such as

support group, pschological counselling, transportation subsid, ood bas-ets

Patient, amil and communit health education, including stigma reduc-

tion

programme strateg Integration with DOTS programme

Sources o DR-TB identifed and corrected

Legislation or treatment protocols accepted

Project manual published and disseminated

Agreement o criteria or prioritization o patient waiting lists

Location o care defned and unctional (ambulator s hospitalization)

Integration o MDR-TB serices with HIv care Integration o all health-care proiders into the DR-TB control programme


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CHAPTER 4

Deitios:case registratio, bacteriolog

ad treatmet outcomes


4.2 Defnitions o drug resistance and diagnostic Categor Iv 20

4.3 Site o DR-TB disease (pulmonar and extrapulmonar) 20

4.4 Bacteriolog and sputum conersion 21

4.5 Categor Iv patient registration group based on preious

antituberculosis treatment 21

4.6 Defnitions or diagnostic Categor Iv treatment outcomes 23

Box 4.1 Helpul hints on registrations and defnitions 25

4.1 Cater objectiesThis chapter establishes case denitions, patient registration categories, bac-

teriological terms, treatment outcome denitions and cohort analysis proce-

dures or patients who meet WHO Category IV diagnostic criteria.1 It is an

extension o the basic DOTS inormation system (1,2).The categories, denitions and procedures dened in this chapter will

acilitate the ollowing:

standardized patient registration and case notication;

assignment to appropriate treatment regimens; case evaluation according to disease site, bacteriology and history o treat-

ment;

cohort analysis o registered Category IV patients and Category IV treat-

ment outcomes.

1 Treatment o tuberculosis: guidelines or national programmes(1) recommends treatment regimensbased on dierent TB diagnostic categories. The diagnostic categories are:

Category I New smear-positive patients; new smear-negative pulmonary TB (PTB) with exten-sive parenchymal involvement; severe concomitant HIV disease or severe orms o extrapulmo-

nary TB.Category II Previously treated sputum smear-positive PTB: relapse; treatment ater interrup-tion; ailures.Category III New smear-negative PTB (other than in Cat I) and less severe orms o extra-pulmonary TB.Category IV Chronic cases (still sputum-positive ater supervised re-treatment) and MDR-TB.


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4.2 Deitios o drug resistace ad diagostic Categor Iv

DR-TB is conrmedthrough laboratory tests that show that the inecting

isolates oMycobacterium tuberculosisgrow in vitro in the presence o one or

more antituberculosis drugs (see Chapter 6 or urther inormation on labo-ratory requirements). Four dierent categories o drug resistance have been

established:

Mono-resistance: resistance to one antituberculosis drug.

Poly-resistance: resistance to more than one antituberculosis drug, other

than both isoniazid and riampicin.

Multidrug-resistance : resistance to at least isoniazid and riampicin.

Extensive drug-resistance: resistance to any fuoroquinolone, and at leastone o three injectable second-line drugs (capreomycin, kanamycin and

amikacin), in addition to multidrug-resistance.

Diagnostic Category IVincludes patients with:

Conrmed MDR-TB.

Suspected MDR-TB. This requires that the relevant health authority (such

as a review panel) recommends that the patient should receive Category IV

treatment. Patients may be entered in the Category IV register and startedon Category IV treatment beore MDR-TB is conrmed onlyi representa-

tive DST surveys or other epidemiologic data indicate a very high probabil-

ity o MDR-TB (see Chapter 5).

Poly-resistant TB. Some cases o poly-resistant TB will require Category

IV treatments. These patients require prolonged treatment (18 months or

more) with rst-line drugs combined with two or more second-line drugs

(see Chapter 8, Table 8.1) and should be entered into the Category IV reg-

ister. (Most programmes choose to keep cases o mono- and poly-resistance

that do not require second-line drugs or require only one second-line drug,in the District TB Register).

4.3 Site o drug-resistat TB disease

(ulmoar ad etraulmoar)

In general, recommended treatment regimens or drug-resistant orms o TB

are similar, irrespective o site. The importance o dening site is primarily or

recording and reporting purposes.

Pulmonary TB. Tuberculosis involving only the lung parenchyma. Extrapulmonary TB. Tuberculosis o organs other than the lungs, e.g.

pleura, lymph nodes, abdomen, genitourinary tract, skin, joints and bones,

meninges. Tuberculous intrathoracic lymphadenopathy (mediastinal and/

or hilar) or tuberculous pleural eusion, without radiographic abnormali-


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4. DEFINITIONS: CASE REGISTRATION, BACTERIOLOGy AND TREATMENT OUTCOMES

ties in the lungs, thereore constitutes a case o extrapulmonary TB. The

denition o an extrapulmonary case with several sites aected depends on

the site representing the most severe orm o disease.

Patients with both pulmonary and extrapulmonary TB should be classied as

a case o pulmonary TB.

4.4 Bacteriolog ad sutum coersio

Bacteriological examinations used in patients with DR-TB include sputum

smear microscopy and culture. Sputum smear microscopy and culture should

be perormed and results reported according to international standards (3).These examinations should be done at the start o treatment to conrm TB

disease and to group the patients according to inectiousness, sputum smear-positive being most inectious.

At least one sputum sample or smear and culture should always be taken

at the time o Category IV treatment start. In order or a patient to be consid-

ered culture- or sputum smear-positive at the start o Category IV treatment,

the ollowing criteria must be met: at least one pre-treatment culture or smear

was positive; the collection date o the sample on which the culture or smear

was perormed was less than 30 days beore, or 7 days ater, initiation o Cat-

egory IV treatment.

Sputum conversion is dened as two sets o consecutive negative smearsand cultures, rom samples collected at least 30 days apart. Both bacterio-

logical techniques (smear and culture) should be used to monitor patients

throughout therapy (see Chapter 11). The date o the rst set o negative cul-

tures and smears is used as the date o conversion (and the date to determine

the length o the initial phase and treatment).

The recording and reporting system assesses the smear- and culture-status

6 months ater the start o treatment as an interim outcome. Programmes

oten use the smear and culture conversion rate at 6 months to assess pro-

gramme perormance (see Chapter 18).

4.5 Categor Iv atiet registratio grou based o istor o

reious atituberculosis treatmet

Category IV patients should be assigned a registration group based on their

treatment history, which is useul in assessing the risk or MDR-TB.

The registration groups describe the history o previous treatment and do

not purport to explain the reason(s) or drug resistance.1

1 These guidelines do not use the terms primary and acquired resistance because these types oresistance cannot be distinguished in most DR-TB control programmes. I DST is done beorethe start o the patients rst antituberculosis treatment, any resistance documented is primaryresistance. I new resistance is ound when DST is later repeated and genetic testing conrms thatit is the same strain, only then can it be concluded that the strain has acquired resistance. Other-

wise, it may be caused by re-inection with a new strain.


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Treatment ater ailure o Category II. A patient who has received Cat-

egory II treatment or TB and in whom treatment has ailed. Failure is

dened as sputum smear positive at ve months or later during treatment.

Transer in. A patient who has transerred in rom another register or

treatment o DR-TB to continue Category IV treatment.

Other. There are several types o patients who may not t into any o the

above categories. Programmes are encouraged to classiy these patients into

groups that are meaningul according to the local epidemiology o disease.

Examples include the ollowing: sputum smear positive patients with un-

known previous treatment outcome; sputum smear positive patients who

received treatment other than Category I or II (possibly in the private sec-

tor); previously treated patients with extrapulmonary TB; patients whohave received several unsuccessul treatments, were considered incurable

by health sta and who have lived with active TB disease with no or inad-

equate treatment or a period o time (duration depends on country situa-

tion) until Category IV treatment became available (so-called back-log

patients; see also Chapter 18.5).

While persistently positive smears at month ve constitute the denition o

ailure, many programmes may want to perorm culture and DST earlier based

on the overall clinical picture. Patients ound to have MDR-TB will need to beswitched to Category IV regimens beore they meet the traditional diagnosis

o ailure. When possible, these patients should be classied separately. This

will allow assessment o the value o these end-points to predict MDR-TB, and

thereby the utility o routine DST in these groups. Otherwise, they should be

classied together with the ailures o the regimens they received.

HIV status is also recorded at the start o treatment and, i unknown, point-

o-care testing is encouraged (see Chapter 18).

4.6 Deitios or diagostic Categor Iv treatmet outcomesThe ollowing are mutually exclusive Category IV outcome denitions (4)that rely on the use o laboratory smear and culture as a monitoring tool and

will be reported in Forms 01, 02 and 07 (see Chapter 18). They have been

constructed to parallel the six DOTS outcomes or drug-susceptible TB (1, 4).All patients should be assigned the rst outcome they experience or the treat-

ment being evaluated or recording and reporting purposes.

Cured. A Category IV patient who has completed treatment according to

programme protocol and has at least ve consecutive negative cultures rom

samples collected at least 30 days apart in the nal 12 months o treatment.

I only one positive culture is reported during that time, and there is no

concomitant clinical evidence o deterioration, a patient may still be con-

sidered cured, provided that this positive culture is ollowed by a minimum

o three consecutive negative cultures taken at least 30 days apart.



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Treatment completed. A Category IV patient who has completed treat-

ment according to programme protocol but does not meet the denition or

cure because o lack o bacteriological results (i.e. ewer than ve cultures

were perormed in the nal 12 months o treatment).

Died. A Category IV patient who dies or any reason during the course o

MDR-TB treatment.

Failed. Treatment will be considered to have ailed i two or more o the

ve cultures recorded in the nal 12 months o therapy are positive, or

i any one o the nal three cultures is positive. (Treatment will also be

considered to have ailed i a clinical decision has been made to terminate

treatment early because o poor clinical or radiological response or adverse

events. These latter ailures can be indicated separately in order to do sub-analysis).

Deaulted. A Category IV patient whose treatment was interrupted or two

or more consecutive months or any reason without medical approval.

Transerred out. A Category IV patient who has been transerred to an-

other reporting and recording unit and or whom the treatment outcome is

unknown.

Patients who have transerred in should have their outcome reported back to thetreatment centre rom which they originally were registered. The responsibility

o reporting their nal outcomes belongs to the original treatment centre.

4.7 Coort aalsis

All patients should be analysed in two dierent cohorts (groups o patients)

depending on the purpose:

The treatment cohortincludes only patients who start Category IV treat-

ment. It is dened by the date o start o Category IV treatment. The

purpose is mainly to assess result o treatment and trends over time.

The diagnostic cohortincludes patients diagnosed with MDR-TB (identi-

ed in the DST register by date o DST result) during a specic period o

time. The purpose is mainly to assess the number o patients with DR-TB,

in subgroups and over time. This allows the programme to evaluate delay

in treatment start and proportion o patents who started treatment.

The recommended timerame or Category IV treatment cohort analysis re-

fects the long duration o Category IV regimens. Cohort analyses should becarried out at 24 months and, i needed, repeated at 36 months ater the last

patient starts treatment (see Chapter 18 and Form 07). For each treatment

cohort, an interim status should be assessed at 6 months ater the start o treat-

ment to monitor programme progress (see Chapter 18 and Form 06).


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Reereces

1. Treatment o tuberculosis: guidelines or national programmes, 3rd ed.Geneva, World Health Organization, 2003 (WHO/CDS/TB/2003.313).

(revision 2005).

2. Revised TB recording and reporting orms and registers version 2006. WorldHealth Organization, 2006 (WHO/HTM/TB/2006.373; available at

(http://www.who.int/entity/tb/dots/r_and_r_orms/en/index.html).

3. Laboratory services in tuberculosis control [Parts I, II and III]. Geneva,World Health Organization, 1998 (WHO/TB/98.258).

4. Laserson KF et al. Speaking the same language: treatment outcome

denitions or multidrug-resistant tuberculosis. International Journal o Tuberculosis and Lung Disease, 2005, 9(6):640645.


BOx 4.1 hELpFUL hInTS On REGISTRATIOnS AnD DEFInITIOnS

Assigig te rst outcome. All patients should be assigned the frst out-

come the experience or recording and reporting purposes. For example, a

patient deaults on a Categor Iv regimen and returns 14 months later to bere-registered and is cured with a second Categor Iv treatment. This patient

should receie a fnal outcome o deaulted in the cohort in which he or she

was frst registered and cured in the second cohort.

Traser out. A patient who is transerred out must be transerred out to an-

other DR-TB treatment centre. For example, a patient in a district with a good

DR-TB programme has completed 8 months o a Categor Iv regimen and is

doing well and has conerted his sputum in month two. He inorms the DR-

TB control programme that he is returning to his home district (500 m awa)

and that the district does not hae a DR-TB control programme. His uncle is

going to purchase the medicines, which he will swallow under the superison

o a local phsician. There are no culture acilities in his home district. Thispatient should be counted as a deault, because he is leaing a DR-TB control

programme that will not be able to trac him. A patient must go to another DR-

TB control programme that can report bac the fnal result to be considered

as transerred-out.

Traserred i. A patient who transers in does not get counted in the cohort

o the centre in which he completes his treatment. The receiing centre must

report bac the fnal outcome o the patient to the original treatment centre.

The original centre should confrm with the receiing centre that the patient

transerred in and the fnal treatment outcome.


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CHAPTER 5

Case-dig strategies


5.2 Bacground inormation and general considerations 27

5.3 Targeting ris groups or DST 27

5.4 Strategies or programmes with minimal access to DST and

limited resources 29

5.5 DST specimen collection 30

5.6 Case-fnding in paediatric patients 30

5.7 Case-fnding in HIv-inected patients 30

5.8 Case-fnding o patients with mono- and pol-drug resistance 31

5.9 Use o rapid drug-resistance testing 31

5.10 Use o second-line DST in case-fnding and diagnosing XDR-TB 33

Table 5.1 Target groups or DST 28

Figure 5.1 Algorithm or the use o rapid drug-resistance testing 32

Box 5.1 Countr examples o case-fnding strategies 33

5.1 Cater objecties

This chapter describes strategies or case-nding and diagnosis o patients

with either suspected or conrmed DR-TB. Several approaches to case-nd-

ing and enrolment into DR-TB control programmes are discussed, taking into

consideration that such programmes may have limited technical and nancial

capacity. The strategies range rom testing all patients with TB to testing only

a selected group o patients.

The chapter reviews case-nding o patients with DR-TB with respect to:

risk actors or drug resistance;

strategies or case-nding in programmes with minimal access to DST and

limited resources;

inormation on DST collection; the use o rapid DST methods1 to identiy drug resistance;

1 Rapid DST methods in these guidelines reer to molecular techniques that detect the genetic de-terminants o resistance. However, liquid, agar and other validated DST media that determinethe presence o resistance within 23 weeks can oten be substituted as rapid DST method whenmolecular methods are not available.


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5. CASE-FINDING STRATEGIES

the use o DST o second-line drugs and case detection o XDR-TB;

important issues in case-nding o drug resistance in the HIV-inected

patient.

Ke recommedatios (* da dad da)

Patients at ris o DR-TB should be screened or drug resistance;

In people liing with HIv, when possible, DST should be perormed at the

Management of MDR-TB

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