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 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.

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:

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).