Who TB - Ltbi

Guidelines on the
management of
latent tuberculosis
infection
WHO Library Cataloguing-in-Publication Data
Guidelines on the management of latent tuberculosis infection.
1.Latent Tuberculosis. 2.Immunologic Tests. 3.Mycobacterium Tuberculosis – immunology. 4.Antitubercular Agents.
5.Guideline. I.World Health Organization.
ISBN 978 92 4 154890 8 (NLM classification: WF 200)
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WHO/HTM/TB/2015.01
Guidelines on the
management of
latent tuberculosis
infection
Guidelines on the management of latent tuberculosis infection
Contents
Acknowledgements 2
Abbreviations 5
Declaration and management of conflict of interest 6
Executive summary 8
1. Background and process 10

1.1. Background 10
1.2. Scope of the guidelines 10
1.3. Target audience 10
1.4. Development of the guidelines 11
1.5. Quality of evidence and strength of the recommendations 12
2. Recommendations 13
2.1. Identification of at-risk populations for LTBI testing and treatment 13
2.2. Algorithm to test and treat LTBI 15
2.3. Treatment options for LTBI 18
2.4. Preventive treatment for contacts of MDR-TB cases 20
3. Issues in Implementation 22
3.1. Adverse events monitoring 22
3.2. Risk of drug resistance following LTBI treatment 22
3.3. Adherence and completion of preventive treatment 23
3.4. Ethical considerations 24
3.5. Cost effectiveness 24
3.6. Programme management, monitoring and evaluation 24
4. Research gaps 26
4.1. Risk of progression to active TB disease and differential impact by
population risk group 26
4.2. Defining the best algorithm to test and treat LTBI 26
4.3. Treatment options for LTBI and adverse event monitoring 26
4.4. Risk of drug resistance following LTBI treatment 27
4.5. Adherence and completion of treatment 27
4.6. Cost-effectiveness studies 27
4.7. Preventive treatment for MDR-TB contacts 27
4.8. Programme management 27
5. References 28
6. Annexes 30
Annex 1: List of primary target countries for the guidelines 30
Annex 2: List of systematic reviews conducted 32
Annex 3: Recommended drug dosage 33
Annex 4: Evidence to decision framework (online only)
1
Acknowledgements
Overall coordination and writing of the guidelines

Haileyesus Getahun and Alberto Matteelli helped coordinate the development and drafting of the
guidelines, under the overall direction of Mario Raviglione.
WHO Steering Group

Dennis Falzon (Global TB Programme, WHO), Nathan Ford (HIV/AIDS Department, WHO), Haileyesus
Getahun (Global TB Programme, WHO), Chris Gilpin (Global TB Programme, WHO), Christian
Lienhardt (Global TB Programme, WHO), Knut Lonnroth (Global TB Programme, WHO), Alberto
Matteelli (Global TB Programme, WHO), Lisa Nelson (HIV/AIDS Department, WHO), Andreas Reis
(Knowledge, Ethics and Research Department, WHO), Mukund Uplekar (Global TB Programme,
WHO).
Co-chairs of the WHO Guidelines Development Group

Holger Schünemann (McMaster University Health Sciences Centre, Canada); Jay Varma (US Centers
for Diseases Control and Prevention, USA).
GRADE methodologist of the WHO Guidelines Development Group

Holger Schünemann (McMaster University Health Sciences Centre, Canada).
Members of WHO Guidelines Development Group

Ibrahim Abubakar (National Centre for Infectious Disease Surveillance and Control, University
College London and Public Health England, London, United Kingdom of Great Britain and Northern
Ireland); Draurio Barreira (National TB Programme, Ministry of Health, Brasilia, Brazil); Susana
Marta Borroto Gutierrez (Pedro Kourí Institute of Tropical Medicine, La Habana, Cuba); Judith
Bruchfeld (Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden); Erlina
Burhan (Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, University of
Indonesia, Jakarta, Indonesia); Solange Cavalcante (Rio de Janeiro Municipal Health Secretariat
FIOCRUZ, Rio de Janeiro, Brazil); Rolando Cedillos (Servicio de Infectología y Programade Atención
Integral en ITS/VIH/SIDA, San Salvador, El Salvador); Cynthia Bin-Eng Chee (Tan Tock Seng Hospital,
Singapore); Richard Chaisson (Center for TB Research, John Hopkins University, USA); Lucy
Chesire (TB Advocacy Consortium, Nairobi, Kenya); Elizabeth Corbett (London School of Hygiene
and Tropical Medicine, Blantyre, Malawi); Justin Denholm (Royal Melbourne Hospital, Melbourne,
Australia); Gerard de Vries (KNCV TB Foundation, Den Haag, The Netherlands); Margaret Gale-
Rowe (Public Health Agency of Canada, Ottawa, Canada); Un-Yeong Go (Department of HIV/AIDS
and TB Control Korea, Korea Centers for Disease Control and Prevention, Republic of Korea); Alison
Grant (London School of Hygiene and Tropical Medicine, London, United Kingdom of Great Britain
and Northern Ireland); Robert Horsburgh (Department of Epidemiology, Boston University School
of Public Health, Boston, USA); Asker Ismayilov (Main Medical Department, Ministry of Justice,
Azerbaijan); Philippe LoBue (Division of Tuberculosis Elimination, Centers for Disease Control and
Prevention, USA); Guy Marks (Woolcock Institute of Medical Research University of Sydney, Sydney,
Australia); Richard Menzies (Respiratory Division, McGill University, and Montreal Chest Institute,
Montreal, Canada); Giovanni Battista Migliori (WHO Collaborating Centre for TB and Lung Diseases
Fondazione S. Maugeri, Tradate, Italy); Davide Mosca (Migration Health Department, International
Organization of Migration, Geneva, Switzerland); Ya Diul Mukadi (Infectious Disease Division, Bureau
for Global Health, US Agency for International Development, Washington, USA); Alwyn Mwinga
(Zambart Project, Lusaka, Zambia); Lisa Rotz (Centers for Disease Control and Prevention, Atlanta,
USA); Holger Schünemann (Clinical Epidemiology & Biostatistics, McMaster University, Hamilton,
Canada); Surender Kumar Sharma (Department of Medicine, All India Institute of Medical Sciences,
2
New Delhi, India); Timothy Sterling (Vanderbilt University School of Medicine, Nashville, USA);
Tamara Tayeb (National TB Programme, Ministry of Health, Riyadh, Saudi Arabia); Marieke van der
Werf (European Centre for Disease Prevention and Control, Stockholm, Sweden); Wim Vandevelde
(European AIDS Treatment Group, Brussels, Belgium); Jay Varma (US Centers for Diseases Control
and Prevention, USA); Natalia Vezhnina (Regional Advisor on HIV/TB and Penal System Projects,
Russian Federation); Constantia Voniatis (Coordinator of Clinical Laboratories, Ministry of Health,
Nicosia, Cyprus); Robert John Wilkinson (Institute of Infectious Disease and Molecular Medicine,
University of Cape Town, Cape Town, South Africa); Takashi Yoshiyama (Division of Respiratory
Medicine, Japan Anti-Tuberculosis Association, Tokyo, Japan); Jean Pierre Zellweger (Medical
Adviser, Tuberculosis Competence Centre, Berne, Switzerland).
WHO Consultants for Systematic Reviews

Saskia Den Boon (Independent consultant, United Kingdom of Great Britain and Northern Ireland);
Esmee Doets (Pallas health research and consultancy BV, Rotterdam, The Netherlands); Enrico
Girardi (Istituto Nazionale Malattie Infettive L. Spallanzani, Rome, Italy); Darshini Govindasamy
(independent consultant, South Africa), Ross Harris (Public Health England, London, United
Kingdom of Great Britain and Northern Ireland); Sandra Kik (Mc Gill University, Montreal, Canada);
Katharina Kranzer (Department of Infectious Disease and Epidemiology, London School of Hygiene
and Tropical Medicine, London, United Kingdom of Great Britain and Northern Ireland); Anouk Oordt-
Speets (Pallas health research and consultancy BV, Rotterdam, The Netherlands); Molebogeng
Rangaka (Public Health England, London, United Kingdom of Great Britain and Northern Ireland);
Monica Sane Schepisi (Istituto Nazionale Malattie Infettive L. Spallanzani, Rome, Italy); Giovanni
Sotgiu (Sassari University, Sassari, Italy); Helen Stagg (Public Health England, London, United
Kingdom of Great Britain and Northern Ireland); Femke van Kessel (Pallas health research and
consultancy BV, Rotterdam, The Netherlands); Anja van’t Hoog (Amsterdam Institute for Global
Health and Development, Amsterdam, The Netherlands), Marije Vonk Noordegraaf-Schouten (Pallas
health research and consultancy BV, Rotterdam, The Netherlands).
Peer reviewers
Amy Bloom (US Agency for International Development (USAID), USA); Graham Bothamley
(Tuberculosis Network, European Study Group Clinical trials, United Kingdom of Great Britain
and Northern Ireland); Gavin Churchyard (The Aurum Institute, South Africa); Daniela Maria Cirillo
(San Raffaele del Monte Tabor Foundation, San Raffaele Scientific Institute, Milan, Italy); Raquel
Duarte (General Directorate of Health, Portugal); Michel Gasana (National TB Programme,
Rwanda); Stephen Graham (Centre for International Child Health, Australia); Connie Erkens (KNCV
Tuberculosis Foundation, The Netherlands); Brian Farrugia (Geriatric Medicine and Chest Clinic,
Malta); Barbara Hauer (Robert Koch Institute, Germany); Diane Havlir (University of California, San
Francisco, USA); Einar Heldal (The International Union against TB and Lung Diseases, Norway);
Rein Houben (Tuberculosis Modelling and Analysis Consortium, United Kingdom of Great Britain
and Northern Ireland); Mohamed Akramul Islam (BRAC Health Programme, Bangladesh); Jerker
Jonsson (Swedish Institute for Infectious Disease Control, Sweden); Michael Kimerling (Bill & Melinda
Gates Foundation, USA); Christopher Lange (Clinical Infectious Diseases, Medical Clinic Research
Center, Borstel, Germany); Wang Lixia (National Centre for TB control and Prevention, China); Joan
O’Donnell (National Disease Surveillance Unit, Ireland); Anshu Prakash (Ministry of Health and Family
Welfare, India); Ejaz Qadeer (National TB Control Programme, Federal Ministry of Health, Pakistan);
Lidija Ristic (Committee for TB, Ministry of Health, Serbia); Laura Sanchez-Cambronero (Ministry
of Health, Social Services and Equality, Spain); Andreas Sandgren (European Centre for Disease
Prevention and Control, Stockholm, Sweden); Martina Sester (Saarland University, Germany);
Joseph Kimagut Sitienei (Ministry of Public Health, Kenya); Alena Skrahina (Republic Scientific and
Practical Center for Pulmonology and Tuberculosis, Minsk, Belarus); Soumya Swaminathan (National
Institute for Research in Tuberculosis, Chennai, India); Ivan Solovic (National Institute for TB, Lung
Diseases and Thoracic Surgery, Vysne Hagy, Slovakia); Elena Suciliene (Children‘s Hospital, Affiliate
of Vilnius University Hospital Santariskiu Klinikos, Lithuania); Maarten van Cleeff (Project Director
TBCTA, KNCV Tuberculosis Foundation, The Netherlands); Francis Varaine (International Medical
Co-ordinator, Médecins sans Frontières, France); Martina Vasakova (Respiratory Diseases and
3
Pulmonology Department at Thomayer Hospital Prague, Czech Republic); Irina Vasilyeva (Ministry
of Health, Russian Federation); Mercedes Vinuesa Sebastián (Ministry of Health, Spain); Brita
Askeland Winje (Norwegian Institute of Public Health, Norway); Dalene von Delft (TB PROOF, Cape
Town, South Africa); Dominik Zenner (Public Health England, United Kingdom of Great Britain and
Northern Ireland).
WHO Headquarters and Regional offices

Mohamed Abdel Aziz (WHO/ EMRO); Masoud Dara (WHO/EURO); Malgorzata Grzemska (WHO/
HQ); Ernesto Jaramillo (WHO/HQ); Nobuyuki Nishikiori (WHO/WPRO); Diana Weil (WHO/HQ); Karin
Weyer (WHO/HQ).
Acknowledgement of financial support

The development of these guidelines was financially supported by the Ministry of Health of Italy. Core
WHO funds were used as well. The European Centre for Disease Prevention and Control supported
the systematic review entitled “What interventions are effective to improve initiation, adherence
and completion of LTBI treatment?”, through a contract to Pallas health research and consultancy
BV. Similarly Public Health England supported the systematic reviews on “Predictive utility of the
tuberculin skin test and interferon-gamma release assay among individuals who are not prescribed
tuberculosis preventive therapy” and “Systematic literature review and meta-analysis on the best
treatment options for latent tuberculosis infection”.
4
Abbreviations
GRADE Grading of Recommendations Assessment, Development and Evaluation
IGRA interferon-gamma release assays
LTBI latent TB infection
MDR-TB multidrug-resistant TB
TNF tumour necrosis factor
TST Mantoux tuberculin skin test
5
Declaration and management of conflict of interest
All the contributors completed a WHO Declaration of Interest form. All stated declarations of
interest were evaluated by three members of the Steering Group (the Legal Department of WHO
was consulted when necessary) for the existence of any possible financial conflict of interest which
might warrant exclusion from membership of the Guidelines Development or Peer Review Group or
from the discussions as part of the guidelines development process. Intellectual conflict of interest
was not considered for exclusion from membership of the Guidelines Development Group, as
broader expertise on LTBI was considered as criteria for the selection. In addition, the diversity and
representation in the Group was large enough to balance and overcome any potential intellectual
conflict of interest. During the guidelines development process and the meeting, any emergence of
intellectual conflict of interest was monitored by the Chairs and the Coordinator of the Secretariat,
and any perceived intellectual conflict of interest was discussed with members of the Guidelines
Development Group.
The following interests were declared:
Guidelines Development Group:

Ibrahim Abubakar declared that his employer received grants from National Institute of Health
(£2.7 million for PREDICT study: Prognostic Evaluation of IGRAs and Skin test in a cohort of 10,000
contacts and migrants) and UK Department of Health (£900 000 for a randomized controlled trial
to assess isoniazid-rifapentine compared to isoniazid-rifampicin on LTBI treatment completion
and £490 000 for Academic, Clinical & Enterprise study, and detection of latent TB in emergency
departments). He is currently the chair of the UK National Institute for Health and Care Excellence
(NICE) guideline development group developing guidelines on TB which includes active and latent
TB treatment. NICE pays his employer (University College of London) for his time at about £500
a day. He was a member of the European Centre for Disease Prevention and Control guideline
development group on IGRAs published in 2011, for which he did not receive any remuneration. He
has written extensively on this subject include a recent commentary in the Lancet on LTBI in the UK.
Cynthia Bin-Eng Chee declared that she has attended meetings pertaining to IGRAs sponsored by
Qiagen (1st meeting of Asia TB experts community, Chiba, Japan 13 May 2012 and the 2nd Meeting
of Asia TB Experts Community, Bangkok, Thailand, July 2013) and University of California, San
Diego (3rd Global IGRA Symposium, Waikoloa, Hawaii January 2012) with estimated overall value of
US$ 4500 for travel and accommodation.
Richard Chaisson declared that he received remuneration for consulting on TB drug development
from Vertex of US$ 2000 in 2012 one time only and received research grants from National Institutes
of Health, CDC and Gates Foundation of more than US$ 15 million which is ongoing.
Liz Corbett declared that her employer received research grants concerning the public health impact
of combined TB prevention from Wellcome Trust grants.
Guy Marks declared that his employer received research grants (related to TB, though not specifically
on LTBI) from National Health and Medical Research Council of Australia.
Richard Menzies declared that he received research support from Canadian Institutes of Health
Research with a total grant related to latent TB infection – approximately Canadian Dollars 6 million
over a 6-year period. Main research is an randomized control trial comparing 4 month-rifampicin to
9-month isoniazid for LTBI (about Canadian Dollars 1 million each year).
Surender Kumar Sharma declared that his employer received a research grant for “impact of
HIV infection on latent TB among patients with HIV/TB co-infection” supported by Department of
Biotechnology, Ministry of Science & Technology, Government of India (US$ 133 197.56) for which
the project work is over.
6
Timothy Sterling declared that he received remuneration from Sanofi for a one -day consultancy
meeting (and preparation) at FDA to answer questions related to the CDC-sponsored Study 26 of
the TB Trials Consortium where he was the protocol chair (US$ 3800 in 2012).
Expert review Group:

Gavin Churchyard declared that he received research support grants for the following trials at the
Aurum Institute: Rifaquin approximately €500 000 expired in 2011; Remox less than €200 000 which
is ongoing; Thibela TB US$ 32 million expired in 2012; evaluation of Expert MTB/RIF US$ 13 million
which is ongoing; evaluation of TB/HIV integration US$ 250 000 expired in 2011.
Raquel Duarte declared that she received payments from 2011 to 2014 for lectures on TB screening
in patients with immune mediated inflammatory diseases candidates for biological therapy from
Pfizer, Abbot and Janssen.
Diane Havlir declared that she received support grants from National Institutes of Health for research
on TB.
Christopher Lange declared that he received remuneration from Celltrion Korea for consultation on
the risk of TB related to treatment with bio similar TNF antagonists for one time in 2013.
Martina Sester declared that she received non-monetary support from Qiagen and Oxford
Immunotech to perform investigator-initiated research studies, where the kits were in part provided
free-of-charge by the two companies. She received travel support from Qiagen for presentation of
the data in scientific meetings. She is a co-inventor for a patent application entitled “in vitro process
for the quick determination of a patient’s status relating to infection with Mycobacterium tuberculosis”
(international patent number WO2011113953/A1).
Dalene von Delft declared that she received support for giving presentations or speeches at the
UNION Conferences in 2012 and 2013 from the Treatment Action Group and USAID; support from
Janssen Pharmaceuticals to attend the Leadership summit Critical Path to TB Drug Regimens;
support from American Society of Tropical Medicine and Hygiene (ASTMH)-AERAS to attend
meetings.
Dominik Zenner declared that he is a coauthor of one of the underpinning systematic reviews on
LTBI treatment and also the head of the TB screening unit in Public Health England and has a
professional interest in the subject matter.
All declarations of interest are on electronic file at the Global Tuberculosis Programme of WHO.
Guidelines update date: 2020
7
Executive summary
Latent tuberculosis infection (LTBI) is defined as a state of persistent immune response to stimulation
by Mycobacterium tuberculosis antigens without evidence of clinically manifested active TB. A
direct measurement tool for M. tuberculosis infection in humans is currently unavailable. The vast
majority of infected persons have no signs or symptoms of TB but are at risk for developing active
tuberculosis (TB) disease. This can be averted by preventive treatment.
These Guidelines on the management of latent tuberculosis infection were developed in accordance
to the requirements and recommended process of the WHO Guideline Review Committee, and
provide public health approach guidance on evidence-based practices for testing, treating and
managing LTBI in infected individuals with the highest likelihood of progression to active disease.
The guidelines are also intended to provide the basis and rationale for the development of national
guidelines. The guidelines are primarily targeted at high-income or upper middle-income countries
with an estimated TB incidence rate of less than 100 per 100 000 population. Resource-limited and
other middle-income countries that do not belong to the above category should implement the
existing WHO guidelines on people living with HIV and child contacts below 5 years of age.
The following are the key recommendations of the guidelines:
• Systematic testing and treatment of LTBI should be performed in people living with HIV, adult
and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor (TNF)
treatment, patients receiving dialysis, patients preparing for organ or haematologic transplantation,
and patients with silicosis. Either interferon-gamma release assays (IGRA) or Mantoux tuberculin
skin test (TST) should be used to test for LTBI. (Strong recommendation, low to very low quality of
evidence)
• Systematic testing and treatment of LTBI should be considered for prisoners, health-care workers,
immigrants from high TB burden countries, homeless persons and illicit drug users. Either IGRA
or TST should be used to test for LTBI. (Conditional recommendation, low to very low quality of
evidence)
• Systematic testing for LTBI is not recommended in people with diabetes, people with harmful
alcohol use, tobacco smokers, and underweight people provided they are not already included
in the above recommendations. (Conditional recommendation, very low quality of evidence)
• Individuals should be asked about symptoms of TB before being tested for LTBI. Chest
radiography can be done if efforts are intended also for active TB case finding. Individuals with
TB symptoms or any radiological abnormality should be investigated further for active TB and
other conditions. (Strong recommendation, low quality of evidence)
• Either TST or IGRA can be used to test for LTBI in high-income and upper middle-income countries
with estimated TB incidence less than 100 per 100 000 (Strong recommendation, low quality
of evidence). IGRA should not replace TST in low-income and other middle-income countries.
(Strong recommendation, very low quality of evidence)
• Treatment options recommended for LTBI include: 6-month isoniazid, or 9-month isoniazid, or
3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months isoniazid plus rifampicin, or
3–4 months rifampicin alone. (Strong recommendation, moderate to high quality of evidence).
8
In addition, the Guidelines Development Panel noted the following critical issues for consideration in
the implementation of the recommendations set out in these guidelines:
• Strict clinical observation and close monitoring for the development of active TB disease among
contacts of multidrug-resistant TB (MDR-TB) cases preferably for at least two years over the
provision of preventive treatment. Clinicians can consider individually tailored treatment regimens
based on the drug susceptibility profile of the index case, particularly for child contacts below 5
years of age, when benefits can outweigh harms with reasonable confidence.
• Regular clinical monitoring of individuals receiving treatment for latent TB through a monthly visit
to the health-care provider;
• Establishment of national TB drug resistance surveillance systems while implementing national

latent TB management services;
• Introduction of flexible interventions and incentives by national TB programmes that are responsive
to the specific needs of population groups at risk, as well as tailored to the local context and their
needs to ensure acceptable initiation of, adherence to and completion of LTBI treatment.
• Documentation of treated individuals through a functional, routine monitoring and evaluation

system that is aligned with national patient monitoring and surveillance systems.
• Creation of conducive policy and programmatic environment, including the promotion of universal
health coverage, development of national and local policies, standard operating procedures, as
well allocation of dedicated resources.
9
1. Background and process
1.1. Background
Latent tuberculosis infection (LTBI) is defined as a state of persistent immune response to stimulation
by Mycobacterium tuberculosis antigens without evidence of clinically manifested active TB (1). One-
third of the world’s population is estimated to be infected with M. tuberculosis (2). The vast majority
of infected persons have no signs or symptoms of TB disease and are not infectious, but they are at
risk for developing active TB disease and becoming infectious. The lifetime risk of reactivation TB for
a person with documented LTBI is estimated to be 5–10%, with the majority developing TB disease
within the first five years after initial infection (3). However, the risk of developing TB disease following
infection depends on several factors, the most important one being the immunological status of the
host.
Reactivation TB can be averted by preventive treatment. Currently available treatments have an

efficacy ranging from 60% to 90% (4). The potential benefit of treatment needs to be carefully
balanced against the risk of drug-related adverse events. Population-wide mass LTBI testing and
treatment are not feasible due to imperfect tests, risk of serious and fatal side-effects and the high
cost. The benefits are greater than the harms for infected individuals in population groups in which
the risk of progression to active disease significantly exceeds that for the general population. The
management of LTBI requires a comprehensive package of interventions that includes: identifying
and testing those individuals who should be tested, delivering effective and safe treatment in a way
that the majority of those starting a treatment regimen will complete it with no or minimal risk of
adverse events, and ensuring monitoring and evaluation of the process.
WHO guidelines for the management of LTBI are currently only available for people living with HIV
(5) and for children below 5 years of age who are household contacts of TB cases (6). Several WHO
Member States had requested WHO for clear policy guidance on the management of LTBI, with due
consideration to testing and treatment options. In addition, guidelines on the management of LTBI
would be one of the necessary tools for facilitating the implementation of the Global TB Strategy
after 2015 to achieve its ambitious targets of 90% reduction in TB incidence and 95% reduction in
TB deaths that was endorsed by the World Health Assembly in May 2014.
With the present guidelines, WHO intends to provide guidance on how to identify and prioritize at-risk
population groups who would benefit from LTBI testing and treatment and recommend diagnostic
and treatment approaches with due consideration to ethical requirements.
1.2. Scope of the guidelines

The overall objective of the guidelines is to provide public health approach guidance on evidence-
based practices for testing, treating and managing LTBI in individuals with the highest risk of
progression to active disease. The guidelines are expected to provide the basis and rationale
for the development of national guidelines for LTBI management based on available resources,
epidemiology of TB including intensity of transmission, the health-care delivery system of the
country, and other national and local determinants. The specific objectives of the guidelines include
identifying and prioritizing at-risk population groups for targeted intervention of LTBI testing and
treatment, including defining an algorithm and recommending specific treatment options.
1.3. Target audience

The proposed guidelines are, in principle, intended to benefit all WHO Member States regardless
of their epidemiology of TB as the intent is to improve the diagnosis and management of LTBI in
population groups with the highest likelihood of progression to active disease. However, the
guidelines are primarily targeted at high-income or upper middle-income countries with an estimated
10
TB incidence rate of less than 100 per 100 000 population. The Panel judged that these countries
are most likely to benefit from the guidelines due to their current TB epidemiology and resource
availability (Annex 1). Additionally, LTBI management in high-risk groups is one of the priority actions
for a TB elimination strategy in low-incidence countries, which is part of the Global End TB Strategy
after 2015. Resource-limited countries and other middle-income countries that do not belong to the
above category should implement existing WHO guidelines on people living with HIV (5) and child
contacts below 5 years of age (6) as a priority.
National TB control programmes or their equivalents in the ministries of health are the primary target
audience for these guidelines. However, the guidelines is also aimed at policy makers in other line
ministries working in the areas of health, prison services, social services or immigration (such as
ministries of justice or correctional services; ministries dealing with immigration).
1.4. Development of the guidelines

As part of the WHO Guideline Review Committee recommended process (7), three groups were
established to develop the guidelines:
1. The WHO Guideline Steering Group chaired by the Global TB Programme and involving
departments of HIV/AIDS and Knowledge, Ethics and Research to lead the guideline development
process;
2. The Guidelines Development Group (which is known as the Panel hereafter) composed of
external content experts, national TB programme managers, academicians and representatives
of patients groups and civil society, to provide inputs throughout all stages of the guideline
development process. Members of the Panel were selected on the basis of balancing diversity,
relevant expertise, and geographic and gender representativeness of both stakeholders and
patient groups; and
3. The External Review Group composed of individuals interested in latent TB content to review the
draft of the guidelines.
The Steering Group identified key questions and a comprehensive list of systematic reviews required
to formulate the recommendations. It also developed the scoping document for the development of
the guidelines. The Panel reviewed the scoping document and agreed with the Steering Group on
the scope of the guidelines as well as key questions and outcomes to guide the systematic reviews.
The following seven key questions were identified:
1. Which populations will benefit most from LTBI diagnosis and treatment?
2. What is the most appropriate algorithm to identify individuals to be treated for LTBI?
3. What is the best treatment option for LTBI?
4. In individuals receiving treatment for LTBI, what are the best ways to monitor and manage hepatic
toxicity and other adverse events?
5. What interventions are effective to improve initiation, adherence and completion of LTBI treatment?
6. Should preventive therapy be recommended for contacts of patients with multidrug-resistant TB
(MDR-TB)?
7. Is the treatment and management of LTBI cost effective?
A list of potential outcomes of interest for each question was circulated to all members of the Panel
and each member scored the importance of each outcome on a scale of 1 to 9 as below:
• 1 to 3 to indicate an outcome considered not important

• 4 to 6 to indicate an outcome considered important
• 7 to 9 to indicate an outcome considered critical.
The average of the scores for each outcome was used to inform the decision making.
11
A total of 14 systematic reviews informed this guideline development process. The Panel met in
person, and communicated by conference call and email correspondence. Meetings were co-
chaired by a technical expert and a Grading of Recommendations Assessment, Development and
Evaluation (GRADE) methodologist. Recommendations were drafted taking into consideration the
benefits and harms profile, costs, feasibility, acceptability, and values and preferences of clients
and health-care providers. Recommendations and their relative strength were determined by
consensus, and when a consensus could not be reached open voting was used to arrive at a
decision. Consensus was defined as unanimous or majority agreement. Relevant recommendations
from existing and valid WHO guidelines were included in the final guidelines document as deemed
necessary (5,6,8). Additional inputs from the Expert Review Group were also obtained. All remarks
made by the Expert Review Group members were evaluated by the WHO Steering Group and
considered for incorporation into the final Guidelines version.
1.5. Quality of evidence and strength of the recommendations

The quality of evidence and strength of the recommendations were assessed using the GRADE
methodology whenever possible (9). In the GRADE process, the quality of a body of evidence is
defined as the extent to which one can be confident that the reported estimates of effect (desirable
or undesirable) available from the evidence are close to the actual effects of interest. The usefulness
of an estimate of the effect (of the intervention) depends on the level of confidence in that estimate.
The higher the quality of evidence, the more likely a strong recommendation can be made; however,
the decision regarding the strength of the evidence also depends on other factors.
The strength of the recommendations reflects the degree of confidence of the Panel that the desirable
effects of the recommendations outweigh the undesirable effects. The desirable effects considered
included beneficial health outcomes (e.g. prevention and early diagnosis of TB, reduced TB-related
morbidity and mortality), less burden and more savings; whereas undesirable effects included
harms, more burden and more costs. Burdens considered included the demands of adhering to the
recommendations that programmes, patients or caregivers (e.g. family) may have to bear, such as
having to undergo more frequent tests, taking additional medications or opting for a treatment that
has a risk for toxicity.
The following levels of assessment of the evidence were used in the GRADE profiles:
Evidence level Rationale
High Further research is very unlikely to change our confidence in the estimate of effect.
Moderate Further research is likely to have an important impact on our confidence in the effect.
Low Further research is very likely to have an impact on the estimate of effect and is likely to
change the estimate.
Very low Any estimate of effect is very uncertain.
The recommendations in these guidelines were graded into two categories as follows:
1. A strong recommendation is one for which the Panel was confident that the desirable effects
of adherence to the recommendation outweigh the undesirable effects. This could be either in
favour of or against an intervention.
2. A conditional recommendation is one for which the Panel concluded that the desirable effects
of adherence to the recommendation probably outweigh the undesirable effects, but the Panel
was not confident about these trade-offs. Reasons for not being confident included: absence of
high-quality evidence (data to support the recommendation are scant); presence of imprecise
estimates of benefits or harms (new evidence may result in changing the balance of risk to
benefit); uncertainty or variation regarding how different individuals value the outcomes (only
applicable to a specific group, population or setting); small benefits and benefits that may not be
worth the costs (including the costs of implementing the recommendation).
12
2. Recommendations
The Panel issued recommendations on the identification of individuals for latent TB testing and
treatment, the algorithmic approach to test and treat LTBI, and the treatment options. The
recommendations of the Panel were mainly based on critical appraisal of the evidence, the balance
of anticipated benefits and harms, the values and preferences of clients and health-care providers
as well as resource implications.
The overall logical approach conformed to the Panel for the development of the guidelines and the
formulation of the recommendations was as follows: (1) identification of the risk groups that are
eligible for treatment of latent TB infection (recommendation in section 2.1, page 13); followed by (2)
evaluation of the accuracy and drawbacks of the screening tests (recommendation in section 2.2,
page 15); and (3) evaluation of the effectiveness and harms of the treatment regimens to prevent
progression (recommendation in section 2.3, page 18).
2.1. Identification of at-risk populations for LTBI testing and treatment
In high-income and upper middle-income countries with estimated TB incidence less than 100
per 100 000 population
• Systematic testing and treatment of LTBI should be performed in people living with HIV, adult and
child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor (TNF) treatment,
patients receiving dialysis, patients preparing for organ or haematologic transplantation and patients
with silicosis. Either interferon-gamma release assays (IGRA) or Mantoux tuberculin skin test (TST)
should be used to test for LTBI. (Strong recommendation, low to very low quality of evidence)
• Systematic testing and treatment of LTBI should be considered for prisoners, health workers,
immigrants from high TB burden countries, homeless persons and illicit drug users. Either IGRA
or TST should be used to test for LTBI. (Conditional recommendation, low to very low quality of
evidence)
• Systematic testing for LTBI is not recommended in people with diabetes, people with harmful
alcohol use, tobacco smokers, and underweight people unless they are already included in the
above recommendations. (Conditional recommendation, very low quality of evidence)
For resource-limited countries and other middle-income countries that do not belong to the
above category (according to existing and valid WHO guidelines) (5,6):
• People living with HIV and children below 5 years of age who are household or close contacts of
people with TB and who, after an appropriate clinical evaluation, are found not to have active TB but
have LTBI should be treated. (Strong recommendation, high quality of evidence)
Remarks: Testing and treatment of LTBI should adhere to strict human rights and the highest ethical
considerations. For example, positive test results or status of treatment for LTBI should not affect a person’s
immigration status or delay the ability to immigrate. For people living with HIV and child contacts below 5 years
of age, the existing WHO guidelines should be consulted (5,6).
The rationale for the Panel to make strong recommendations despite low to very low quality of
evidence was based on its strong judgment on the increased likelihood of progression to active
TB disease and the benefits of treatment outweighing the potential harms in the identified at-risk
population groups. Similarly, the Panel made its conditional recommendations primarily because of
the weak quality of the evidence and implementation considerations.
2.1.1. Summary of the evidence

Three systematic reviews were conducted to determine which at-risk population groups would be
prioritized for LTBI testing and treatment among 24 pre-defined population groups. Evidence on
13
increased prevalence of LTBI, risk of progression from LTBI to active TB disease and increased
incidence of active TB was available for the following 15 risk groups: (i) adult and child TB contacts,
(ii) health-care workers and students, (iii) people living with HIV, (iv) patients receiving dialysis, (v)
immigrants from high TB burden countries, (vi) patients initiating anti-tumour necrosis factor (TNF)
therapy, (vii) illicit drug users, (viii) prisoners, (ix) homeless people, (x) patients receiving organ and
haematologic transplantation, (xi) patients with silicosis, (xii) patients with diabetes, (xiii) people with
harmful alcohol use, (xiv) tobacco smokers, and (xv) underweight people.
The first systematic review assessed the prevalence of M. tuberculosis infection as determined either
by TST or commercially available IGRAs. A total of 276 studies (with 299 entries) were included.
Comparison between LTBI prevalence among risk groups and prevalence among the general
population was made using LTBI prevalence estimates derived from modelling (2); and pooled risk
ratios were calculated for the risk groups. A considerable heterogeneity in risk ratios was observed.
Nevertheless, increased risk of LTBI was reported for both TST and IGRA in at least 65% of the
studies for the following risk groups: prisoners, homeless people, elderly people, immigrants from
high TB burden countries, adult and child TB contacts, and illicit drug users.
A second systematic review assessed the risk of progression from LTBI to active TB. Eight individual
studies provided the evidence of an increased risk of progression for the following categories:
people living with HIV, adult contacts of TB cases, patients undergoing dialysis, underweight people,
individuals with fibrotic radiologic lesions and recent converters to the TST.
The third systematic review was conducted to compare the pooled incidence rate ratio of active
TB in the pre-defined risk groups compared with the general population. Data of increased risk of
active TB were reported in the following risk groups: people living with HIV, adult and child contacts
to a TB case, patients with silicosis, health-care workers (including students), immigrants from high
TB burden countries, prisoners, homeless, patients receiving dialysis, patients receiving anti-TNF
drugs, patients with cancer, people with diabetes mellitus, people with harmful alcohol use, tobacco
smokers and underweight people.
2.1.2. Balance of benefits and harms

The Panel reviewed the evidence generated from the systematic reviews and discussed each of the
population risk groups identified in detail for the prevalence of latent TB, risk of progression into active
TB and the incidence of active TB compared with the general population. The Panel concluded that
there is clear evidence of benefit from systematic testing and treating of LTBI in the following groups:
people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-TNF
treatment, patients receiving dialysis, patients preparing for organ or haematologic transplantation,
and patients with silicosis.
The Panel concluded that the evidence of benefits outweighing harms in the following population
risk groups is weak, but judged that the benefits of systematic testing and treating may outweigh
the harms: health-care workers, immigrants from high TB burden countries, prisoners, homeless
persons and illicit drug users. The decision to systematically test for and treat LTBI in these
population groups should be in accordance with local TB epidemiology and context, health system
structures, availability of resources and overall health priorities. Priority must be given to individuals
with history of recent infection status conversion, tested either by IGRA or TST, from negative to
positive. Similarly, the Panel concluded that recent immigrants from high TB burden countries to low
TB burden countries should be prioritized. However, the Panel underscored that a person’s status
—tested positive for LTBI or receiving LTBI treatment — should not affect the process, procedure
and status of immigration.
The Panel noted the paucity of data on the benefits and harms of systematic latent TB testing and
treatment in diabetic patients, people with harmful alcohol use, tobacco smokers and underweight
people and concluded that the benefits of systematic and routine testing and treatment in these risk
groups do not outweigh the risks unless individuals/patients also belong to the groups mentioned
in the above recommendations.
14
The Panel recognized the potential limitations of the systematic reviews, which were restricted to a
single database (Medline) over a 10-year period for both the comparison of prevalence of LTBI and
progression to active TB disease in a specific risk group over the general population. It also noted
that the inclusion of studies with no restriction on publication year or language through contacting
30 experts in the field mitigated this limitation. The Panel judged that the available evidence was
adequate to issue the recommendations particularly taking into consideration the urgent need for
WHO guidelines. It also emphasized the importance of further research on the benefits and harms
of LTBI testing and treatment in persons with silica exposure, patients receiving steroid treatment,
patients with rheumatologic conditions, indigenous populations and cancer patients.
2.1.3. Values and preferences of clients and health-care providers

Individual benefit outweighing risk should be the mainstay of latent TB testing and treatment. The
Panel agreed that prioritization of groups based on their risk and the local and national context (e.g.
epidemiology, resource availability) will be acceptable by individuals as well as key stakeholders
including clinicians and programme managers. It was noted that the high risk of ongoing TB
transmission in certain risk groups, such as health-care workers (including students), prisoners
(including prison staff), homeless and illicit drug users, require attention so that the benefit of
treatment is not compromised through reinfection. The TB prevention value of antiretroviral therapy
for people living with HIV was also noted.
2.1.4. Resource considerations

The decision of national TB programmes and other stakeholders to identify the priority risk groups
for programmatic management of LTBI needs to consider availability and efficient use of resources.
The Panel noted that prioritizing high-risk groups, such as people living with HIV, immigrants from
high TB burden countries and contacts with TB cases for latent TB testing and treatment have the
potential to yield savings for the health-care system. However, cost-effectiveness analyses based on
rigorous empirical data are scarce for other risk groups.
2.2. Algorithm to test and treat LTBI
• Individuals should be asked about symptoms of TB before being tested for LTBI. Chest radiography
can be done if efforts are intended also for active TB case finding. Individuals with TB symptoms
or any radiological abnormality should be investigated further for active TB and other conditions.
(Strong recommendation, very low quality of evidence)
• Either TST or IGRA can be used to test for LTBI in high-income and upper middle-income countries
with estimated TB incidence less than 100 per 100 000. (Strong recommendation, very low quality of
evidence)
• IGRA should not replace TST in low-income and other middle-income countries. (Strong
recommendation, very low quality of evidence) (8)
Remark: HIV testing should be incorporated into the medical evaluation of LTBI treatment candidates based
on national or local policies.
The rationale for the Panel’s decision for a strong recommendation for symptom screening and
chest radiography prior to initiating treatment was due to the crucial importance of exclusion of
active TB disease and inclusion of LTBI for better patient outcomes. Similarly, the rationale for a
strong recommendation that IGRA should not replace TST in low-income and other middle-income
countries, despite the very low level of evidence, is justified by the Panel’s consideration of patient
relevant outcomes, performance of the test in these settings and costs (8).

A systematic review was conducted to determine the sensitivity and specificity of symptoms, and
chest radiography screening for active pulmonary TB in HIV-negative persons and persons with
unknown HIV status. The review identified 11 studies from general population surveys that provided
15
Figure 1. Algorithm for targeted diagnosis and treatment of LTBI in individuals

from risk groups
Ask for any symptoms of tuberculosis in individuals from the risk groups*
Yes No
TST or IGRA
Positive Negative**
Chest
radiography
TB and other disease

Any abnormality No abnormality
investigations***
Treat for LTBI
* Any symptoms of TB include any one of: cough, haemoptysis, fever, night sweats, weight loss, chest pain,
shortness of breath, fatigue. HIV test could be offered based on national or local guidelines or clinical
judgment. Similarly chest radiographs can be done if efforts are intended also for active TB case finding.
** Clients for whom LTBI treatment is not indicated should be provided information about TB including on the
importance of seeking care if symptoms of TB developed.
*** National TB guidelines should be followed while investigating for TB. In addition, those individuals in whom
TB is excluded after investigations (including individuals with fibrotic radiologic lesions) can be considered
for LTBI treatment.
16
data on screening with either symptoms or with chest radiography or with both. To illustrate how
different screening and diagnostic algorithms are expected to perform in ruling-out active TB, a model
was constructed to compare the following seven screening strategies: (i) any TB symptom, (ii) chest
radiography with any abnormality, (iii) a combination of chest radiography with any abnormality or
any TB symptom, (iv) chest radiography with suggestive TB abnormalities, (v) cough more than 2–3
weeks, (vi) if there is cough more than 2–3 weeks then chest radiography as a follow up test, and (vii)
if any TB symptom is present then chest radiography. The combination of any abnormality in chest
radiography and/or presence of any TB suggestive symptoms (i.e. any one of cough, haemoptysis,
fever, night sweats, weight loss, chest pain, shortness of breath and fatigue) would offer the highest
sensitivity and negative predictive value to rule out TB.
A systematic review was conducted to explore tests and clinical proxies that can best identify
individuals most-at-risk of progression to incident TB disease. While the systematic review did
not identify any clinical parameters that would assist in the prediction of progression to active TB
diseases, 29 studies were about the predictive utility of IGRA and TST. The main effect measure of
interest was the risk ratio, comparing TB incidence following a positive test results versus a negative
test result in individuals not receiving preventive therapy, or alternatively the incidence rate ratio in the
few studies that reported the person years of follow-up amongst test positives and test negatives.
The overall pooled risk ratio estimate for the TST was 2.64 (95% CI: 2.04–3.43, n = 22 studies) and
8.45 (95% CI: 4.13–17.31, n = 16 studies) for IGRA. The pooled risk ratio estimate for IGRA was
13.55 (95% CI: 6.08–30.21) in high-income and upper middle-income countries with TB incidence
less than 100 per 100 000 compared to 2.32 in the remaining countries (95% CI: 1.41–3.81).
Because it was difficult to judge if the differences in the pooled estimates of risk ratios for TST and
IGRA were due to true differences between the tests or if they reflected the result of heterogeneous
study populations included in the analysis, the main data analysis was limited to the eight studies
that compared TST and IGRA to each other in the same study population (head-to-head analysis).
This analysis showed the pooled risk ratio estimate for TST to be 2.58 (95% CI: 1.72–3.88) and for
IGRA 4.94 (95% CI: 1.79–13.65). The pooled risk ratio in the three studies that evaluated both the
TST and IGRA was 2.07 (95% CI: 1.38–3.11) for the TST and 2.40 (95% CI: 1.26–4.60) for IGRA. In
both analyses, the confidence intervals around effect measures for the TST and IGRA overlapped
and were imprecise. There was insufficient data to provide evidence on predictive utility of the tests
among specific high-risk subpopulations or groups.
Table 1:
Pooled estimates in the predictive utility of IGRA and TST in head-to-head studies that
evaluated incident active TB in untreated individuals
Outcome Pooled I2 Pooled estimate I2 Remark

estimate of (P-value) of IGRA (P-value)
TST
Risk ratio 2.58 14% (0.320) 4.94 72.3% (0.001) Systematic

(8 studies) (95% CI: (95% CI:1.79–13.65) review to
1.72–3.88) complement
this information
Incidence risk 2.07 0% (0.604) 2.40 41% (0.183) with additional
ratio clinical and other
(95% CI: (95% CI: 1.26–4.60)
parameters did
(3 studies) 1.38–3.11)
not yield results

The Panel reviewed the evidence generated from the systematic reviews and discussed benefits
and harms of the alternative screening options to rule out active TB. The Panel noted the potential
limitation of using data from the general population as a proxy for ruling out active TB among at-
risk populations. However, it concluded that this would have no implication in the development of
the algorithm that will be used to test and treat individuals from high-risk populations. The Panel
reiterated that active TB disease should be excluded before LTBI testing and treatment.
17

Symptom screening and chest radiography were considered acceptable for individuals and
programme managers, and the benefit outweighs increased costs and logistic demand.
The Panel noted that comparative analysis between TST and IGRA in the head-to-head studies showed
no evidence that one test should be preferred over the other to assess progression to TB disease. The
Panel also noted that equity and access could vary depending on the type of test used. For example,
the single visit required for IGRA compared to two consultation visits required for TST may favour client
preferences. However, the Panel could not be confident of the overall programmatic impact of this in
terms of access and equity for clients due to the additional cost required. It was noted that serial testing
for LTBI including for health-care workers was beyond the scope of these guidelines.

The Panel noted that resource requirements could vary and that the decision to implement LTBI
testing and treatment needs to consider several factors, including the structure of the health system,
feasibility of implementation, infrastructure requirements and Bacillus Calmette–Guérin (BCG)
vaccination coverage. The Panel noted that the incremental cost-effectiveness of IGRAs compared
to TST appeared to be influenced mainly by the accuracy of the two diagnostic tests, with BCG
vaccination playing a decisive role in reducing the specificity of TST and leading the choice towards
IGRA-only strategies. However, IGRAs are more costly and technically complex to do than the TST.
Given comparable performance but increased cost, replacing TST with IGRAs as a public health
intervention in low-income and other middle-income countries is not recommended (8).
2.3. Treatment options for LTBI
The following treatment options are recommended for the treatment of LTBI: 6-month isoniazid, or
9-month isoniazid, or 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months isoniazid
plus rifampicin, or 3–4 months rifampicin alone. (Strong recommendation, moderate to high quality of
evidence)
Remark: There was consensus of the Panel on the equivalence of 6-month isoniazid, 9-month isoniazid,
and 3-month rifapentine plus isoniazid. However, the Panel could not reach a consensus and voted on the
equivalence of 3–4 months isoniazid plus rifampicin and 3–4 months rifampicin alone as alternative options to
6-month isoniazid. Sixty per cent of the Panel members voted for 4-month rifampicin alone as an equivalent
option to 6-month isoniazid while 53% voted for 3–4 months isoniazid plus rifampicin as an equivalent option
to 6-month isoniazid. Rifampicin- and rifapentine-containing regimens should be prescribed with caution to
people living with HIV who are on antiretroviral treatment due to potential drug-to-drug interactions. See annex
3 for drug dosage.

A systematic review was conducted to evaluate the efficacy and safety of treatment for LTBI (11).
Fifty three studies, all of which were randomized controlled trials and recorded at least one of
the two pre-specified endpoints (preventing active TB, hepatotoxicity of Grade III or above), were
included. Data from the systematic review was available for 15 treatment regimens, although
relatively few direct comparisons were reported, some with sparse data, particularly for modern
regimens. Pyrazinamide-containing regimens were excluded from further consideration because
of reported toxicity. The estimate of the rates of severe hepatotoxicity and death of pyrazinamide-
containing regimens was measured in comparison with an historical isoniazid control (10). Rifampin-
pyrazinamide combinations had fatality and hospitalization rates of 0.9 (95% CI: 0.4–1.9) and 2.8
(95% CI: 1.8–4.3) per 1000 rifampicin–pyrazinamide therapy initiations, respectively, compared with
fatality rates of 0.0–0.3 deaths per 1000 persons in individuals under isoniazid preventive therapy.
No placebo or treatment trial directly compared the efficacy and safety of the 9-month isoniazid
regimen. It was also noted that clinical trials comparing the 3-month regimen of weekly rifapentine
plus isoniazid with placebo or no treatment were not available. This is because when the 3-month
weekly rifapentine plus isoniazid regimen trials were being carried out,comparison with placebo/no
treatment arms was not ethically acceptable.
18
The expert panel comparatively appraised the evidence on efficacy and safety of available treatment
options. The results of the pair-wise comparisons with placebo are reported in Table 2 — isoniazid
for 6 months was used as a reference comparator in the analysis of rates of incident TB, and
hepatotoxicity (Grade III/IV) with other regimens (Table 3).
Table 2:
Regimens that showed significant efficacy when compared to placebo and profile of
heptotoxicity
Comparator Intervention Development of incident TB Hepatotoxicity
OR (95% CI) Quality of OR (95% CI) Quality of

evidence evidence
Placebo Isoniazid 6 months 0.61 (0.48–0.77) Low 0.99 (0.42–2.32) Low
Placebo Isoniazid 12–72 0.53 (0.41–0.69) Low 0.59 (0.23–1.55) Very low
months
Placebo Rifampicin 3–4 months 0.48 (0.26–0.87) Moderate - -
Placebo Rifampicin and 0.52 (0.33–0.84) Low - -

isoniazid 3–4 months
In general these comparisons did not show the superiority of one regimen over any other. However,
in terms of safety, a 3–4 months rifampicin regimen and a 3-month weekly rifapentine plus isoniazid
regimen had fewer hepatotoxicity events compared to the 6-month and 9-month isoniazid regimen,
respectively.
In the absence of any direct comparison of efficacy of 6- and 9-month isoniazid, the Panel reviewed
a reanalysis of the United States Public Health Service (USPHS) trials conducted in the 1950s and
1960s that concluded that optimal protection from isoniazid appears to be obtained by nine months
(12). Based on this, the Panel judged that 9-month isoniazid can be considered as an equivalent
treatment option to 6-month isoniazid.
Table 3:
Comparison of efficacy of 6-month isoniazid with other regimens for the development
of incident TB and hepatotoxicity
Comparator Intervention Development of incident TB Hepatotoxicity
OR (95% CI) Quality of OR (95% CI) Quality of

evidence evidence
Isoniazid Rifampicin 3–4 months 0.78 (0.41–1.46) Moderate 0.03 (0.00–0.48) Low
6-month
Isoniazid Rifampicin and 0.89 (0.65–1.23) Low 0.89 (0.52–1.55) Very low
6-month isoniazid 3–4 months
Isoniazid 3-month weekly 1.09 (0.60–1.99) Low 1.00 (0.50–1.99) Low

6-month rifapentine plus
isoniazid*
Isoniazid 3-month weekly 0.44 (0.18–1.07) Low 0.16 (0.10–0.27) Moderate

9-month rifapentine plus
isoniazid
*exclusively among people living with HIV.
19

The Panel reviewed the evidence for efficacy of the different treatment regimens against incident
TB compared to the placebo, the hepatotoxicity profile of each regimen, and the comparison of
the different regimens against 6-month isoniazid as a reference. The Panel unanimously agreed
on the equivalence of 6-month isoniazid, 9-month isoniazid and 3-month weekly rifapentine plus
isoniazid regimens as alternative treatment options to each other. However, the Panel could not
reach a consensus and voted on the equivalence of 3–4 months isoniazid plus rifampicin and 3–4
months rifampicin alone to 6-month isoniazid. Sixty per cent of the Panel members who attended
the meeting voted for 3–4 months rifampicin alone as an equivalent option to 6-month isoniazid
while 53% of them voted for 3–4 months isoniazid plus rifampicin as an equivalent option to 6-month
isoniazid. For this reason, the Panel concluded that the following regimens can be recommended
as options to treat LTBI: 6-month isoniazid, or 9-month isoniazid, or 3-month weekly rifapentine plus
isoniazid, or 3–4 months rifampicin alone, or 3–4 months isoniazid plus rifampicin. The Panel also
noted that the risk of hepatotoxicity is considerably low in children compared to adults (13).

The Panel agreed that shorter duration regimens are preferred over longer duration regimens from
the perspective of individuals receiving treatment, clinicians providing the treatment and programme
managers, and concluded that the 3-month regimen of weekly rifapentine plus isoniazid has
advantage over the other regimens. Similarly, the Panel agreed that 6-month isoniazid is preferred
over 9-month isoniazid due to resource requirements, feasibility and acceptability by patients. The
Panel noted the reported positive acceptability of rifampicin- and rifapentine-containing regimens
by individuals receiving treatment, and further concluded that the rifampicin (3–4 months isoniazid
plus rifampicin and 4-month rifampicin only) and isoniazid (6- and 9-month) containing regimens
could be self-administered by individuals receiving treatment. The Panel noted that the 3-month
weekly rifapentine plus isoniazid regimen should be given under direct observation as the evidence
available so far is based on this circumstance. It also noted that such provision of rifapentine under
direct supervision will lower acceptability by individuals receiving treatment. Therefore, it was strongly
suggested to revisit this once further evidence is available on the value of self-administration.
Rifampicin- and rifapentine-containing regimens should be prescribed with caution to people living
with HIV who are on antiretroviral treatment due to potential drug-to-drug interactions. The Panel
expressed concern about the current high cost of rifapentine and absence of registration in many
countries that limits its availability, with consequent inequities in access.

The Panel noted that different treatment options have different resource requirements and concluded
that programme managers need to decide upon the treatment options taking into consideration
their resource capacity and national and local context. The Panel further noted that the need for
direct supervision of the 3-month weekly rifapentine plus isoniazid regimen increases resource
requirements, in addition to the current high cost of the drug.
2.4. Preventive treatment for contacts of MDR-TB cases
Serious limitations of the quality of evidence prevent drawing any recommendations on MDR-TB
preventive therapy as a public health measure. Strict clinical observation and close monitoring for the
development of active TB disease for at least two years is preferred over the provision of preventive
treatment for contacts with MDR-TB cases.

A systematic review was conducted to define the effectiveness of anti-TB drugs in preventing active
TB in contacts of MDR-TB patients. Four studies were included for the analysis; all were cohort
studies of which one (14) was a prospective study exclusively involving children below 5 years of
age while the others were retrospective studies involving both adults and children (15–17). Drug
regimens used for preventive treatment varied widely across the studies. For the final analysis, two of
20
the studies in which all or majority of MDR-TB contacts received preventive treatment with isoniazid
(14, 16) were excluded. The other study contained only 11 contacts receiving a regimen with at
least one active agent and was excluded because of its small size (16). Therefore, the quality of
evidence was determined only for one comparison study which used a tailored regimen taking into
account the resistance pattern of the index case among childhood contacts (14). In this single study
two of 41 children receiving tailored preventive therapy developed TB (confirmed and probable TB)
compared to 13 of 64 children not receiving preventive treatment (OR=0.2, 95% CI: 0.04–0.94).
The Panel noted the scarcity of available evidence on effectiveness and safety of using anti-TB drugs
to prevent active TB among adult and childhood contacts of MDR-TB cases. Regimens that can
be used for the treatment of contacts with MDR-TB are known to have poor safety and tolerability
particularly among adults. Additionally, regimens used for the treatment of contacts of MDR-TB
cases, which are often composed of one or two drugs, are inadequate to treat active disease should
this develop, carrying the further risk of acquisition of additional resistance. Many healthy children
who will not develop MDR-TB will be placed on potentially toxic regimens for which paediatric
formulations are unavailable. Moreover, the tailoring of regimens is further hampered by the lack of
reliable drug susceptibility testing for certain drugs (e.g. ethionamide, pyrazinamide, ethambutol).

The Panel emphasized the urgent need for adequately powered randomized controlled trials to
define the benefits and harms of treatment of MDR-TB contacts for clients and health-care providers.
The Panel expressed its concern that wider use of treatment of MDR contacts without established
evidence would set a precedent and challenge the conduct of essential clinical trials. In addition, it
is noted that the infecting strains in the contact may have a different resistance pattern to those of
the source case. This may happen because of coincidental infection from another index case, mixed
strains in the index case, or infection from the index case before the strain in the latter acquired
resistance. The lack of paediatric formulations for some drugs was mentioned as a concern.

The Panel recognized that determination of the drug susceptibility profile for drugs to be used as
preventive treatment for MDR contacts poses both technical and logistic challenges. Furthermore,
the need for close clinical monitoring and follow-up of contacts and prescribing treatment regimens
will incur extra costs and strain the capacity of MDR-treatment services. Broad implementation of
preventive treatment may divert precious second-line drugs of proven effectiveness (levofloxacin,
moxifloxacin and ethionamide) from curative services. The need for active pharmacovigilance for
individuals put on preventive treatment for MDR-TB has resource implications (18).
2.4.5. Conclusions
The Panel noted the serious limitations of the quality of evidence to draw any recommendations on
MDR-TB preventive therapy as a public health measure. Weighing the lack of evidence against the
severe consequences of developing MDR-TB, the Panel concluded that the management of contacts
of MDR-TB patients needs to be guided by a comprehensive individual risk assessment that takes
into consideration the balance between risk and benefits for the individual. Strict clinical observation
and close monitoring for the development of active TB disease for at least two years is preferred over
the provision of preventive treatment for contacts with MDR-TB cases. On the other hand, it should be
noted that, in circumstances where there is a reasonable likelihood that the exposed person may have
also been exposed to drug-susceptible TB, the individual should be given a course of standard LTBI
treatment according to national guidelines. However, the Panel noted that clinicians as part of sound
clinical practice can consider individually tailored treatment regimens based on the drug susceptibility
profile of the index case particularly for child contacts below 5 years of age when benefits can outweigh
harms with reasonable confidence, and keep in mind the technical shortcomings of drug susceptibility
testing for many of the second-line anti-TB drugs. In individual cases where preventive therapy is
considered for contacts of MDR-TB cases, the programme needs to ensure that the necessary resources
are in place to provide quality-assured drug susceptibility testing, all the necessary medications, and
to monitor closely for harms, breakthrough disease and acquired resistance.
21
3. Issues in Implementation
3.1. Adverse events monitoring

Individuals who receive treatment for LTBI do not have active disease, and therefore, it is
mandatory to minimize risks during treatment. Drug-specific adverse reactions can occur with
isoniazid (asymptomatic elevation of serum liver enzyme concentrations, peripheral neuropathy
and hepatotoxicity); rifampicin and rifapentine (cutaneous reactions, hypersensitivity reactions,
gastrointestinal intolerance and hepatotoxicity). While most adverse drug reactions are minor and
occur rarely, the Panel noted that maximum attention should be paid to prevention of drug-induced
hepatotoxicity.
A systematic review was conducted to assess the best way to monitor and manage hepatotoxicity
and other adverse drug reactions, but no studies were identified. A review of national guidelines
(19–23) showed the presence of consistent recommendations across the different guidelines based
on expert opinion, which were useful to inform the judgment of the Panel.
The Panel underlined the importance of routine regular clinical monitoring of individuals receiving
treatment for latent TB through a monthly visit to health-care providers. The prescribing health-care
provider should explain the disease process and the rationale of the treatment and emphasize the
importance of completing the treatment. Those receiving treatment should be educated to contact
their health-care providers should they develop symptoms, such as anorexia, nausea, vomiting,
abdominal discomfort, persistent fatigue or weakness, dark-coloured urine, pale stools or jaundice.
Whenever a health-care provider cannot be consulted at the onset of these symptoms, treatment
should be immediately stopped.
The Panel noted that there was insufficient evidence to support baseline laboratory testing for
measurements of serum aspartate aminotransferase, alanine aminotransferase, and bilirubin.
However, the Panel strongly encourages baseline laboratory testing for individuals with the following
risk cofactors: history of liver disease; regular use of alcohol; chronic liver disease; HIV infection; age
more than 35 years; and pregnancy or the immediate postpartum period (i.e., within three months
of delivery). For individuals with abnormal baseline test results, routine periodic laboratory testing
should be done.
3.2. Risk of drug resistance following LTBI treatment

A systematic review was conducted to determine whether LTBI treatment leads to significant
development of resistance. The systematic review considered the following treatment regimens:
Isoniazid for 6- to 12-month duration: Thirteen studies comparing 6- to 12-month isoniazid preventive
therapy versus no treatment or placebo were included in the systematic review (seven involving HIV
uninfected populations); no difference in the risk of resistance among incident TB cases was found
(risk ratio = 1.45 (95% CI: 0.85–2.47)). There was little evidence of heterogeneity (p=0.923) and
the risk ratio for HIV-uninfected and HIV-infected populations was comparable. The quality of the
evidence was moderate.
Isoniazid for 36 months in HIV-infected individuals: Three studies comparing 36- and 6-month
isoniazid were reviewed but only one study provided resistance rates, and no significant difference
in drug resistance was found (risk ratio = 5.96 (95% CI: 0.24–146) (24). The two other studies
reported that the observed proportion of resistant cases were similar to the expected rate in the
background population, but did not provide a direct comparison of resistance rates between those
receiving 36 months compared to those receiving 6 months treatment (25,26). Therefore, it was
concluded that there is no evidence to indicate whether or not continuous use of isoniazid increases
the risk of isoniazid resistance.
22
Rifamycin-containing regimens: Five studies were included in the comparison of rifamycin resistance
in individuals treated with a rifamycin-containing regimen versus regimen not containing rifamycin.
There were very few cases of rifamycin resistance, a total of six (0.1%) cases in 5790 individuals
receiving LTBI treatment with a rifamycin and five (0.09%) cases in the 5537 individuals in the control
group with a relative risk of 1.12 (95% CI: 0.41–3.08). The quality of the evidence was very low after
downgrading for risk of bias, indirectness and imprecision.
The Panel concluded that the available evidence showed no significant association between anti-TB
drug resistance and the use of isoniazid and rifamycins for LTBI. However, the Panel noted the very
low quality of evidence, particularly for rifamycin regimens. In light of this, the Panel emphasized the
importance of excluding active TB disease using all available investigations according to national TB
guidelines and taking into account the recommendations provided in Section 2.2. The importance
of establishing national TB drug resistance surveillance systems in countries implementing national
latent TB management programmes was emphasized.
3.3. Adherence and completion of preventive treatment

Adherence to the full course and completion of treatment are important determinants of clinical
benefit to the individual as well as to the success of the programme.
A systematic review was conducted to explore the interventions that are effective to improve
initiation, adherence and completion of treatment for LTBI. Twenty articles reported on LTBI treatment
initiation rate and 35 on treatment completion rate in eight different population groups reviewed.
Completion rates were shown to vary greatly across risk groups, with pool estimates ranging from
22% (95% CI: 6%–43%) in prisoners to 82% (95% CI: 66%–94%) in people living with HIV. In general,
completion rates were lower among prisoners and immigrants compared with people living with HIV
and contacts, and were inversely proportional to the duration of treatment.
Thirty-three articles were included for the determinants of treatment initiation, adherence and
completion. The analysis identified the following 10 determinants as detrimental to treatment
completion: (i) adverse drug reactions, (ii) longer duration of treatment, (iii) immigrant status, (iv)
long distance from health facility, (v) history of incarceration, (vi) absence of perception of risk,
(vii) presence of stigma, (viii) alcohol and drug use, (ix) unemployment, and (x) time lag between
diagnosis and treatment.
Evidence on the efficacy of interventions to improve treatment adherence and completion was
obtained from 17 articles. Shorter treatment duration was significantly associated with increased
adherence in two randomized trials (OR = 1.5, 95% CI: 1.0–2.3) (27,28). One randomized trial showed
a significant increase in completion rate in the 3-month weekly rifapentine plus isoniazid regimen
compared to the 9-month isoniazid regimen (29). However, this study was confounded by the fact that
the shorter regimen was also administered under direct observation. There is contradictory evidence
on the role of monetary incentives to improve treatment completion rates: while two randomized
trials showed benefit of incentives (either monetary or methadone) on treatment completion rates
among illicit drug users (OR = 18.4, 95% CI: 7.7–43.7) (30,31), two other randomized trials among
the homeless (32) and inmates (33) did not show any significant impact of monetary incentives in
improving treatment completion rates. Significant increases in completion rates were demonstrated
with peer-support and coaching among adolescents and adults (OR = 1.4, 95% CI: 1.1–1.9) (34–
36); nurse case management among homeless (OR = 3.01, 95% CI: 2.15–4.20) (37); cultural case
management among immigrants (OR = 7.8, 95% CI: 5.7–10.7) (38); and educational interventions
among inmates (OR = 2.2, 95% CI: 1.04–4.72) (33).
The Panel noted that the available evidence is heterogeneous and inconclusive to recommend
on the best interventions to improve adherence and completion of treatment. However, the Panel
underlined the importance of introducing interventions that are responsive to the specific needs
of the risk groups. National TB programmes should design flexible interventions that are tailored
to respond to the local context and needs of the population to ensure acceptable initiation of,
adherence to and completion of LTBI treatment.
23
3.4. Ethical considerations

In addition to the general ethical considerations in TB programmes (39), LTBI testing and treatment
raises a range of ethical issues. First, latent TB is by definition an asymptomatic state and this alters
ethical obligations that would be imposed by active TB. For example, the lack of immediate risk
of transmission associated with LTBI makes it unethical to restrict migration policy based on the
status of LTBI in the individual (40). Secondly, the uncertainty regarding accurate assessment of
individual risk for development of active TB poses a challenge in communication. Such concepts
need to be sensitive to the local cultural and social context to be adequately understood during the
informed consent process for both screening and treatment. Thirdly, latent TB disproportionately
affects individuals and groups that are already socially and medically vulnerable and as such special
efforts are needed to ensure that significant vulnerability in target groups does not affect the validity
of consent or limit the effectiveness of public health interventions.
There is strong moral justification for appropriate national policies and practices to reduce the impact
of latent TB, particularly in vulnerable groups. Policies should also be evaluated under an ethical
perspective after implementation, both to consider possible unexpected impact and to ensure that
the evidence on which they are based remains current and relevant (41).
3.5. Cost effectiveness

A systematic literature review was conducted to critically appraise and summarize current evidence
on the cost-benefit and cost-effectiveness associated with screening for and treatment of LTBI.
Studies that evaluated costs and outcomes of any screening strategy and any drug regimen for
LTBI compared to no intervention in any setting and population group were selected. The outcomes
considered were incremental cost per quality-adjusted life year or life year gained, and incremental
cost per TB case averted. Thirty nine articles were included and the majority of articles (82%) reported
on analyses conducted in upper middle-income countries with TB incidence less than 100 in 100
000 population.
Cost inputs (adjusted for currency and inflation to US$ value as of 2012), varied widely among
studies; such as the cost of testing for detecting LTBI using TST varied from US$ 10.9 in a study
from Italy to an average of US$ 31.5 in studies from the UK. Similarly, detecting LTBI using IGRA test
varied from US$ 22.5 in a study from Mexico to an average of US$ 97.1 in studies from the UK. Wide
variations were also observed for the cost of screening of eligible candidates for latent TB treatment
and the overall cost. For example, the costs of side-effects monitoring (including liver function
tests and clinical monitoring) ranged from US$ 8.3 to US$ 687.3. The average cost of treating LTBI
(including cost of drugs and monitoring) ranged from US$ 381.9 in Italy to US$ 1 129.9 in the UK.
Studies showed that testing and treating immigrants from high TB incidence countries (above 120–
150 per 100 000) to low TB incidence countries may determine savings for the health-care system or
have a favourable incremental cost-effectiveness ratio. Similar results were found in studies among
people living with HIV and contacts of patients with active TB.
In conclusion, the available evidence suggests that screening for and treatment of LTBI may be a
cost-effective intervention for population groups characterized by high prevalence of LTBI and/or
high risk of progression to active TB, such as persons migrating from high TB incidence countries,
contacts of active TB cases and persons living with HIV. However, a marked variability across studies
in economic inputs, in epidemiologic and TB natural history parameters, as well as in assumptions
on effectiveness of preventive treatment made the extrapolation measures of cost-effectiveness
from one setting to another problematic.
3.6. Programme management, monitoring and evaluation

The introduction of treatment for LTBI as a public health intervention entails the documentation of
treated individuals through functional and routine monitoring and evaluation systems that are aligned
with national patient monitoring and surveillance systems. Appropriate recording and reporting tools
24
need to be developed, and standardized indicators established to regularly inform decision making
for programme implementation. In some instances, these may require changes in the national legal
and policy framework that has to be addressed according to the local and national context.
Critical public health considerations for routine monitoring and evaluation include: initiation and
completion of treatment, active surveillance of adverse events and the development of active TB
during and after the completion of treatment for latent TB. Additionally, programme monitoring is
needed to evaluate quality, programme effectiveness and impact. Nationally standardized indicators
and data capturing mechanisms are also required.
The Panel further noted that national TB programmes need to create a conducive policy and
programmatic environment, including the development of national and local policies and standard
operative procedures to facilitate the implementation of the recommendations in these guidelines.
This could include promoting universal health coverage, prioritizing the risk groups based on the
epidemiology of TB, health infrastructure and programmatic management issues. Furthermore,
dedicated resources need to be allocated including for human resource development and service
delivery.
25
4. Research gaps
The review of the evidence for formulating the recommendations exposed a number of upstream
research gaps to better understand, diagnose and treat LTBI. These could include the development
of diagnostic tests with improved performance and predictive value for reactivation TB and drugs
that can cure LTBI or that can be provided for short duration and with less adverse events as an
urgent measure. There is also a need for intensified research to identify suitable biomarkers and
drugs selectively acting on non-dividing M. tuberculosis. In addition to these fundamental research
gaps, the following priority research gaps were identified to inform the revision of these guidelines.
It is imperative that donors and the scientific research community respond to these gaps in order to
update the guidelines and optimize programme implementation.
4.1. Risk of progression to active TB disease and differential impact

by population risk group
Measuring the risk of progression from LTBI to active disease in a number of risk groups is crucial to
determine the potential benefits of LTBI treatment and design appropriate public health interventions.
In addition to direct measurement of incidence in cohort studies (such as TST positive cohort in
a risk group versus TST positive cohort in the general population), alternative methods can be
explored (such as the use of genotyping to measure the risk of reactivation in comparison studies).
Generating evidence on the benefits and harms of systematic treatment of LTBI in all risk groups
and particularly the following groups is essential: diabetic patients, people with harmful alcohol
use, tobacco smokers, underweight people, persons with silica exposure, patients receiving steroid
treatment, patients with rheumatologic conditions, indigenous populations and cancer patients.
In addition, evidence needs to be generated on differential harm of LTBI testing and treatment in
specific risk groups, on differential acceptability of testing and treatment, and on potential socially
adverse events (such as stigma).
4.2. Defining the best algorithm to test and treat LTBI

Operational and clinical studies to identify undiagnosed active TB before LTBI treatment initiation are
important. These could include assessing the diagnostic performance of the algorithm proposed
in these guidelines with carefully designed appropriate studies as a priority. In addition, diagnostic
algorithms tailored to the needs of specific risk groups should be developed and evaluated for
performance, ease and capacity to assist in its implementation.
4.3. Treatment options for LTBI and adverse event monitoring

The development of treatment regimens that are shorter and better tolerated compared with those
recommended in these guidelines is a priority for research. Studies to measure efficacy and the
risk of toxicity and adverse events in specific risk groups (e.g. people who use drugs or people
with alcohol use disorder) are essential. Drug interactions between rifamycin-containing regimens
and antiretroviral drugs (including second- and third-line drugs) among people living with HIV are
another priority gap that needs to be addressed.
Prospective, randomized studies are required to measure the incremental benefits of routine
monitoring of liver enzymes over education and clinical observation alone in terms of preventing
severe clinical adverse events. It is of paramount importance to stratify this evidence by population
risk groups. This knowledge would be greatly beneficial in terms of cost-effectiveness, as routine
laboratory monitoring could be costly and unfeasible.
26
4.4. Risk of drug resistance following LTBI treatment

Programme-based surveillance systems and clinical studies are needed to monitor the risk of drug
resistance following LTBI treatment. Special consideration needs to be given to rifamycin-containing
regimens because of the dearth of data. Similarly, studies on the efficacy of currently recommended
treatment options in areas of highly prevalent drug resistance are required.
4.5. Adherence and completion of treatment

Carefully designed studies, including randomized clinical trials, are required to generate evidence on
the effectiveness of context-specific interventions to enhance adherence and treatment completion.
Such studies should be tailored to specific risk groups, with consideration to available resources
and infrastructure of the health system.
4.6. Cost-effectiveness studies

Many cost-effectiveness evaluations are available in the literature, but their extensive heterogeneity
prevents the comprehensive appraisal of cost-effectiveness of LTBI management interventions,
stratified by population groups and type of intervention. Direct measurement of cost-effectiveness in
specific settings and populations would be vital to expand the LTBI strategy at the national or local
level.
4.7. Preventive treatment for MDR-TB contacts

Adequately powered randomized controlled trials are necessary to define the benefits and harms of
treatment of MDR-TB contacts. Trials should be performed in both adult and paediatric populations
with specific focus on the risk–benefit ratio. The composition, dosages and duration of the LTBI
regimen for MDR-TB need to be optimized and the potential role of newer drugs with good sterilization
properties should be investigated. Studies should examine the adverse effects of the long-term
use of fluoroquinolones in preventive treatment. Improved strategies to reinforce pharmacovigilance
should be developed.
4.8. Programme management

Epidemiological research is needed to understand the burden of LTBI and inform the development
of nationally and locally tailored interventions. Similarly, standard approaches and tools need to
be developed and assessed to monitor and evaluate the public health impact of programmatic
implementation of LTBI management.
27
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29
Annex 1:
Primary target countries for the guidelines on LTBI
management*
Country name Income status Estimated TB Country name Income status Estimated TB
incidence per incidence per
100 000 (2013) 100 000 (2013)
Albania upper-middle 18 Croatia high 13
Algeria upper-middle 81 Cuba upper-middle 9.3
American upper-middle 18 Curaçao high 1.4

Samoa
Cyprus high 5.8
Andorra high 7.3
Czech Republic high 5.5
Antigua and high 13
Barbuda Denmark high 7
Argentina upper-middle 24 Dominica upper-middle 4.8
Aruba high 12 Dominican upper-middle 60

Republic
Australia high 6.2
Ecuador upper-middle 56
Austria high 8.4
Estonia high 22
Azerbaijan upper-middle 85
Fiji upper-middle 36
Bahamas high 9.8
Finland high 5.7
Bahrain high 18
France high 8.8
Barbados high 1.4
French high 22
Belarus upper-middle 70 Polynesia
Belgium high 9.1 Germany high 5.8
Belize upper-middle 37 Greece high 5
Bermuda high 0 Grenada upper-middle 4.1
Bosnia and upper-middle 46 Guam high 33

Herzegovina
Hungary upper-middle 18
Brazil upper-middle 46
Iceland high 3.6
Brunei high 58
Darussalam Iran (Islamic upper-middle 21
Republic of)
Bulgaria upper-middle 29
Iraq upper-middle 45
Canada high 5
Ireland high 8.8
Cayman high 9.8
Islands Israel high 5.8
Chile high 16 Italy high 5.7
China upper-middle 70 Jamaica upper-middle 6.6
China, Hong high 76 Japan high 18

Kong SAR
Jordan upper-middle 5.8
China, Macao high 88
SAR Korea, high 97
Republic of
Colombia upper-middle 32
Kuwait high 24
Costa Rica upper-middle 11
Latvia high 50
* For practical purposes (such as analysis of systematic reviews) these countries were labelled as Category A countries
whereas the rest of the countries were labelled Category B.
30
Country name Income status Estimated TB Country name Income status Estimated TB
incidence per incidence per
100 000 (2013) 100 000 (2013)
Lebanon upper-middle 16 Spain high 13
Libya upper-middle 40 St. Kitts and high 0

Nevis
Lithuania high 65
Suriname upper-middle 39
Luxembourg high 8.7
Sweden high 7.2
Malaysia upper-middle 99
Switzerland high 6.6
Maldives upper-middle 40
The former upper-middle 17
Malta high 11 Yugoslav
Republic of
Mauritius upper-middle 21
Macedonia
Mexico upper-middle 21
Tonga upper-middle 13
Monaco high 2.1
Trinidad and high 21
Montenegro upper-middle 21 Tobago
Netherlands high 6.1 Tunisia upper-middle 32
New Caledonia high 19 Turkey upper-middle 20
New Zealand high 7.3 Turkmenistan upper-middle 72
Northern high 70 Turks and high 6.9

Mariana Caicos Islands
Islands United Arab high 1.8
Norway high 8.2 Emirates
United high 14
Oman high 11
Kingdom
Palau upper-middle 44
United States high 3.3
Panama upper-middle 48
Uruguay high 30
Poland high 22
US Virgin high 7.7
Portugal high 26 Islands
Puerto Rico high 1.6 Venezuela upper-middle 33

(Bolivarian
Qatar high 40 Republic of)
Romania upper-middle 87
Russian high 89
Federation
Saint Lucia upper-middle 5.7
Saint Vincent upper-middle 24

and the
Grenadines
San Marino high 1.5
Saudi Arabia high 14
Serbia upper-middle 18
Seychelles upper-middle 30
Singapore high 47
Sint Maarten high 5.1
Slovakia high 7.7
Slovenia high 7.5
31
Annex 2:
List of systematic reviews conducted
Systematic review 1: What is the prevalence of LTBI among risk groups?
Systematic review 2: What is the risk of progression of LTBI to active TB disease among risk groups.?
Systematic review 3: What is the incidence of active TB among risk groups?
Systematic review 4: Among individuals at risk of LTBI, which investigations and clinical parameters
are most predictive of the absence of active TB?
Systematic review 5: Among persons at high risk of latent tuberculosis infection (LTBI) who are not
on tuberculosis preventive therapy, which test(s) alone or in combination with other proxies for LTBI,
when positive, can best identify individuals most at risk of progression to incident tuberculosis (TB)
disease?
Systematic review 6: Systematic literature review and meta-analysis on the best treatment options
for latent tuberculosis infection
Systematic review 7: What is the best way to monitor and manage hepatic toxicity and other adverse
events in individuals receiving treatment for LTBI?
Systematic review 8: Does treatment for LTBI lead to significant development of resistance against
the drugs used?
Systematic review 9: What is the effectiveness of anti-tuberculosis drugs (any regimen) in preventing
active TB in contacts of MDR-TB patients?
Systematic review 10: For each recommended LTBI treatment regimen, what are the initiation and
completion rates?
Systematic review 11: For each recommended LTBI treatment regimen, what are the determinants
of treatment initiation, adherence and completion?
Systematic review 12: In individuals who are eligible for LTBI treatment, what are the interventions
with demonstrated efficacy to improve LTBI treatment initiation, adherence and completion?
Systematic review 13: Will duration of protection from LTBI treatment be a barrier to LTBI management
implementation?
Systematic review 14: What is the cost-effectiveness of LTBI management interventions?
32
Annex 3:
Recommended drug dosage
Drug regimen Dose per body weight Maximum dose
Daily Isoniazid alone for Adults = 5 mg/kg 300 mg

6 or 9 months
Children = 10 mg/kg
Daily Rifampicin alone Adults= 10 mg/kg 600 mg

for 3-4 months
Children = 10 mg/kg
Daily isoniazid plus Isoniazid Isoniazid = 300 mg

rifampicin for 3–4
Adults = 5 mg/kg Rifampicin= 600 mg
months
Children = 10 mg/kg
Rifampicin
Adults and children = 10 mg/kg
Weekly rifapentine plus Adults and Children Isoniazid = 900 mg

isoniazid for 3 months
Isoniazid: 15 mg/kg Rifapentine = 900 mg
(12 doses)
Rifapentine (by body weight):
10.0–14.0 kg = 300 mg
14.1–25.0 kg = 450 mg
25.1–32.0 kg = 600 mg
32.1–49.9 kg = 750 mg
≥50.0 kg = 900 mg
33
For further information, please contact:
World Health Organization 9789241548908
20, Avenue Appia CH-1211 Geneva 27 Switzerland
Global TB Programme
E-mail: tbdocs@who.int
Web site: www.who.int/tb

Who TB - Ltbi

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Guidelines on the

© World Health Organization 2015

Declaration and management of conflict of interest 6

1. Background and process 10

Overall coordination and writing of the guidelines

WHO Steering Group

Co-chairs of the WHO Guidelines Development Group

GRADE methodologist of the WHO Guidelines Development Group

Members of WHO Guidelines Development Group

WHO Consultants for Systematic Reviews

WHO Headquarters and Regional offices

Acknowledgement of financial support

GRADE Grading of Recommendations Assessment, Development and Evaluation

IGRA interferon-gamma release assays

LTBI latent TB infection

TNF tumour necrosis factor

TST Mantoux tuberculin skin test

Declaration and management of conflict of interest

The following interests were declared:

Guidelines Development Group:

Expert review Group:

Guidelines update date: 2020

The following are the key recommendations of the guidelines:

• Establishment of national TB drug resistance surveillance systems while implementing national

• Documentation of treated individuals through a functional, routine monitoring and evaluation

1. Background and process

Reactivation TB can be averted by preventive treatment. Currently available treatments have an

1.2. Scope of the guidelines

1.3. Target audience

1.4. Development of the guidelines

The following seven key questions were identified:

• 1 to 3 to indicate an outcome considered not important

1.5. Quality of evidence and strength of the recommendations

Evidence level Rationale

Very low Any estimate of effect is very uncertain.

2.1. Identification of at-risk populations for LTBI testing and treatment

2.1.1. Summary of the evidence

2.1.2. Balance of benefits and harms

2.1.3. Values and preferences of clients and health-care providers

2.1.4. Resource considerations

2.2. Algorithm to test and treat LTBI

2.2.1. Summary of the evidence

Figure 1. Algorithm for targeted diagnosis and treatment of LTBI in individuals

TB and other disease

Treat for LTBI

Outcome Pooled I2 Pooled estimate I2 Remark

Risk ratio 2.58 14% (0.320) 4.94 72.3% (0.001) Systematic

2.2.2. Balance of benefits and harms

2.2.3. Values and preferences of clients and health-care providers

2.2.4. Resource considerations

2.3. Treatment options for LTBI

2.3.1. Summary of the evidence

Comparator Intervention Development of incident TB Hepatotoxicity

OR (95% CI) Quality of OR (95% CI) Quality of

Placebo Isoniazid 6 months 0.61 (0.48–0.77) Low 0.99 (0.42–2.32) Low

Placebo Rifampicin 3–4 months 0.48 (0.26–0.87) Moderate - -

Placebo Rifampicin and 0.52 (0.33–0.84) Low - -

Comparator Intervention Development of incident TB Hepatotoxicity

OR (95% CI) Quality of OR (95% CI) Quality of

Declaration and management of conflict of interest 6

1. Background and process 10