1. Background

Latent tuberculosis infection (LTBI) is defined as a state of persistent immune response to stimulation by M. tuberculosis antigens with no evidence of clinically manifest active TB (1)¹. As there is no “gold standard” test for TB infection, the global burden is not known with certainty; however, about one fourth of the world’s population is estimated to be infected with M. tuberculosis (2),(3). The vast majority have no signs or symptoms of TB disease and are not infectious, although they are at risk of developing active TB disease and becoming infectious. Several studies have shown that in recent decades, on average, 5–10% of those infected will develop active TB disease over the course of their lives, usually within the first 5 years after initial infection (4),(5). The risk for active TB disease after infection depends on several factors, the most important being immunological status (1). At the first United Nations high-level meeting on TB in 2018, Member States committed to provide TB preventive treatment to at least 30 million people in 2018–2022: 6 million people living with HIV (PLHIV), 4 million children < 5 years who are household contacts of people with TB, and 20 million other household contacts (6).

Prevention of active TB disease by TB preventive treatment is a critical component of the WHO End TB Strategy and efforts to eliminate TB (7),(8),(9). The efficacy of currently available TB preventive treatment ranges from 60% to 90% (1). The potential benefit of treatment should, however, be carefully balanced against the risk for drug-related adverse events. Mass, population-wide LTBI testing and treatment are not feasible because the tests are imperfect, there are risks of serious and potentially fatal adverse drug reactions, with a high cost and unproven public health impact. The benefits of TB preventive treatment are more likely to outweigh harms in infected individuals belonging to population groups in whom the risk for progression to active disease significantly exceeds that of the general population. The programmatic management of TB preventive treatment (PMTPT) involves a comprehensive package of interventions: identifying and testing those individuals who should be tested, delivering effective, safe treatment in such a way that the majority of those starting a treatment regimen will complete it with no or minimal risk of adverse events, and monitoring and evaluation of the process. PMTPT fits within a larger framework of preventive actions envisaged by Pillars 1 and 2 of the End TB Strategy, ranging from screening for active TB, infection control, prevention and care of HIV and other co-morbidities and health risks, access to universal health care, social protection and poverty alleviation.

2. Rationale

WHO guidelines on PMTPT are premised upon the probability that the condition will progress to active TB disease in specific risk groups, on the underlying epidemiology and burden of TB, the feasibility of the intervention, and the likelihood of a broader public health impact. They are expected to provide the basis for the development of national guidelines for LTBI management, adapted to the local circumstances. Although these revised guidelines envisage a massive expansion in population level treatment of LTBI, global coverage of the intervention is still very low even in the priority target groups (10). The Latent TB Infection : Updated and consolidated guidelines for programmatic management released by WHO in 2018 brought together recommendations previously dispersed in several other guidelines to facilitate access to the most recent policies that are still valid for PLHIV (11), for children under 5 years who are household contacts of people with pulmonary TB (12), for other contacts of people with TB, and for clinical risk groups (13),(14),(15),(16). In addition, the 2018 guidelines updated 7 previous recommendations and included 7 new ones. Since the publication of these guidelines in early 2018 new evidence became available that made it necessary to revisit some of the recommendations once more.

3. Scope of the current update

The current update considered evidence for three questions, worded in PICO format², namely:

• In people of all ages at risk of active TB, does a 4-month daily rifampicin regimen safely prevent TB disease compared to other recommended TB preventive treatment regimens? (PICO 6)
• In people of all ages at risk of active TB, does a 1-month daily rifapentine plus isoniazid regimen safely prevent TB disease compared to other recommended TB preventive treatment regimens? (PICO 7)
• In pregnant and postpartum women, is isoniazid preventive treatment for TB as safe as other preventive treatment regimens? (PICO 9)

In addition to these new questions the wording of some of the recommendations dating from before the current update, along with their accompanying conditions, was revised to improve clarity. Some recommendations in previous guidelines applied differently to high and low TB incidence countries and settings (using a threshold of 100 TB cases per 100,000 population nationally to differentiate), primarily out of concerns about variable intensity of background TB transmission, as well as programmatic capacity to rule out active TB reliably and to provide adequately for newer treatments regimens and care. In 2019, the GDG that produced the WHO consolidated guidelines on tuberculosis: tuberculosis preventive treatment decided to stress these conditions under implementation considerations instead of restricting the recommendations based upon a TB incidence threshold.

When making their decisions about the wording and strength of the recommendations the GDG members took into account not only the evidence for effectiveness and safety of an intervention but also considered other dimensions important to both patient and programme, namely values, preferences, resource requirements, cost, impact on health equity, acceptability and feasibility. This is detailed in the GRADE Evidence to Decision Tables (Annex 3).

4. Target audience

The WHO consolidated guidelines on tuberculosis: tuberculosis preventive treatment provides a comprehensive set of recommendations for PMTPT geared towards the implementers of the WHO End TB Strategy and also for countries intent upon TB elimination (9). The guidelines are to be used primarily in national TB and HIV and maternal and child programmes or their equivalents in ministries of health and for other policy-makers working on TB, HIV, infectious diseases and maternal and child health. They are also appropriate for staff of ministries of justice, correctional services and other government agencies which deliver healthcare, including prison services, social services and immigration. The guidelines are also intended for clinicians in the public or the private sectors working on TB, HIV, infectious diseases, prevention, child health and noncommunicable diseases such as chronic kidney disease and cancer. The persons directly affected by the guidelines are risk groups for whom TB preventive treatment is recommended.

Footnotes

1

Given that the main difference from active TB is the absence of disease and given that infection cannot always be considered latent, the condition is sometimes referred to as TB infection (TBI).

2

Population, Intervention, Comparator and Outcome. The three PICOs in the current update were renumbered to position them within the sequence of questions covered by the 2018 guidelines update (16). See Annex 2 for a complete listing of PICOs and evidence summaries made for both the 2018 and the current (2019) updates