Latent tuberculosis infection (LTBI) is defined as a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB (1). As there is no "gold standard" test for LTBI, the global burden is not known with certainty; however, up to one third of the world's population is estimated to be infected with M. tuberculosis (2)(3)(4), and the vast majority have no signs or symptoms of TB disease and are not infectious, although they are at risk for active TB disease and for becoming infectious. Several studies have shown that, 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 (5). The risk for active TB disease after infection depends on several factors, the most important being immunological status (1).
Prevention of active TB disease by treatment of LTBI is a critical component of the WHO End TB Strategy (6).
The efficacy of currently available treatments 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, populationwide LTBI testing and treatment are not feasible because the tests are imperfect, there are risks of serious and fatal side-effects, and the cost would be high, for an unproven public health impact. For infected individuals in population groups in which the risk for progression to active disease significantly exceeds that of the general population, however, the benefits are greater than the harm. Management of LTBI 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.
Current WHO guidelines on LTBI are based on the probability that the condition will progress to active TB disease in specific risk groups, on the underlying epidemiology and burden of TB, the availability of resources and the likelihood of a broader public health impact. Therefore, management of LTBI is recommended for people living with HIV (7) and for children under 5 years who are household contacts of people with pulmonary TB (8) in all settings including those with a high TB incidence (estimated annual TB incidence rate,  100 per 100 000 population) and for adult contacts of people with TB and other clinical risk groups living in settings with a low TB incidence (estimated annual TB incidence rate < 100 per 100 000 population) (9)(10)(11). The cut-off point for defining a country as having a low or a high TB incidence was set by consensus by the previous Guideline Development Group (GDG) (9,10). Although their recommendations led to a significant increase in preventive treatment of TB, particularly among people living with HIV, global coverage of the intervention is still very low (12). Furthermore, the fragmented recommendations resulted in a multiplicity of guideline documents, which posed challenges for smooth implementation. Therefore, several WHO Member States requested consolidated guidelines on LTBI management to ensure harmonized, smooth programmatic implementation. Increased interest has also been shown in programmatic management of LTBI as part of the End TB Strategy, including TB elimination (13).
The present consolidated guidelines include a comprehensive set of WHO recommendations for the management of LTBI and will facilitate implementation of the End TB Strategy. They include updated recommendations from the 2011 WHO guidelines on intensified TB case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings as well as recommendations on the use of LTBI testing. Other relevant recommendations approved by the guideline review committee are also included (Box 1). The guidelines presented here are the most recent and most comprehensive WHO guidelines for programmatic management of LTBI. They are expected to provide the basis and rationale for the development of national guidelines for LTBI management, adapted to the national and local epidemiology of TB, the availability of resources, the health infrastructure and other national and local determinants.
The guidelines are to be used primarily in national TB and HIV control programmes or their equivalents in ministries of health and for other policy-makers working on TB and HIV and infectious diseases. They are also appropriate for officials in other line ministries with work in the areas of health, including prison services, social services and immigration (such as ministries of justice or correctional services) and clinicians and public health practitioners working on TB, HIV, infectious diseases, prevention, child health and noncommunicable diseases such as chronic kidney disease and cancer.

# Development of the guidelines
In conformity with the process recommended by the WHO guideline review committee (14), three groups were established: a guideline steering group, composed of WHO staff, including from regional offices; the GDG, composed of a guideline methodologist, external content experts, national TB programme managers, academicians and representatives of patient groups and civil society, who provided input at all stages of the process; and the external review group, composed of experts with interest in LTBI, who reviewed the draft guidelines.
The steering group prepared the scoping document for the guidelines, which identified key questions in PICO (population, intervention, comparator, outcomes) format, the systematic reviews required as a basis for the recommendations and the process for preparing the guidelines. The group also considered questions on aspects of programmatic management of LTBI for which new evidence was likely to be available.

# BOX 1.
Guidelines that have been updated or consolidated Use of tuberculosis interferon-gamma release assays (IGRAs) in low-and middle-income countries. Geneva: World Health Organization; 2011 ().
The following seven key questions were identified: A list of potential outcomes of interest for each question was circulated to all members of the GDG, who scored the importance of each outcome on a scale of 1 to 9: 1-3: not important; 4-6: important; and 7-9: critical. The average of the scores for each outcome was used to prioritize the outcome and to select the most important outcomes for each PICO question. The outcomes selected for each question and the scores for their importance are presented in Annexes 1 and 2.
Seven new or updated systematic reviews were conducted for these guidelines. The existing recommendations were discussed in the GDG and updated, as appropriate, including for clarity, as deemed necessary. Furthermore, an online survey was conducted to determine the preferences and values of affected populations for the management of LTBI (Annex 3). A series of virtual meetings, co-chaired by a technical expert and a guideline methodologist, were organized to appraise the evidence for each PICO and formulate recommendations. The "evidence-to-decision" tables developed on the "GRADEpro interface" were used to guide discussions on benefits and harm, the quality of the evidence, cost, feasibility, acceptability, equity, values and preferences (14). The recommendations and their strength were determined by the GDG on the basis of these factors. The guideline methodologist facilitated the discussions in order to reach consensus, which was defined as unanimous or majority agreement. Recommendations from existing WHO guidelines were initially assessed by the steering group and were later discussed and approved by the GDG. Valid recommendations that did not require updating were also included. The guidelines and the supporting documents were reviewed and endorsed by all GDG members. Remarks from the external review group were evaluated by the steering group for incorporation into the final version of the guidelines.
There are 10 existing, 7 updated and 7 new recommendations. The GRADE (grading of recommendations, assessment, development and evaluation) tables for the seven new recommendations are presented in Annex 1. The detailed evidence-to-decision tables for each PICO and the results of the systematic reviews are shown in Annex 2 and the survey on values and preferences in Annex 3.

# Quality of evidence and strength of the recommendations
The quality of evidence and the strength of the recommendations were assessed with the GRADE method (15). In this process, the quality of a body of evidence is defined as the degree of confidence that the estimates of effect (desirable or undesirable) are close to the actual effects of interest. The usefulness of an estimate of 1 This PICO was not included in the original scoping document submitted to the WHO Guidelines Review Committee but was added later at the suggestion of the GDG and in agreement with the Secretariat of the guidelines review committee.
effect depends on the level of confidence in that estimate: the higher the quality of evidence, the more likely a strong recommendation can be made. A decision on the strength of the evidence also depends on other factors. The strength of a recommendation reflects the degree of confidence of the GDG that the desirable effects outweigh the undesirable effects. The desirable effects included beneficial health outcomes (e.g. prevention and early diagnosis of TB, reduced TB-related morbidity and mortality), a smaller burden of TB and more savings; whereas the undesirable effects include harm, a greater burden and more costs. The "burdens" included adherence to the recommendations by programmes, patients and caregivers (e.g. families), such as more frequent tests and taking additional medications.
The quality of evidence was categorized into four levels:
We are very confident that the true effect lies close to that of the estimate of the effect.
We are moderately confident that the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Our confidence in the effect estimate is limited: the true effect may be substantially different.

# Very low
We have very little confidence in the effect estimate: the true effect is likely to be substantially different.
The recommendations in these guidelines are either strong or conditional.
A strong recommendation is one for which the GDG was confident that the desirable effects of adherence would outweigh the undesirable effects. This could be either in favour of or against an intervention.
A conditional recommendation is one for which the GDG concluded that the desirable effects of adherence would probably outweigh the undesirable effects, but the GDG was not confident about the trade-off.
The reasons for lack of confidence included: absence of high-quality evidence (few data to support the recommendation); imprecise estimates of benefit or harm (new evidence might change the ratio of risk to benefit); uncertainty or variation in the value of the outcomes for different individuals (applicable only to a specific group, population or setting); and small benefits or benefits that might not be worth the cost (including the cost of implementing the recommendation).

# Publication, implementation, evaluation and expiry
These guidelines will be published on the WHO website in at least four languages (English, French, Spanish and Russian) and can be downloaded freely. The printed guidelines will be widely distributed at international and regional conferences and meetings of programme managers in all regions. Implementation of the recommendations will be monitored regularly in the annual data collection system of WHO Global TB Data Monitoring. WHO will update the guidelines 5 years after their publication or earlier if new evidence becomes available that necessitates a revision.

# Presentation of the guidelines and recommendations
The overall structure of these guidelines and the recommendations follow the logical cascade of management of LTBI: identification of at-risk populations (adults and children living with HIV, HIV-negative adult and child contacts of TB cases and other HIV-negative at-risk groups); ruling out active TB disease; testing for LTBI; providing treatment; monitoring adverse events; adherence to and completion of treatment; and monitoring and evaluation. The recommendations are categorized as existing (recommendations that were published in previous guidelines approved by the review committee and are still valid); updated (recommendations that were published in previous guidelines approved by the review committee, for which the evidence was reviewed, discussed in the GDG and updated, including for clarity); and new (recommendations that were made for the current guidelines).

# Identification of populations for testing and treatment of latent tuberculosis infection
Not all individuals infected with M. tuberculosis develop active TB. It is estimated that the lifetime risk of an individual with LTBI for progression to active TB is 5-10% (5). The risk is particularly high among children under the age of 5 years and among people with compromised immunity (1). As preventive treatment entails risks and costs, preventive treatment of M. tuberculosis infection should be selectively targeted to the population groups at highest risk for progression to active TB disease, who would benefit most from treatment of LTBI.
In selecting at-risk populations for programmatic management of LTBI, consideration should be given to the epidemiology and pattern of transmission of TB in the country, so that treatment offers lasting protection.
A critical component of programmatic management should therefore be a comprehensive individual clinical assessment that takes into account the balance between the risks and benefits for the individual receiving treatment.
This section describes at-risk populations for whom systematic LTBI testing and treatment is recommended.

# Adults and adolescents living with HIV
Adults and adolescents living with HIV, with unknown or a positive tuberculin skin test (TST) and are unlikely to have active TB should receive preventive treatment of TB as part of a comprehensive package of HIV care. Treatment should be given to these individuals irrespective of the degree of immunosuppression and also to those on antiretroviral treatment (ART), those who have previously been treated for TB and pregnant women.

# Summary of evidence
TB is the most frequent cause of AIDS-related deaths worldwide, despite progress in access to ART (16). TB caused about 400 000 deaths among people living with HIV in 2016, representing one third of all HIV deaths. Global data in 2016 indicated that people living with HIV were 21 times (95% confidence interval  16;27) more likely to develop active TB than those without HIV infection (12).
A systematic review of 12 randomized controlled trials (RCTs) of 8578 people living with HIV (17) found that preventive treatment reduced the overall risk for TB by 33% (relative effect  0.67, 95% CI 0.51;0.87) among people living with HIV. For those who were TST positive, the reduction increased to 64% (RR 0.36, 95% CI 0.22; 0.61). Although not statistically significant, the reduction was 14% among TST-negative people (RR 0.86, 95% CI 0.59; 1.26) and those of unknown TST status (RR 0.86, 95% CI 0.48; 1.52). Most of the studies in the review were, however, conducted before ART became available, and there is now increasing evidence from observational studies and RCTs of the efficacy of preventive treatment in people receiving ART. A double-blind RCT of 1329 people living with HIV and receiving ART indicated that those on ART with negative TST or IGRA benefited more from IPT than those who were TST or IGRA positive (18). An RCT of 2056 people living with HIV (19) and follow-up data (20) showed additive benefits of preventive treatment plus ART in reducing both TB incidence and overall mortality. The protective effect lasted for more than 5 years (20).

# Rationale for the recommendation
The GDG reviewed the evidence from the systematic reviews and discussed each population risk group identified in detail for the prevalence of LTBI, risk of progression to active TB and the incidence of active TB as compared with that in the general population. They concluded that the evidence shows a clear benefit of systematic testing and treatment of LTBI for people living with HIV.
Preventive treatment should be given to adults and adolescents living with HIV, regardless of their immune status and whether they are on ART, given the evidence of the additional protective effect with ART. A systematic review of studies conducted before ART became available showed the value of providing preventive treatment immediately after successful completion of TB treatment among people living with HIV in countries with high TB incidence (7,21). Therefore, preventive treatment is recommended for people who were previously treated for TB. No evidence was found, however, for preventive treatment of people who had successfully completed treatment for multidrug-resistant (MDR) or extensively drug-resistant TB or those who are concomitantly receiving ART.
Pregnant women living with HIV are at risk for TB, which can have severe consequences for both the mother and the fetus (22). As isoniazid and rifampicin, the drugs commonly used in preventive treatment, are safe for use in pregnant women (23), pregnancy should not disqualify women living with HIV from receiving preventive treatment. Nevertheless, sound clinical judgement is required to determine the best time to provide it.
There is no evidence about repeated courses of preventive treatment, and hence no recommendation is made in the present guidelines. In settings with high TB transmission (as defined by local authorities), however, IPT for 36 months or longer is recommended conditionally (24) (see section 5). Clinical trials of repeated courses of preventive treatment are lacking and will be essential for updating these guidelines.

# Infants and children living with HIV

# Summary of evidence
A systematic review conducted for the previous guidelines included two studies conducted in South Africa.
One suggested a considerable reduction in mortality and protection against TB among HIV-infected children who received isoniazid for 6 months (25). The other RCT, however, showed no benefit of preventive treatment in HIV-infected infants with no known exposure to a TB case who were identified in the first 3-4 months of life, given rapid access to ART and carefully monitored every month for new exposure to TB or disease (26).
Few RCTs included children on ART. In one trial of 167 children on ART, the incidence of TB was lower in those given preventive treatment than in those who were not, but the difference was not statistically significant (incidence rate ratio 0.51, 95% CI 0.15;1.75) (27). A cohort study suggested an additive protective effect of preventive treatment in children receiving ART (28).

# Rationale for the recommendations
For infants aged <12 months old living with HIV, the GDG noted that preventive treatment should be given only to those infants who have a history of household contact with a person with TB and do not have TB disease according to investigations conducted in line with national guidelines because of limited data on the benefits. The GDG strongly recommended preventive treatment for children aged  12 months living with HIV, despite the low quality of the evidence, because of the clear benefits seen in adults with HIV and the high risk for active TB among people living with HIV.
The GDG noted that, although the evidence for the efficacy of preventive treatment in children on ART is limited, it is biologically plausible, given the evidence of additive effects in adults with HIV receiving ART. Thus, preventive treatment is recommended for children, regardless of whether they are on ART.
There is no evidence on the use of preventive treatment in children living with HIV after successful completion of TB treatment. Like adults, however, children living with HIV who are exposed to reinfection and recurrence of TB would benefit from preventive treatment. Therefore, based on this judgement, the GDG conditionally recommended that all children living with HIV who have been successfully treated for TB and are living in settings with high TB incidence, prevalence and transmission (as defined by national authorities) should receive a course of preventive treatment. Preventive treatment can be started immediately after the last dose of TB therapy or later, according to clinical judgement.

# HIV-negative household contacts of a person with pulmonary TB

# Summary of evidence
We updated a systematic review conducted for the previous guidelines (9, 10), focusing on household contacts in countries with high TB incidence. The aim of the review was to determine the prevalence of LTBI, progression to active TB disease and the cumulative prevalence of active TB among household contacts, stratified by age.
We added 19 studies published between 2014 and 2016. The evidence-to-decision and the GRADE tables are presented in Annexes 1 and 2.
The prevalence of LTBI was higher among children and adolescents aged > 15 years and adults than in children  15 years (0.22, 95% CI 0.08;0.60, three studies). All household contacts, regardless of their age or LTBI status, were nevertheless at substantially higher risk for progression to active TB than the general population (Table 1).

# Rationale for the recommendations
The GDG noted the significantly higher risk of infants and young children < 5 years for developing active TB. Furthermore, the disease can develop rapidly in young children, and they are at greatest risk for severe and disseminated disease, associated with high morbidity and mortality. Therefore, the GDG strongly recommended preventive treatment for child household contacts aged < 5 years, regardless of the background epidemiology of TB, but only after active TB disease has been ruled out. Preventive treatment could also be considered conditionally for household contacts in other age groups, according to clinical judgement on the balance between harm and benefit for individuals and the national and local epidemiology of TB, with special consideration of on-going transmission of TB. The GDG also noted that the availability of resources and the capacity of the health infrastructure to assess the intensity and the risk of exposure and development of active TB, to weigh harm and benefit and to exclude active TB disease before initiation of treatment are important considerations in the conditionality of the recommendation.

# Other HIV-negative at-risk groups
Patients initiating anti-TNF treatment, patients receiving dialysis, patients preparing for an organ or haematological transplant and patients with silicosis should be systematically tested and treated for

# LTBI. (Strong recommendation, low-very low-quality evidence. Updated recommendation)
In countries with a low TB incidence, systematic testing for and treatment of LTBI may be considered for prisoners, health workers, immigrants from countries with a high TB burden, homeless people and people who use illicit drugs. (Conditional recommendation, low-very low-quality evidence. Existing recommendation) Systematic testing for LTBI is not recommended for 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 evidence. Existing recommendation)
Remark: People should be tested and treated for LTBI with strict adherence to human rights and the strongest ethical considerations. For example, positive test results or treatment for LTBI should not affect a person's immigration status or delay the possibility of immigrating.
Source of existing recommendations: Guidelines on the management of latent tuberculosis infection. Geneva: World Health Organization; 2015 ().

# Summary of evidence
The GDG considered the three systematic reviews that were conducted for the previous LTBI guidelines to determine which of the 24 defined at-risk population groups should be priorities for LTBI testing and treatment for this update (9,10). Evidence of an increased prevalence of LTBI, an increased risk of progression from LTBI to active TB disease and an increased incidence of active TB was available for the following 15 risk groups: adult and child TB contacts, health care workers and students, people living with HIV, patients on dialysis, immigrants from countries with a high TB burden, patients initiating anti-TNF therapy, people who use illicit drugs, prisoners, homeless people, patients receiving an organ or haematological transplant, patients with silicosis, patients with diabetes, people with harmful use of alcohol, tobacco smokers and underweight people. An increased risk for progression to active TB was reported for 4 of the 15 groups: people living with HIV, adult and child TB contacts, patients on dialysis and underweight people. Increased risks for active TB were reported for all groups except underweight people.

# Rationale for the recommendations
The GDG noted that people in HIV-negative clinical risk groups, such as patients initiating anti-TNF treatment, patients on dialysis, patients preparing for organ or haematological transplant and patients with silicosis, would benefit from testing for and treatment of LTBI regardless of the background TB epidemiology, because of their increased risks for progression to active TB disease. The GDG made strong recommendations despite the low-to very low-quality evidence on the basis of its judgement that the identified at-risk population groups were at increased risk for progression to active TB disease and that the benefits of treatment outweigh the potential harm.
The GDG also concluded that the evidence for the benefits of systematic testing and treatment of LTBI might not outweigh the harm in the following population risk groups: health care workers, immigrants from countries with a high TB burden, prisoners, homeless people and people who use illicit drugs. The GDG judged, however, that the benefits might outweigh the harm to a greater extent in settings with a low TB incidence than in those with a high TB incidence because of the background TB epidemiology and the risks for transmission and reinfection. A decision to test for and treat LTBI systematically in these population groups should be made in accordance with the local TB epidemiology and context, health system structure, availability of resources and overall health priorities. Priority must be given to individuals who were recently infected with TB, as documented by conversion from negative to positive in LTBI tests (either IGRA or TST). The GDG also concluded that recent immigrants from countries with a high TB burden to one with a low burden should be prioritized. The GDG emphasized, however, that a person's status -testing positive for LTBI or receiving LTBI treatment -should not affect the process, procedure or status of immigration.
The GDG noted the paucity of data from clinical trials on the benefits and harm of systematic LTBI testing and treatment of patients with diabetes, people with harmful use of alcohol, tobacco smokers and underweight people. They concluded that the benefits of systematic, routine testing and treatment of these risk groups do not outweigh the risks, unless they are part of the groups covered in the recommendations, regardless of background TB epidemiology.
The GDG agreed that prioritization of groups on the basis of their risk and the local and national context (e.g. epidemiology, resource availability) would be acceptable to individuals and to key stakeholders, including clinicians and programme managers. It noted that the high risk for ongoing TB transmission of certain risk groups, such as health care workers (including students), prisoners (and prison staff), immigrants from highincidence countries, homeless people and people who use illicit drugs, requires attention, so that the benefit of treatment is not compromised by reinfection.

# Considerations for implementation
A decision of national TB programmes and other stakeholders on priority risk groups for programmatic management of LTBI should primarily take into account the evidence in providing a lasting prevention from progression to active TB (e.g. absence of continuous transmission and reinfection) with benefits outweighing risks to the individuals belong to the group and the efficient use of resources. The GDG noted that prioritization of at-risk groups for LTBI testing and treatment could yield savings for the health care system. The GDG noted the value of ART for preventing TB in people living with HIV, underlining the importance of ensuring provision of ART for all people living with HIV as per the current WHO policy (29).

# Algorithms for ruling out active tuberculosis disease
This section recommends algorithms for ruling out active TB disease before providing preventive treatment. Remark: Chest radiography should not be a requirement for initiating preventive treatment.

# Summary of evidence
Active TB disease must be excluded before initiating preventive treatment. In 2011, WHO conducted a systematic review and a meta-analysis of individual patient data and recommended a symptom-screening rule of a combination of current cough, weight loss, night sweats and fever in order to exclude active TB. The review showed that the rule had a sensitivity of 79%, a specificity of 50% and a negative predictive value of 97.7% at a TB prevalence of 5%. Most of the people living with HIV who were included in studies in the systematic review were not receiving ART (30).
During updating of the guidelines, we conducted a systematic review to assess the performance of the foursymptom screening rule in people living with HIV who were and were not receiving ART; 17 studies with such information were retained. The evidence-to-decision and the GRADE tables are presented in Annexes 1 and 2.
The pooled sensitivity of the four-symptom screening rule for people living with HIV on ART was 51.0% (95% CI 28.4;73.2), and the specificity was 70.7% (95% CI 47.7;86.4); the pooled sensitivity of the rule for people living with HIV but not receiving ART was 89.3% (95% CI 82.6;93.6), and the specificity was 27.2% (95% CI 17.3;40.0). Two studies provided data on addition of abnormal chest radiographic findings to the screening rule for people living with HIV on ART. The pooled sensitivity was higher (84.6%, 95% CI 69.7; 92.9), but the specificity was lower (29.8%, 95% CI 26.3;33.6) than those of the symptom screen alone.
In all studies, the median prevalence of TB among people living with HIV on ART was 1.5% (interquartile range, 0.6-3.5%). At a 1% prevalence of TB, the negative predictive value of the symptom screening rule was 99.3%; addition of abnormal chest radiographic findings increased the negative predictive value by 0.2%.
No studies of the addition of chest radiography to the symptom rule for pregnant women were found in the review. The algorithm for TB screening in adults and adolescents living with HIV is shown in Fig. 1.
Overall, the GDG agreed that the four-symptom screening rule is very useful for ruling out active TB before providing preventive treatment to people living with HIV, regardless of whether they receive ART. It noted the potential benefits of adding an abnormal chest radiographic finding to the four-symptom screening rule, while recognizing a marginal improvement in performance. Moreover, increased use of chest radiography would add more false-positive results to the screening rule, which would require more investigations for TB and other illnesses. Therefore, the GDG reiterated that chest radiography should be added as an additional investigation only if it does not pose a barrier to the provision of preventive treatment for people living with HIV. Although no study was found of the additive role of chest radiography in testing pregnant women, the GDG noted that pregnant women living with HIV could also benefit, as long as good clinical practices are observed to prevent any significant risk to the fetus (31). Poor weight gain is defined as reported weight loss, very low weight-for-age ( 5%) since the last visit or growth curve flattening,
Children and infants < 1 year of age should be given preventive treatment only if they have a history of household contact with a TB case and active TB has been excluded in investigations.

# Summary of evidence
Infants and children living with HIV should be screened for TB routinely, as part of standard clinical care, regardless of whether they are receiving TB prophylaxis or ART. A systematic review conducted for the previous guidelines identified limited evidence on the best approach to screening infants and children for TB (7). On the basis of these few studies and expert opinion, the previous guidelines group recommended a screening rule consisting of poor weight gain, fever, current cough and a history of contact with a TB case. We conducted a new systematic review to assess the performance of this screening rule. The only publication found was the conference abstract of a study of 176 hospitalized children with HIV aged  12 years in Kenya (32). The study had a sensitivity of 100% (95% CI, 76.8;100.0) and a specificity of 4.3% (95% CI, 1.8;8.7).

# Rationale for the recommendation
The GDG noted the paucity of data on the usefulness of the screening rule for children living with HIV. The single study showed that the symptom screening rule currently recommended for children with HIV performs well, but no study has been reported on the harm or challenges of the rule, such as resource requirements for implementation. Symptom-based screening is generally accepted by clients and is feasible in resourceconstraint settings.
Therefore, the GDG decided to make the same strong recommendation. Children living with HIV who screen positive for TB may have TB and should be evaluated for TB and other diseases. If the evaluation shows no TB, children with HIV should be offered preventive treatment, regardless of their age, while only infants < 12 months of age who have a history of household contact with a person with TB and have been investigated for TB according to national guidelines should receive preventive treatment. The GDG also noted that clinicians should broaden the differential diagnosis to include other diseases that may cause current cough, fever and poor weight gain in children with HIV. The algorithm for TB screening in children aged  1 year living with HIV is shown in Fig. 2.

# HIV-negative infants, children and adults who are household contacts of a person with pulmonary TB 3.2.1 HIV-negative infants and children < 5 years of age

# Summary of evidence
We updated a previous systematic review of screening algorithms for HIV-negative people and people with unknown HIV status (33). The review revealed only one study of young children (mean age, 19.2 months) in which various symptoms were evaluated, such as failure to thrive and prolonged cough. The report did not discuss the combination of symptoms for excluding TB (34). Fig. 3 is a simple algorithm for ruling out active TB in child household contacts aged < 5 years before preventive treatment (8). The algorithm can be used by health workers at peripheral level. Research on symptom-based screening of children's TB contacts indicates that this contact management strategy is safe and more feasible in resource-limited settings than contact screening based on diagnoses (35,36). Furthermore, a recent modelling study suggested that providing preventive treatment without LTBI testing is cost-effective for child contacts under 5 years of age (37).

# HIV-negative household contacts aged  5 years and other at-risk groups
The absence of any symptoms of TB and the absence of abnormal chest radiographic findings may be used to rule out active TB disease among HIV-negative household contacts aged  5 years and other at-risk groups before preventive treatment. (Conditional recommendation, very low-quality evidence. New recommendation)

# Summary of evidence
We updated the previous systematic review used for the 2015 guidelines (9, 10) to determine the sensitivity and specificity of screening based on symptoms and/or chest radiography for ruling out active TB in HIV-Fig. 2 Algorithm for screening children aged  1 year living with HIV for TB negative people and people of unknown HIV status. The review covered 33 studies, including 17 newly identified. The evidence-to-decision and the GRADE tables are presented in Annexes 1 and 2. To illustrate how the various screening and diagnostic algorithms are expected to rule out active TB, a simple model was constructed to compare the following six screening criteria: (i) any TB symptom, (ii) any cough, (iii) cough for > 2-3 weeks, (iv) chest radiographic abnormality suggestive of TB, (v) any chest radiographic abnormality and (vi) a combination of any chest radiographic abnormality or any TB symptom. The model suggested that the combination of any chest radiographic abnormality and the presence of any symptoms suggestive of TB (i.e. any cough of any duration, haemoptysis, fever, night sweats, weight loss, chest pain, shortness of breath and fatigue) would offer the highest sensitivity (100%) and negative predictive value (100%) for ruling out TB.
Fig. 4 presents the algorithm for targeted diagnosis and treatment of LTBI and exclusion of active TB in household contacts aged 5 years and other at-risk populations.

# Rationale for the recommendation on HIV-negative household contacts
The GDG noted the lack of any new data and agreed to continue use of the existing symptom-based algorithms (Fig. 3) for HIV-negative infants and children who are household contacts of TB cases. The GDG reiterated that active TB should be ruled out primarily by investigations, according to national guidelines. It noted that screening of child contacts could include LTBI testing and chest radiography, although the absence of those investigations should not pose a barrier for either diagnosis of active TB disease or provision of preventive treatment. In the absence of these tests, clinical assessment alone is sufficient to decide on eligibility for preventive treatment particularly for children < 5 years of age who are household contacts of a bacteriologically confirmed pulmonary TB.
Children must be free of any TB and non-TB related symptoms to be considered well.
The commonest TB-related symptoms are persistence of: cough, fever, not eating well/anorexia, weight loss/failure to thrive, fatigue, reduced playfulness and decreased activity. If TB disease is suspected, refer to Chapter 3 in the Guidance for national tuberculosis programmes on the management of tuberculosis in children. The GDG also noted that symptom screening with or without the addition of chest radiography should be acceptable for individuals and programme managers. Chest radiography could increase the confidence of health care providers that active TB has been ruled out, thus reducing any concern about development of drug resistance; however, addition of chest radiography could incur costs for clients and inconvenience, as more clients would have to be investigated for TB and other diseases. The GDG noted the difficulty of assessing the preferences of children, which were not systematically documented.

# Considerations for implementation
Addition of abnormal chest radiographic findings to the symptom screening rule would complicate logistics, increasing the cost, workload, infrastructure and availability of qualified staff. The GDG noted that chest radiography should not be a requirement or a barrier for initiating TB preventive treatment in people living with HIV because of the need for additional resources, in view of the marginal gain in negative predictive value. National TB guidelines should be followed in investigating TB. In addition, people in whom TB is excluded after investigations (including those with fibrotic radiological lesions) can be considered for LTBI treatment.
national guidelines and sound clinical practice. People living with HIV who present any of the four symptoms but in whom active TB is excluded by investigations may be considered for preventive treatment.
The four-symptom screening method is recommended for all people living with HIV at every visit to a health facility or contact with a health worker. As combining chest radiography with symptom screening at every visit could represent a significant burden on the health system as well as on clients, it should be used only to exclude active TB before giving preventive treatment, with due respect for good clinical practice. The role of chest radiography in regular TB screening and its optimal frequency is uncertain. Local authorities should define its application and frequency on the basis of their local epidemiology, health infrastructure and resource availability.
It is critical to ensure proper follow-up and investigation for TB and other diseases in household contacts with abnormal chest radiographic findings or TB symptoms. The investigations should be performed in accordance with national guidelines and sound clinical practice. Contacts in whom active TB is excluded after investigations may be considered for preventive treatment.
Chest radiography and trained health care workers (e.g. radiologists) must be available to implement the screening rule. Where chest radiography is not available, absence of any TB symptoms alone may be considered as a criteria before preventive treatment. This would offer the highest sensitivity among symptombased screening rules, and its negative predictive value is high in most settings.

# Testing for latent tuberculosis infection

# Summary of evidence
There is no gold standard method for diagnosing LTBI. TST and IGRA require a competent immune response in order to identify people infected with TB and are imperfect tests for measuring progression to active disease.
A previous systematic review was updated to compare the predictive performance of IGRA and TST for identifying incident active TB in countries with a high TB incidence (38). Only studies in which TST was compared with IGRA in the same population ("head-to-head" studies) were included. Relative risk ratios for TB for people who tested positive and those who tested negative with TST and IGRA were estimated. The evidence-to-decision and the GRADE tables are presented in Annexes 1 and 2.
Five prospective cohort studies were identified, with a total of 7769 participants; four were newly identified. Three of the studies were conducted in South Africa and two in India (18,(39)(40)(41)(42). The studies included people living with HIV, pregnant women, adolescents, health care workers and household contacts. The pooled risk ratio estimate for TST was 1.49 (95% CI, 0.79; 2.80), and that for IGRA was 2.03 (95% CI, 1.18; 3.50). Although the estimate for IGRA was slightly higher than that for TST, the 95% CIs for the estimates for TST and IGRA overlapped and were imprecise. Furthermore, there was limited evidence for the predictive utility of the tests in specific at-risk populations.

# Rationale for the recommendations
The evidence reviewed and the recommendations apply to the use of the two commercially available IGRAs (QuantiFERON-TB Gold In-Tube and T-SPOT.TB) only. The GDG concluded that the comparison of TST and IGRA in the same population does not provide strong evidence that one test should be preferred over the other for predicting progression to active TB disease. The GDG noted that TST may require significantly fewer resources than IGRA and may be more familiar to practitioners in resource-constrained settings; however, recurrent global shortages and stock-outs of TST reduce its use in scaling up programmatic management of LTBI.
The GDG also noted that equity and access could affect the choice and type of test used. The preferences of clients and programmes are, however, affected by several factors, such as the requirement for sophisticated laboratory infrastructure (e.g. for IGRA) and possible additional costs for clients (e.g. for travel) and programmes (e.g. for building and testing). The GDG strongly recommended the two tests as equivalent options, with relatively similar advantages and disadvantages.
The GDG stressed that the global shortage of TST should be addressed urgently and called for more investment into research on novel tests for LTBI with better predictive value.
The GDG cautioned that imperfect performance of these tests can lead to false-negative results, particularly for young children and immunocompromised individuals such as people living with HIV. The GDG noted the importance of the tests for identifying recent conversion from a negative to a positive result, particularly among contacts of people with pulmonary TB, which is good practice for initiating TB preventive treatment. Nevertheless, recent studies among health care workers tested serially for LTBI in the USA showed that conversions from negative to positive and reversions from positive to negative are more commonly identified with IGRA than with TST (43). Thus, sound clinical judgement must be used in interpreting the results of these tests when used serially.
The GDG recommended that LTBI testing should not be a requirement for initiating TB preventive treatment for people living with HIV and child household contacts aged < 5 years, particularly in countries with a high TB incidence, given that clear benefits outweigh the risks. HIV-negative infant and child household contacts aged < 5 years and people living with HIV who have a negative LTBI test should be assessed case by case for their individual risk of exposure to TB and the added advantage of receiving preventive treatment.

# Considerations for implementation
The GDG noted that the availability and affordability of the tests could determine which LTBI test is used. Other considerations include the structure of the health system, feasibility of implementation and infrastructure requirements.
The incremental cost-effectiveness of IGRAs and TSTs appears to be influenced mainly by their accuracy. Bacille Calmette-Guerin (BCG) vaccination plays a decisive role in reducing the specificity of TST, leading the choice towards IGRA-only strategies. The GDG noted, however, that the impact of BCG vaccination on the specificity of TST depends on the strain of vaccine used, the age at which the vaccine is given and the number of doses administered. When BCG is given at birth, as is the case in most parts of the world, it has a variable, limited impact on TST specificity (44). Therefore, the GDG agreed that a history of BCG vaccination has a limited effect on interpretation of TST results later in life; hence, BCG vaccination should not be a determining factor in selecting a test.
IGRAs are more costly and more technically complex to perform than the TST. Operational difficulties should be considered in deciding which test to use. For example, IGRA requires a phlebotomy, which can be difficult, particularly in very young children, laboratory infrastructure, technical expertise and expensive equipment; however, only a single visit is required to obtain a result (although patients may have to make a second visit to learn the result). TST is less costly and can be performed in the field, but it requires a cold chain, two health care visits and training in intradermal injection, reading and interpretation.

# Treatment options for latent tuberculosis infection
- TREATMENT OPTIONS FOR LATENT TUBERCULOSIS INFECTION Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence. (Strong recommendation, high-quality evidence. Existing recommendation) Rifampicin plus isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged < 15 years in countries with a high TB incidence. (Strong recommendation, low-quality evidence. New recommendation) Rifapentine and isoniazid weekly for 3 months may be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence. (Conditional recommendation, moderate-quality evidence. New recommendation) The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3-4 months of isoniazid plus rifampicin, or 3-4 months of rifampicin alone. (Strong recommendation, moderate-high-quality evidence. Existing recommendation)

# Remark: Rifampicin-and rifapentine-containing regimens should be prescribed with caution to people living with HIV who are on ART because of potential drug-drug interactions.
In settings with high TB incidence and transmission, adults and adolescents living with HIV who have an unknown or a positive TST and are unlikely to have active TB disease should receive at least 36 months of IPT, regardless of whether they are receiving ART. IPT should also be given irrespective of the degree of immunosuppression, history of previous TB treatment and pregnancy.

# Summary of evidence

# Daily isoniazid monotherapy 6 months' isoniazid monotherapy
Six months' daily monotherapy with isoniazid is the standard treatment for both adults and children living in countries with either high or low TB incidence. Several systematic reviews have demonstrated its preventive efficacy. A systematic review of RCTs involving people living with HIV (17) showed that isoniazid monotherapy reduces the overall risk for TB by 33% (RR 0.67; 95% CI 0.51;0.87), and the preventive efficacy reached 64% for people with a positive TST (RR 0.36; 95% CI 0.22;0.61). Furthermore, the efficacy of the 6-month regimen was not significantly different from that of 12 months' daily isoniazid monotherapy (RR 0.58; 95% CI 0.3;1.12) (17). A recent systematic review of RCTs also showed a significantly greater reduction in TB incidence among participants given the 6-month regimen than in those given a placebo (odds ratio, 0.65; 95% CI 0.50;0.83) (45).

# months' isoniazid monotherapy
No controlled clinical trials were found of 9 months' versus 6 months' isoniazid monotherapy. Re-analysis and modelling of the United States Public Health Service trials of isoniazid conducted in the 1950s and 1960s, however, showed that the benefit of isoniazid increases progressively when it is given for up to 9-10 months and stabilizes thereafter (46).

# months' isoniazid monotherapy
A systematic review and meta-analysis of three RCTs of people living with HIV in settings with high TB prevalence and transmission showed that continuous IPT can reduce the risk for active TB by 38% more than 6 months' isoniazid (47). The effect was greater in people with a positive TST (49% for active TB and 50% for death). In those with a negative TST, neither effect was significant, although the point estimate indicated a reduction in TB incidence of 27%.

# Daily rifampicin plus isoniazid for 3-4 months
A systematic review (48) and its update in 2017 (45) showed that the efficacy and the safety profile of 3-4 months' daily rifampicin plus isoniazid were similar to those of 6 months' isoniazid. The previous GDG therefore concluded that daily rifampicin plus isoniazid could be used as an alternative to isoniazid in settings with low TB incidence (9,10). We conducted a new review to compare the effectiveness in children of rifampicin plus isoniazid daily for 3 months with isoniazid for 6 or 9 months. The evidence-to-decision and the GRADE tables are presented in Annexes 1 and 2. We identified one RCT and two observational studies (49)(50)(51). The authors of the RCT (50) reported no clinical disease in either group and used new radiographic findings suggestive of active TB as a proxy for clinical disease. Fewer participants given daily rifampicin plus isoniazid than those given 9 months of isoniazid developed radiographic changes (RR 0.49, 95% CI 0.32;0.76). The authors also reported a lower risk for adverse events (RR 0.33, 95% CI 0.20;0.56) and a higher adherence rate (RR 1.07, 95% CI 1.01;1.14) among children given daily rifampicin plus isoniazid. Similar findings were reported in the two observational studies (49, 51).

# Daily rifampicin monotherapy for 3-4 months
A previous systematic review conducted for the 2015 LTBI guidelines (48), updated in 2017 (45), found similar efficacy for 3-4 months' daily rifampicin and 6 months of isoniazid (odds ratio, 0.78; 95% CI, 0.41;1.46). The review also showed that individuals given rifampicin daily for 3-4 months had a lower risk for hepatotoxicity than those treated with isoniazid monotherapy (odds ratio, 0.03; 95% CI 0.00;0.48).

# Weekly rifapentine plus isoniazid for 3 months
A new systematic review was conducted to compare the effectiveness of a 3-month weekly regimen of rifapentine plus isoniazid with that of isoniazid monotherapy. The review covered four RCTs (52-55), which were analysed for three subgroups: adults with HIV infection, adults without HIV infection and children and adolescents, who could not be stratified according to HIV status because the relevant studies were lacking. The evidence-to-decision and the GRADE tables are presented in Annexes 1 and 2.
Two of the RCTs involved adults with HIV from South Africa, Peru and in a number of countries with a low incidence of TB. No significant difference was found in the incidence of active TB between participants given a 3-month weekly regimen of rifapentine plus isoniazid and 6 or 9 months of isoniazid monotherapy (RR 0.73, 95% CI 0.23;2.30). Furthermore, the risk for hepatotoxicity was significantly lower with the 3-month weekly regimen of rifapentine plus isoniazid in adults with HIV (RR 0.26, 95% CI 0.12;0.  15). One RCT included a comparison between a 3-month weekly regimen of rifapentine plus isoniazid and continuous isoniazid monotherapy in adults with HIV infection (52). No significant difference in TB incidence was found in an intention-to-treat analysis; however, a per-protocol analysis showed a lower rate of TB infection or death in participants given continuous isoniazid. In all the studies, the 3-month regimen of weekly rifapentine plus isoniazid was given under direct observation.
In a study of the 3-month weekly regimen of rifapentine plus isoniazid in 112 pregnant women, the rates of spontaneous abortion and birth defects were similar to those in the general US population (56).

# Rationale for the recommendations
The selection of treatment options by programmes and clinicians should consider the characteristics of the clients who are to receive treatment to ensure that it is not only initiated but also completed. The GDG agreed that the benefits of all the treatment options outweigh the potential harm. They also noted that all the treatment options can be self-administered. An RCT showed that self-administered treatment of the 3-month regimen of weekly rifapentine plus isoniazid is not inferior to directly observed treatment (57); however, there is little further evidence on self-administration of this regimen. The GDG noted that a requirement for a direct observation could be a significant barrier to the implementation. The GDG further noted that individuals receiving treatment, clinicians providing treatment and programme managers prefer shorter to longer regimens.
On the basis of existing practice, albeit, in the absence of a direct comparison, the GDG judged that 9 months' isoniazid is an equivalent option to 6 months of isoniazid in countries with a low TB incidence and a strong health infrastructure. It noted, however, that 6 months' isoniazid is preferable to 9 months from the point of view of feasibility, resource requirements and acceptability to patients.
The recommendation that people living with HIV should be given at least 36 months of daily isoniazid monotherapy is conditional, as continuous IPT depends on the epidemiology and transmission of TB, the health infrastructure and programme priorities.
The GDG agreed unanimously that the benefits of 3 months' daily rifampicin plus isoniazid for infants and children < 15 years of age outweigh the harm, given its safety profile, the higher rate of completion as compared with isoniazid monotherapy and the availability of child-friendly, fixed-dose combinations of rifampicin and isoniazid. The GDG therefore made a strong recommendation despite the low quality of the evidence.

# Considerations for implementation

# Drug resistance and surveillance
There is no evidence of a significant association between bacterial resistance to TB drugs and use of isoniazid or rifamycins for the treatment of LTBI (58,59). Nonetheless, active TB disease must be excluded before TB preventive treatment is initiated (section 3), and regular follow-up is required to ensure early identification of people who develop active TB while receiving TB preventive treatment. National surveillance systems for resistance to TB drugs should be established in countries implementing programmatic management of LTBI.

# Interactions with antiretroviral drugs
Regimens containing rifampicin and rifapentine should be prescribed with caution to people living with HIV who are on ART because of potential drug-drug interactions. These regimens should not be administered to people receiving protease inhibitors or nevirapine. The GDG noted that the 3-month regimen of weekly rifapentine plus isoniazid can be administered to patients receiving efavirenz-based antiretroviral regimens without dose adjustment, according to a study of pharmacokinetics (60). Administration of rifapentine with raltegravir was found to be safe and well tolerated (61). Rifapentine-containing regimens should not be administered with dolutegravir until more information becomes available. The GDG stressed the urgent need for studies of the pharmacokinetics of the 3-month regimen of weekly rifapentine plus isoniazid concomitantly with other drugs, particularly ART.

# Monitoring of adverse events
As individuals who receive treatment for LTBI do not have active disease, their risk for adverse events during treatment must be minimized. Adverse reactions have been associated 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 of these reactions are minor and occur rarely, specific attention should be paid to preventing drug-induced hepatotoxicity.
Individuals receiving treatment for LTBI should be monitored routinely at monthly visits to health care providers, who should explain the disease process and the rationale of the treatment and emphasize the importance of completing it. Patients receiving treatment should be advised to contact their health care provider at any time if they become aware of symptoms such as anorexia, nausea, vomiting, abdominal discomfort, persistent fatigue or weakness, dark-coloured urine, pale stools or jaundice. If a health care provider cannot be consulted at the onset of such symptoms, the patient should stop treatment immediately.
There is insufficient evidence to support testing of baseline liver function (62). It is, however, strongly encouraged, where feasible, for individuals with the following risk factors: history of liver disease, regular use of alcohol, chronic liver disease, HIV infection, age > 35 years, pregnancy or in the immediate postpartum period (within 3 months of delivery). For individuals with abnormal baseline test results, sound clinical judgement is required to ensure that the benefit of TB preventive treatment outweighs the risks, and they should be tested routinely at subsequent visits. Appropriate laboratory testing should also be performed for patients who become symptomatic while on treatment (e.g. liver function tests for those with symptoms of hepatotoxicity).
Individuals at risk for peripheral neuropathy, such as those with malnutrition, chronic alcohol dependence, HIV infection, renal failure or diabetes, or who are pregnant or breastfeeding, should receive vitamin B6 supplements when taking isoniazid-containing regimens.

# Adherence to and completion of preventive treatment
Adherence to the full course and completion of treatment are important determinants of clinical benefit to individuals and to the success of programmes. A systematic review conducted for the WHO 2015 LTBI guidelines (9, 10) provided heterogeneous results for interventions to improve treatment adherence and completion, and the evidence was considered inconclusive. The GDG noted that interventions to ensure adherence and completion of treatment should be tailored to the specific needs of risk groups and the local context. The WHO guidelines for treatment of drug-susceptible active TB propose several interventions to support adherence (63), which could be applied to treatment of LTBI. Fixed-dose combinations such as cotrimoxazole plus isoniazid and isoniazid plus rifampicin should be used where possible to reduce the number of pills to be taken. Concerns about adherence should not be a barrier to use of preventive treatment.

# Preventive treatment for contacts of patients with multidrug-resistant tuberculosis
In selected high-risk household contacts of patients with multidrug-resistant tuberculosis, preventive treatment may be considered based on individualised risk assessment and a sound clinical justification.
(Conditional recommendation, very low-quality evidence. New recommendation)
The preventive treatment should be individualized after a careful assessment of the intensity of exposure, the certainty of the source case, reliable information on the drug resistance pattern of the source case and potential adverse events.
The preventive treatment should be given only to household contacts at high risk (e.g. children, people receiving immunosuppressive therapy and people living with HIV).
The drugs should be selected according to the drug susceptibility profile of the source case.

# Confirmation of infection with LTBI tests is required.

# This recommendation must not affect on-going placebo-controlled clinical trials of MDR-TB contacts on ethical grounds. The results of such clinical trials are crucial for updating this recommendation.
Strict clinical observation and close monitoring for the development of active TB disease for at least 2 years are required, regardless of the provision of preventive treatment.

# Summary of evidence
A systematic review of the effectiveness of preventive treatment for contacts of people with MDR-TB conducted for the 2015 LTBI guidelines (9, 10) was updated. The updated review comprised 10 studies (6 newly identified and 4 from the previous review) that allowed comparisons between participants who received preventive treatment for MDR-TB and those who did not. Because of clinical heterogeneity among the studies, a metaanalysis could not be performed. Of the 10 studies, one was excluded because only isoniazid monotherapy was used, and an additional five studies were excluded as fewer than 20 participants completed preventive TB treatment. Therefore, the quality of the evidence was based on only four studies. The evidence-to-decision and the GRADE tables are presented in Annexes 1 and 2.
No TB case was reported in either the intervention or the control group in one study (64), while one case of active TB due to a drug-susceptible strain that was different from that of the source case was reported in another study (65). The remaining two studies (66,67)  The drugs used in these studies were mainly fluoroquinolones (e.g. moxifloxacin, levofloxacin) with or without other agents (e.g. ethambutol, ethionamide). None of studies included a comparison of the risk for adverse events, although one reported that no serious adverse events could be attributed to fluoroquinolone-based preventive treatment (66). The median proportion of participants who discontinued treatment because of adverse events in all the studies was 5.1% (interquartile range, 1.9-30.2%).
Overall, the GDG judged that the potential benefits of targeted preventive treatment for MDR-TB contacts based on individual risk assessments outweigh the harm but acknowledged uncertainty about the efficacy of the intervention due to the lack of RCTs. It also noted that provision of preventive treatment for MDR-TB contacts would be acceptable, particularly to patients and health care workers. The GDG stressed that treatment should be given to selected individuals after a careful risk assessment, including intensity of exposure, certainty of the source case, reliable information on the drug resistance pattern of the index case and potential adverse events. It should be given only to household contacts at high risk (e.g. children, people on immunosuppressive therapy and people living with HIV). Confirmation of infection by LTBI testing is required before individualized treatment is initiated.

# Considerations for implementation
Close monitoring and treatment adherence
Close monitoring of adverse events and adherence to treatment is essential. The types of adverse events depend on the drugs used. Common adverse events associated with each drug are listed in the Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis (68). Adverse effects should be monitored according to the WHO framework for monitoring and managing the safety of drugs against active TB (69). The GDG reiterated that strict clinical observation and close monitoring for active TB disease based on sound clinical practice and national guidelines for at least 2 years is required, regardless of the provision of preventive treatment. Consideration should also be given to interactions with antiretroviral, immunosuppressant and other drugs when providing TB preventive treatment.

# Informed consent
As the recommendation is based on very low-quality evidence, clients must be given detailed information about the benefits and harms of the preventive treatment and asked for explicit informed consent. In view of the uncertainty about the balance of benefit to harm, informed consent, preferably in writing, is required, based on the local context and practice in similar situations.

# Selection of drug regimen
The regimen of preventive treatment of MDR-TB contacts should be based on reliable information on the drug resistance profile of the source case. Later-generation fluoroquinolones (e.g. levofloxacin and moxifloxacin) are considered to be important components of a preventive treatment regimen unless the strain of the source case is resistant to them. Although there has been concern about the use of fluoroquinolones in children because retardation of cartilage development was shown in animals (70), similar effects have not been demonstrated in humans (68,71,72). There is limited evidence for the duration of treatment, and this should be based on clinical judgement. The regimens used in the studies conducted so far were given for 6, 9 and 12 months.

# Resources and feasibility
For a programmatic approach, all the necessary resources should be in place, including for quality-assured testing for drug susceptibility, the necessary medications and a system for close monitoring of harm and adverse events. The feasibility of providing preventive treatment should be carefully assessed according to the availability of resources and the history and status of preventive treatment for drug-susceptible TB.

# Issues in implementation 7.1 Ethical considerations
LTBI testing and treatment raise a range of ethical issues (73,74). First, LTBI is by definition an asymptomatic state. This alters the ethical obligations that would be imposed by active TB. For example, the absence of an immediate risk of transmission makes it unethical to restrict migration on the basis of the LTBI status of an individual. Secondly, the difficulty of accurate assessment of individual risk for the development of active TB poses a challenge to communication. Informed consent requires effective, adequate communication of the uncertainty in LTBI testing, the risk for development of active TB, possible side-effects of treatment and the protective benefits. Risk and uncertainty must be communicated in culturally and linguistically appropriate forms and feedback obtained after screening programmes. Thirdly, LTBI disproportionately affects individuals and groups that are already socially and medically vulnerable. Therefore, efforts must be made to ensure equity and human rights, so that the vulnerability of target groups does not preclude their access to screening and treatment. Any intervention for vulnerable groups should include minimization of the risk for stigmatization.
Policies should be evaluated from an ethical perspective after implementation, both to consider possible unexpected effects and to ensure that the evidence on which they are based remains current and relevant (75).

# Programme management, monitoring and evaluation
National programmes should prepare a national plan for programmatic LTBI management, including prioritization of groups at high risk on the basis of local epidemiology and the characteristics of the health system. They should create a conducive policy and programmatic environment, including national and local policies and standard operating procedures to facilitate implementation of the recommendations in these guidelines. This should include promoting universal health coverage and offering public financing for LTBI management. Furthermore, dedicated resources should be allocated, including for human resource development and service delivery in the community. National TB programmes should ensure meaningful engagement with affected populations, their communities, the private sector, other relevant health programmes and line ministries in both planning and implementing the interventions. The national TB programme is also encouraged to ensure access to comprehensive care for co-existing risk factors for TB, such as diabetes, undernutrition and tobacco smoking.
Preventive TB treatment for people living with HIV should be a core component of HIV preventive care and should be the responsibility of national AIDS programmes and HIV service providers. Preventive treatment should not be viewed as an isolated intervention but should be part of a comprehensive package of care.
Coverage of contact investigation and treatment of LTBI among child contacts and people living with HIV are among the top 10 core indicators for monitoring implementation of the End TB Strategy. Programmatic management of LTBI should include monitoring and evaluation systems that are aligned with national patient monitoring and surveillance systems (76). Appropriate recording and reporting tools should be developed, and standardized indicators (Table 3) should be measured to regularly inform decision-making for programme implementation. Some may require changes to national legislation (e.g. making LTBI a notifiable condition) and to the policy framework, which should be addressed according to the local and national context. It is important to engage the private health sector and to ensure proper recording and reporting from both the private and public sectors. Use of electronic case-based monitoring will facilitate recording and reporting for LTBI management.

# Research priorities
The review of the evidence for the recommendations exposed gaps in research that should be filled urgently, in addition to those identified during preparation of the 2015 guidelines.

# Risks of at-risk populations for progression to active TB disease
Evidence on the risks of a number of at-risk populations for progression from LTBI to active disease will be crucial for determining the potential benefits of LTBI treatment and for designing appropriate public health interventions. In particular, strong evidence from clinical trials is lacking for the following groups: patients with diabetes, people with harmful use of alcohol, tobacco smokers, underweight people, people exposed to silica, patients receiving steroid treatment, patients with rheumatological conditions, indigenous populations and cancer patients. Both direct measurement of the incidence of active TB and methods for measuring the risk for active TB disease could be explored, such as use of genotyping to measure the risk for reactivation.
Evidence is also required on differential harm and the acceptability of testing and treatment for LTBI in specific risk groups, including socially adverse events such as stigmatization.

# Defining the best algorithm for ruling out active TB
Operational and clinical studies should be conducted to exclude active TB before preventive treatment is given. The performance and feasibility of the algorithms proposed in these guidelines should be assessed.
In particular, few data are available on children and pregnant women. Strategies to save cost and improve feasibility (e.g. use of mobile chest radiography) should also be explored.

# Improved diagnostic tests and performance of LTBI tests in at-risk populations
Diagnostic tests with improved performance and predictive value for reactivation of TB are critically needed. In addition, the performance of LTBI tests should be evaluated in various at-risk populations, such as the best way of using the available tools (e.g. combination or sequential use of TST and IGRA) in each at-risk population.

# Treatment options for LTBI
Research to find shorter, better-tolerated treatment regimens than those currently recommended is a priority. Studies of efficacy and adverse events in certain risk groups (e.g. people who use drugs, people with alcohol use disorder and elderly people) are essential. In particular, there are no or very limited data on the use of rifapentine in children < 2 years and pregnant women. Studies should be conducted of the pharmacokinetics of interactions between rifamycin-containing regimens and other drugs, particularly antiretroviral drugs. In addition, the durability of protection by preventive treatment should be evaluated in settings in which TB is endemic, including the efficacy of repeated courses of preventive treatment.

# Monitoring of adverse events
Prospective randomized studies are required to determine the incremental benefits of routine monitoring of liver enzyme levels over education and clinical observation alone for preventing severe clinical adverse events, with stratification of the evidence by at-risk population.

# RESEARCH PRIORITIES

# Risk of drug resistance following LTBI treatment
Programme-based surveillance systems and clinical studies are needed to monitor the risk for bacterial resistance to the drugs used in LTBI treatment. Particular consideration should be given to rifamycin-containing regimens because of the dearth of data.

# Adherence to and completion of treatment
Carefully designed studies, including RCTs, are required to generate evidence on the effectiveness of contextspecific interventions for enhancing adherence and completion of treatment. The studies should include specific risk groups, depending on the available resources and the health system infrastructure. Use of "digital health" to improve adherence is an important area. Further research is required on the effectiveness of selfadministration of the 3-month regimen of weekly rifapentine plus isoniazid.
Although a number of studies of the cost-effectiveness of TB preventive treatment are available, their wide heterogeneity obviates a comprehensive appraisal of the cost-effectiveness of LTBI management stratified by population group and type of intervention. Direct measurement of cost-effectiveness in certain settings and populations would allow extension of the LTBI strategy at national or local level.

# Preventive treatment for contacts of people with MDR-TB
RCTs with adequate power are urgently needed to update the recommendation on preventive treatment for contacts of people with MDR-TB. Trials should be performed with both adult and paediatric populations and with at-risk populations such as people living with HIV. The composition, dosage and duration of preventive treatment regimens for MDR-TB should be optimized, and the potential role of newer drugs with good sterilization properties should be investigated. The effectiveness and safety of preventive treatment for contacts of people with MDR-TB should be evaluated in operational conditions. Further evidence on the risk of contacts of people with MDR-TB for progression to active TB will be important for understanding the benefits of preventive treatment.

# Programme management
Epidemiological research should be conducted to determine the burden of LTBI in various geographical settings and risk groups and as a basis for nationally and locally tailored interventions, including integrated communitybased approaches. Research is also needed on service delivery models to ensure that patients are properly managed including the provision of additional interventions for tobacco smokers, illicit drug users, and people with harmful use of alcohol. Household implementation models could improve the effectiveness and efficiency of delivery of interventions. Tools should be developed and assessed to facilitate monitoring and evaluation of programmatic management of LTBI.  (3)(4)(5)7,10,11,13,14) did not indicate whether household contacts with active TB were excluded from the analysis or did not provide sufficient data to calculate the number of household contacts with active TB per age stratum.

# Annex 1. GRADE profile tables for new recommendations
High heterogeneity among studies (I 2 = 94%) probably due to difference in background TB incidence. Risk ratios of two studies (1,5) showed opposite effect.
Small sample size in (5) (n < 50).
Potential misclassification: Seven studies (3,5,6,10,11,13,14) did not indicate whether household contacts with active TB were excluded from the analysis or did not provide sufficient data to calculate the number of household contacts with active TB per age stratum.
High heterogeneity among studies (I 2 = 97%) probably due to the differences in background TB incidence. Risk ratio of one study (5) showed opposite effect.
Wide confidence interval of pooled risk ratio. Small sample sizes in (5) (n < 50) and (12) (n < 100).
Potential selection bias in (15), as only 89% of participants were household contacts.
High heterogeneity among studies (I 2 = 93%) probably due to differences in background TB incidence. Risk ratios in three studies showed opposite effects (5,19,21).
10 Small sample size in (5) and (18) (n < 50).
Potential misclassification: Ten studies (3)(4)(5)10,13,14,20,21,23,26) did not indicate whether household contacts with active TB were excluded from the analysis or did not provide sufficient data to calculate the number of household contacts with active TB per age stratum.
12 High heterogeneity among studies (I 2 = 98%) probably due to differences in background TB incidence.  Serious inconsistencies due to heterogeneity (I 2 = 71%): One study showed an increased risk in the age group 5-15 years. This was not observed in the other studies.
Small number of events.
High heterogeneity among studies probably due to differences in background TB incidence and methods used to diagnose active TB (I 2 = 89.3%).
Cumulative prevalence of active TB in household contacts irrespective of baseline LTBI status in high TB incidence countries

# High Important
Owing to the small number of studies in the other categories, only data from studies with a follow-up of 1-2 years in high TB incidence countries are presented in the table.
One outlier (28) was excluded because of uncertainty about the cases included (co-prevalent vs incident cases).
High heterogeneity among studies (I 2 = 87.6%), probably due to the difference in background TB incidence.
Active TB in household contacts with LTBI and in the general population in high-TB incidence countries (12 months)  Ascertainment bias highly likely, as TB cases in the general population detected passively, while TB cases in contacts detected actively. As a result, the relative and absolute risks might be overestimated. The composition of the general and the study population differed (general population of all ages versus a specific age group).
3 High heterogeneity among studies (I 2 = 83.9%), probably due to differences in background TB incidence. 4 Serious imprecision with a wide confidence interval for the effect estimates, probably due to small study size and number of outcome events. 5 I 2 = 72.5%, indicating moderate heterogeneity, probably due to differences in background TB prevalence; however, there is a trend across age groups and studies. 6 Few events and wide CI.
Active TB in household contacts with LTBI compared with general population in high-TB incidence countries ( These comparisons included studies with a maximum follow-up of 24 months; therefore, TB incidence in the general population was multiplied by a factor of 2 to estimate the number of cases occurring during 24 months.
2 LTBI does not apply to the general population.
3 Ascertainment bias highly likely: TB cases in the general population detected passively, while TB cases in the contacts detected actively. As a result, relative and absolute risks might be overestimated. The composition of the general and study populations differs (general population of all ages versus a specific age group). TB incidence in the population was estimated by multiplying the yearly notification rate by a factor of 2.
High heterogeneity between studies probably due to difference in background TB incidence (I 2 = 84.4%).
Few events and wide CI.
6 I 2 = 88.1%, indicating high heterogeneity probably due to difference in background TB prevalence; however, there is a trend across age groups and studies. These comparisons are based on studies with a maximum follow-up of 24 months; therefore, TB incidence in the general population was multiplied by a factor of 2 to estimate the number of cases occurring during 24 months.
Ascertainment bias highly likely, as TB cases in the general population detected passively, while TB cases in the contacts detected actively. As a result, the relative and absolute risks might be overestimated. The composition of the general and study populations differs (general population of all ages versus a specific age group). TB incidence in the population was estimated by multiplying the yearly notification rate by a factor of 2.
3 Moderate heterogeneity among studies (I 2 = 67.1%) probably due to differences in background TB incidence.
Few events and wide CI. Limitations in study design (see QUADAS-2): High risk of selection bias in one study (31). In all studies, less than half of participants received the reference standard; accuracy was calculated under the assumption that those who did not receive the reference standard were culture and/or smear negative (no active TB).
2 Indirectness (see QUADAS-2): Some concern about applicability of reference standard in 2 studies -no downgrading.  Imprecision: Precise estimates for sensitivity and specificity.
Publication bias: Not applicable (the evidence base for publication bias in studies of diagnostic test accuracy is very limited). Although there was a risk of selection bias, the characteristics of the two groups were similar. Patients with poor compliance were not included in the analysis of treatment outcomes. Downgraded by one level.
There was no clinical disease. The outcome reported was new radiographic findings suggesting possible active disease. No data compared with 6H. Downgraded by one level.
A high risk of detection bias due to lack of blinding. The RH group included participants enrolled during the second period, whose characteristics were different; they were not randomized between the RH group and the 9H group. Downgraded by two levels.
No data compared with 6H. Downgraded by one level.
Risk of bias due to poor comparability of the two groups. Downgraded by one level.
Low event rate and wide 95% CI. Downgraded by one level.
Lack of blinding. Medication adherence test was performed at home by parents. Although there was a risk of selection bias, the characteristics of the two groups were similar. Downgraded by one level.
Wide 95% CI. Downgraded by one level.

# The study reported adherence rates; compliance was considered to be poor if no medication was detected in urine strips or if patients did not return for follow-up visits or were lost to follow-up. Poor compliance was considered non-completion in the analysis. Although one of the trials was conducted in low TB incidence countries, this is unlikely to affect the relative effect of rifapentine + isoniazid compared with isoniazid monotherapy. Not downgraded.
2 95% CIs of both relative and absolute effect include appreciable benefit and harm with 3HP.
Both trials were open-label, which may have introduced bias in ascertainment of adverse events.
Although the trials were open-label, this is unlikely to affect detection of hepatotoxicity, which is usually done by objective measurement (i.e. blood tests.). Not downgraded.
5 Very low event rates. Upper limit of 95% CI of both relative and absolute effect include appreciable harm with 3HP. Downgraded by two levels. No comparison with 6 months of isoniazid. The study included 2.7% HIV-positive participants. Although the trial was conducted in low TB incidence countries, this is unlikely to affect relative effect of rifapentine + isoniazid compared with isoniazid monotherapy. Downgraded by one level.
Although the 95% CI of RR is wide, the number of events was small and the CI of absolute effect is narrow. The result also met pre-stated non-inferiority margin. Not downgraded.
Although the 95% CI of RR is wide, the number of events was small and the CI of absolute effect is narrow. Not downgraded.
An open-label design of the trial may have introduced ascertainment bias.
Although the trial was open-label, this is unlikely to affect detection of hepatotoxicity, which is usually done by objective measurement (i.e. blood tests). Not downgraded. No comparison against 6 months of isoniazid. Although the trial was conducted in low TB incidence countries, this is unlikely to affect relative effect of rifapentine + isoniazid compared with isoniazid monotherapy. Downgraded by one level.

# 3-month weekly rifapentine plus isoniazid or daily isoniazid monotherapy for treatment of LTBI in children and adolescents
Although the 95% CI of the RR is wide, the number of events was small and the CI of absolute effect is narrow. The result also met pre-stated non-inferiority margin. Not downgraded.
Although the 95% CI of the RR is wide, the number of events was small and the CI of absolute effect is narrow. Not downgraded.
An open-label design of the trial may have introduced ascertainment bias.
Although the trial was open-label, this is unlikely to affect detection of hepatotoxicity, which is usually done by objective measurement (i.e. blood tests). Not downgraded.
PICO 7: Should preventive treatment be recommended for contacts of patients with multidrug-resistant or rifampicin-resistant TB?
Preventive treatment for contacts of patients with multidrug-or rifampicin-resistant TB
Five studies that included fewer than 20 participants who completed preventive TB treatment were excluded. In addition, the study by Kristi was excluded as only isoniazid monotherapy was given. Risk of bias in selection of the control group, and none of the studies adjusted for confounders. Downgraded by two levels.
The study by Shaaf et al. was excluded, as the incidence of MDR-TB was not reported.
Small sample sizes and wide 95% CIs. Downgraded by two levels.