Among individuals infected with M. tuberculosis it is estimated that the lifetime risk of progressing to active TB averages to about 5–10% (4). The risk is particularly elevated among children under the age of 5 years and among people with compromised immunity (1). As any treatment entails risk of harms and opportunity costs, TB preventive treatment should be selectively targeted to population groups at highest risk of progression to active TB disease, who would benefit most from it. When identifying populations at increased risk, consideration should be given to the epidemiology and pattern of TB transmission in the country, so that treatment is optimized to offer lasting protection. A comprehensive individual clinical assessment that considers the balance between the risks and benefits for the person receiving treatment is critical. The three parts of this section describe recommendations for LTBI in population groups considered at highest risk and/or vulnerability to poor outcomes.
Adults and adolescents living with HIV
1. Adults and adolescents living with HIV who are unlikely to have active TB should receive TB preventive treatment as part of a comprehensive package of HIV care. Treatment should be given to those on antiretroviral treatment, to pregnant women and to those who have previously been treated for TB, irrespective of the degree of immunosuppression and even if LTBI testing is unavailable. (Strong recommendation, high certainty in the estimates of effect)
Justification and evidence
TB is the most frequent cause of AIDS-related deaths worldwide, despite progress in access to ART (17). TB caused about 251,000 deaths among PLHIV in 2018, representing about one third of all HIV deaths (10). Global data indicate that PLHIV are about 20 times more likely to develop active TB than those without HIV infection.
The recommendation for TB preventive treatment of all PLHIV was first published by WHO in 2011 (11). A systematic review of 12 randomized controlled trials (RCTs) found that preventive treatment reduced the overall risk for TB by 33% (relative risk [RR] 0.67, 95% confidence interval [CI] 0.51; 0.87) among the 8,578 PLHIV included (18). 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 TB preventive treatment in people receiving ART. TB incidence has been reported to be high among all PLHIV who did not receive isoniazid preventive treatment (IPT), including those with CD4>350 per cu mm and who were TST negative (19). One double-blind RCT of 1,329 PLHIV receiving ART indicated that those on ART with negative TST or IGRA benefited more from IPT than those who were TST or IGRA positive (20). An RCT of 2,056 PLHIV showed additive benefits of TB preventive treatment plus ART in reducing both TB incidence and overall mortality (21),(22). The protective effect lasted for more than 5 years.
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 the general population. They concluded that the evidence shows a clear benefit of systematic testing and treatment of LTBI for PLHIV. The wording of the recommendation now refers to LTBI testing rather than TST given that IGRA is also an option (see Recommendation 16). 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 additional protective effect to 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 PLHIV in countries with a TB incidence >100 / 100,000 population (11),(23). 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 TB (MDR-TB) or extensively drug-resistant TB (XDR-TB). The effect of repeated courses of preventive treatment is unclear and hence no recommendation on this is made in the present guidelines; this is the subject of ongoing studies (e.g. WHIP3TB (24)). In settings with high TB transmission, however, daily IPT for 36 months or longer is recommended conditionally (25) (see Recommendation 18). The relative risk of TB transmission is determined by the local authorities on the basis of risk of exposure (e.g. TB incidence, occurrence of undiagnosed or inadequately treated disease, population density, environmental factors) and host immune response (see Definitions, (26)).
Pregnant women living with HIV are at risk for TB, which can have severe consequences for both the mother and the foetus, with increased risk of maternal and infant death (27). Pregnancy should not disqualify women living with HIV from receiving preventive treatment with medicines commonly used to treat active TB that are generally considered safe for use in pregnancy, such as isoniazid and rifampicin (classified as Pregnancy Category C by US FDA (28),(29)). Section 1.4 presents the position of the GDG in 2019 on the use of isoniazid preventive treatment in pregnancy based on an updated evidence review.
Infants and children living with HIV
2. Infants aged < 12 months living with HIV who are in contact with a person with TB and who are unlikely to have active TB on an appropriate clinical evaluation or according to national guidelines should receive TB preventive treatment. (Strong recommendation, moderate certainty in the estimates of effect)
3. Children aged ≥ 12 months living with HIV who are considered unlikely to have active TB on an appropriate clinical evaluation or according to national guidelines should be offered TB preventive treatment as part of a comprehensive package of HIV prevention and care if they live in a setting with high TB transmission, regardless of contact with TB. (Strong recommendation, low certainty in the estimates of effect)
4. All children living with HIV who have successfully completed treatment for TB disease may receive TB preventive treatment. (Conditional recommendation, low certainty in the estimates of effect)
Justification and evidence
These recommendations were first published by WHO in 2011 (11). A systematic review conducted for the original guidelines included two studies, both 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 (30). The other RCT, however, showed no benefit of preventive treatment in HIV-infected infants identified in the first 3–4 months of life in whom there was no known exposure to active TB and who were rapidly placed on ART and monitored carefully every month for new exposure to TB or disease (31). Few RCTs included children on ART. In one trial of 167 children on ART, the incidence of TB was lower in those given TB 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)(32). A cohort study suggested an additive protective effect of preventive treatment in children receiving ART (33).
For infants aged <12 months living with HIV, the GDG noted that TB 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 without clinical manifestations suggestive of active TB, 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 PLHIV. Children ≥ 12 months living with HIV who have clinical manifestations or who are contacts should be evaluated further and treated for active TB or LTBI as indicated (see also Fig. 1).
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 or not.
There is no evidence on the value of preventive treatment in children living with HIV after successful completion of TB treatment. However, children living with HIV who are at risk of reinfection 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 transmission (as defined by national authorities; see also Definitions) may receive a course of TB preventive treatment. This can be started immediately after the last dose of TB curative treatment or later, according to clinical judgement.
Household contacts of pulmonary TB⁵
5. Children aged < 5 years who are household contacts of people with bacteriologically confirmed pulmonary TB and who are found not to have active TB on an appropriate clinical evaluation or according to national guidelines should be given TB preventive treatment even if LTBI testing is unavailable. (Strong recommendation, high certainty in the estimates of effect)
6. Children aged ≥ 5 years, adolescents and adults who are household contacts of people with bacteriologically confirmed pulmonary TB who are found not to have active TB by an appropriate clinical evaluation or according to national guidelines may be given TB preventive treatment. (Conditional recommendation, low certainty in the estimates of effect)
Justification and evidence
The first recommendation was initially published by WHO in 2015 and the second in 2018 (13),(16). A systematic review conducted for the 2015 guidelines was updated in 2018, focusing on household contacts in countries with a TB incidence >100 / 100,00 population (13),(14) (see PICO 1 in Annex 2). 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. Another
19 studies published between 2014 and 2016 were added. Whilst the evidence reviewed related to HIV-negative child contacts, children living with HIV who are a household contact of a person with bacteriologically confirmed pulmonary TB should also receive investigations and treatment as necessary. The recommendation was thus reworded slightly in the current update to remove undue restriction on its application to HIV negative children alone.
The prevalence of LTBI was higher among children and adolescents aged > 15 years and adults than in children < 5 years, who were at greatest risk for progression to active TB disease. In comparison with child household contacts < 5 years, the pooled risk ratios for progression to active TB were lower in children aged 5–15 years (0.28, 95% CI 0.12; 0.65, four studies) and for those > 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 a substantially higher risk for progression to active TB than the general population (Table 2).
Both recommendations may apply to HIV-negative and to HIV-positive children. The GDG noted the significantly higher risk of infants and young children < 5 years to develop active TB. Furthermore, the disease can develop rapidly in young children, and they are at greatest risk of 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 HIV status and background epidemiology of TB, but only after active TB disease has been ruled out.
Preventive treatment is also conditionally recommended 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 ongoing transmission of TB. In this group the confirmation of LTBI using either IGRA or TST would be desirable (see Section 1.3). Based on evidence of moderate to high quality, the 2015 LTBI guidelines strongly recommended the systematic LTBI testing and TB preventive treatment for contacts regardless of age in countries with a TB incidence lower than 100/100,000 population (13). In the current update, the GDG considered that this recommendation could be applied to any country regardless of TB burden if tests for LTBI and to rule out active TB were available and reliable. Treatment may be justifiable without a LTBI test based on an assessment of the individual’s risk of exposure and for the development of active TB in a given setting. The GDG noted that the capacity of the health caregiver to assess the intensity of exposure, risk of infection and reinfection, the risk for development of active TB, and the ascertainment of LTBI by testing, as well as capacity to weigh harm versus benefit of treatment and ability to exclude active TB disease before initiation of treatment are important considerations in the implementation of these recommendations.
Contacts of multidrug-resistant tuberculosis patients
7. In selected high-risk household contacts of patients with multidrug-resistant tuberculosis, preventive treatment may be considered based on individualized risk assessment and a sound clinical justification. (Conditional recommendation, very low certainty in the estimates of effect)
Justification and evidence
This recommendation was added in the 2018 update of the guidelines. Ahead of this a systematic review of the effectiveness of preventive treatment for contacts of people with MDR-TB conducted for the 2015 LTBI guidelines was updated (14).
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 (see PICO 10 in Annex 2). Because of clinical heterogeneity among the studies, a meta-analysis 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. No active TB was reported in either the intervention or the control group in one study (34), while one person with active TB due to a drug-susceptible strain that was different from the presumed source was reported in another study (35). The remaining two studies addressed the efficacy of preventive treatment (36),(37). In one cohort of 119 contacts, 104 with LTBI initiated fluoroquinolone based preventive treatment, of whom 93 (89%) completed treatment, and none developed active TB; while 3 of 15 (20%) contacts who refused treatment developed MDR-TB (OR 0.02, 95% CI 0.00; 0.39) (36). In the other study, confirmed or probable TB developed in 2 of 41 (4.9%) children receiving tailored preventive treatment and in 13 of 64 (20.3%) children who did not receive proper preventive treatment (OR 0.2, 95% CI 0.04; 0.94) (37).
Most TB infection globally is with rifampicin-susceptible strains but recent modelling suggests that MDR-TB infection may increase in future (38). Overall, the GDG judged that the potential benefits of targeted preventive treatment for MDR-TB contacts, based on individual risk assessments, outweighs the harm but acknowledged uncertainty about the efficacy of the intervention due to the lack of RCT evidence. The GDG stressed that treatment should be given to selected individuals after a careful risk assessment, including intensity of exposure, certainty of the source of disease, reliable information on the drug resistance pattern of the source and potential adverse drug reactions. It should be given only to household contacts at high risk (e.g. children, people on immunosuppressive therapy, PLHIV) in whom the provision of MDR-TB preventive treatment would be more acceptable. The recommendation may also apply to HIV-negative individuals. Confirmation of infection by LTBI testing is usually required before treatment is initiated.
Other people at risk
8. People who are initiating anti-TNF treatment, or receiving dialysis, or preparing for an organ or haematological transplant, or who have silicosis should be systematically tested and treated for LTBI. (Strong recommendation, low to very low certainty in the estimates of effect)
9. Systematic LTBI testing and treatment may be considered for prisoners, health workers, immigrants from countries with a high TB burden, homeless people and people who use drugs. (Conditional recommendation, low to very low certainty in the estimates of effect)
10. Systematic LTBI testing and treatment is not recommended for people with diabetes, people who engage in the harmful use of alcohol, tobacco smokers and underweight people unless they also belong to other risk groups included in the above recommendations. (Conditional recommendation, very low certainty in the estimates of effect)
Justification and evidence
These recommendations were first published by WHO in 2015 (13). The GDG considered evidence from three systematic reviews that were conducted for the previous LTBI guidelines to determine which of the 24 defined at-risk population groups should be prioritized for LTBI testing and treatment (13),(14). 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, healthcare workers and students, PLHIV, patients on dialysis, immigrants from countries with a high TB burden (incidence of >100 TB cases per 100,000 population), patients initiating anti-TNF therapy, people who use drugs, prisoners, homeless people, patients preparing for an organ or haematological transplant, patients with silicosis, patients with diabetes, people who engage in the 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: PLHIV; adult and child TB contacts; patients on dialysis and underweight people.
The GDG judged that people in 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 most from testing for and treatment of LTBI regardless of the background TB epidemiology. The GDG considered that the benefits of TB preventive treatment to lower the risk of progression to disease would usually outweigh the potential harm in these groups and made a strong recommendation despite a low to very low certainty in the evidence.
The GDG concluded from the evidence that the benefits of systematic LTBI testing and TB preventive treatment may not always outweigh the harm in healthcare workers and students, immigrants from countries with a high TB burden, prisoners, homeless people and people who use drugs. The GDG judged, however, that the benefits are more likely to outweigh potential harm when the risks for reinfection are lower. In 2019 the GDG updated this recommendation to make it applicable to both high and low TB prevalence countries on condition that the decision to systematically test for LTBI and offer TB preventive treatment in these population groups considers the local TB epidemiology and context, health infrastructure, capacity to exclude active TB reliably, any adverse impact on health equity and overall health priorities. Greater benefit is expected in individuals who were recently infected with TB, as documented by conversion from negative to positive on IGRA or TST (see Section 1.3). The GDG also concluded that recent immigrants, particularly those from countries with a higher TB burden to the one in the host country, may be prioritized6 , especially within the first few years after entry.
Despite evidence for increased prevalence of LTBI and active TB in patients with diabetes, people who engage in the harmful use of alcohol, tobacco smokers and underweight people, the GDG noted the paucity of data from clinical trials on the benefits and harm of systematic LTBI testing and treatment.
They concluded that systematic, routine testing and treatment in people with these risks alone may not outweigh the potential harms, regardless of background TB epidemiology. This should not, however, be construed as a blanket, negative recommendation for any form of testing and treatment among these populations on a case-by-case basis.
The GDG agreed that prioritization of groups based on their risk and the local and national context would be acceptable to people with LTBI and to key stakeholders, including clinicians and programme managers. It noted that the high risk for ongoing TB transmission of certain groups, such as frontline healthcare workers (including students), prisoners (and prison staff), immigrants from areas with a higher TB burden than the host country6 , homeless people and people who use drugs requires attention, so that the benefit of treatment is not compromised by subsequent reinfection. TB preventive treatment should articulate well with other preventive components of the programme aimed at active TB case-finding, infection control and early treatment of active TB (26).
In their normative and planning documents, national TB and HIV authorities and other stakeholders should clearly define the populations to prioritize for PMTPT. This position should aim to provide lasting protection from progression to active TB to a maximum of individuals at risk, thus limiting continued transmission and reinfection and reducing TB incidence over time. PLHIV and household contacts were primarily targeted for global action by Member States at the UN High Level Meeting in 2018 (6). The GDG stressed that the best available evidence should be used to ensure that benefits outweigh risks to the individuals belonging to these groups and to make the best possible use of resources. This could yield savings for the entire healthcare system. Any additional resources needed to implement the guidance should not be viewed as a barrier but should stimulate programmatic action to mobilise more funding. The GDG noted the value of ART in preventing TB in PLHIV, striving for universal access to ART as per WHO policy (39).
TB preventive treatment for PLHIV should be a core component of the HIV package of care and should be primarily the responsibility of national HIV/AIDS programmes and HIV service providers (39),(40). Care needs to be coordinated with the healthcare services responsible for TB. It should be viewed as one of a comprehensive set of interventions. It is also expected that some household contacts and other people eligible for TB preventive treatment (e.g. people receiving dialysis, prisoners) will also be HIV positive and would therefore require individual attention to minimize their likelihood of developing active TB.
Confirmation of LTBI using either IGRA or TST and reliable exclusion of active TB with chest radiography would be desirable before starting TB preventive treatment. In situations where these tests are not available TB preventive treatment should not be withheld from eligible people if active disease has been excluded on clinical grounds alone (see Section 1.2).
The capacity of the programme to provide MDR-TB preventive treatment in addition to other LTBI efforts should be carefully planned for. Providing a component on MDR-TB within PMTPT requires that all the necessary resources be in place, including the capacity to rule out active TB, to perform quality-assured testing for drug susceptibility (in the presumed source case), to deliver the necessary medications and to monitor closely for adverse events and for the emergence of active disease. The choice of MDR-TB preventive treatment is discussed further in Section 1.4.
The identification of populations for LTBI testing and TB preventive treatment raises a range of ethical issues (41),(42). First, LTBI is an asymptomatic and non-contagious state. This makes the ethical obligations different from those associated with active TB. For example, the absence of an immediate risk of transmission makes it unethical to restrict movement of someone with LTBI who refuses treatment. Shortage of evidence for benefit of systematic testing and treatment in certain populations (e.g. people with diabetes or who are underweight) should not stop efforts to offer preventive treatment to individuals with these conditions who are judged to be at increased risk of progression. Secondly, the absence of tests that can measure individual risk for the development of active TB may pose a challenge to communication. Informed consent requires effective, adequate communication to each person about the uncertainty of current LTBI tests to predict progression to active TB, individual host variabilities, and the protective benefit expected of treatment versus adverse reactions. Appropriate mechanisms to obtain informed consent should comply with international human rights standards and account for different languages and literacy skills, and legal status. Risk and uncertainty must be communicated in a way that is culturally and linguistically appropriate to people, including those whose first language is foreign to the local setting, for children, as well as people in prison. User feedback collected during screening programmes is useful to inform implementation. Thirdly, LTBI disproportionately affects individuals and groups that are already disadvantaged due to disease, socio-economic situation, or legal status among others. Therefore, efforts must be made to address existing inequities in access to services and to uphold human rights, so that the vulnerability of target groups does not impede their access to screening and treatment or violate their rights. Any intervention for vulnerable groups – including those who are criminalized, those in prisons, and children – should include measures to minimize the risk for stigmatization, such as protecting confidentiality of personal data and informed consent. The GDG emphasized that a person’s status – testing positive for LTBI or receiving TB preventive treatment – should not affect the immigration procedure or deny entry. This should be reflected in existing laws or other policy regulations. People should be tested for LTBI and receive TB preventive treatment in strict adherence to human rights and ethical considerations (43). Policies should be evaluated by end-users from an ethical perspective and the views and experiences of affected populations gathered after implementation, both to consider possible unexpected effects and to ensure that the evidence on which they are based remains current and relevant (44). Person-centred LTBI care entails, among others, that it is provided in an equitable fashion without placing marginalized and vulnerable populations at an added disadvantage; it focuses on the human rights aspects of TB preventive treatment interventions so that there are appropriate safeguards in law, policy and practice to minimise additional stigma, discrimination, violation of bodily integrity or restrictions on freedom of movement; and people offered testing and treatment appreciate the associated uncertainties to help them participate in care options. These guiding principles would best draw upon a set of established human rights principles, such as consent, noncoercion, confidentiality (42).
⁵ Regardless of HIV status
⁶ Estimated TB incidence rates for all countries are updated annually by WHO (10).