Persons with LTBI (latent tuberculosis infection) have no signs or symptoms and are not contagious; however, they are at risk of progression from latency to active disease. On average, this happens in 5-10% of those affected during their lifetime, but some (“at-risk”) populations have a substantially higher risk of progression than the average. Hence, diagnosis and treatment of LTBI may represent an attractive strategy for TB prevention
by Giorgia Sulis, Lucia Urbinati, Alberto Matteelli
Division of Infectious and Tropical Diseases – WHO Collaborating Centre for “TB/HIV co-infection and for TB elimination”, University of Brescia, Brescia, Italy
Management of Latent Infection to End the TB Epidemic
Latent tuberculosis infection (LTBI) is a condition in which TB bacteria (M. tuberculosis) survive in the body in a dormant state. In 1999 it was calculated that one third of the world population has LTBI (1), providing an estimate of the huge magnitude of the human reservoir of M. tuberculosis.
Persons with LTBI have no signs or symptoms and are not contagious; however, they are at risk of progression from latency to active disease. On average, this happens in 5-10% of those affected during their lifetime, but some (“at-risk”) populations have a substantially higher risk of progression than the average (2). Hence, diagnosis and treatment of LTBI may represent an attractive strategy for TB prevention. Historically, diagnosis and treatment of LTBI did not attract interest for TB control, as diagnosis and treatment of active TB is a more direct intervention to reduce transmission and incidence of the disease. However, the benefits of treating LTBI for individuals with high risk of progression (e.g. those with HIV infection) are well known since decades; moreover, in low TB incidence countries (i.e. 10 cases per 100,000 population or lower) it is now recognized that further decrease of incidence, and eventually TB elimination, will not be possible without addressing LTBI.
From a programmatic perspective, and under a public health approach, the management of LTBI stands on three main components: i) identifying those who should be tested, ii) defining the testing algorithm, and iii) the relevant treatment options. In addition, several supportive interventions need to be put in place, from involving multiple services of the health system, to ensuring sustained procurement of diagnostics and drugs, to setting up a manageable recording and reporting system for effective monitoring and evaluation.
According to the World Health Organization (WHO) policies, all people living with HIV (PLHIV) and children under 5 years of age who are household or close contacts of a TB case should be systematically assessed and treated for LTBI, given their extremely high risk of disease progression. Testing is not required for PLHIV, but it is encouraged whenever possible, based on the use of TST (tuberculin skin test) and limiting treatment to those with a positive test (3). In children, however, testing is not recommended. In both groups, LTBI treatment should be offered as soon as active TB is safely excluded. A 6-month regimen of isoniazid (300 mg daily in PLHIV; 10 mg/kg per day, range 7-15 mg/kg, with a maximum dose of 300 mg/day in children) is the mainstay of treatment in resource constrained countries; lifelong (approximated to 36 months) isoniazid treatment is conditionally recommended for PLHIV in areas with a high TB/HIV-burden, to account for the large risk of reinfection (3, 4). Unfortunately, LTBI management in these populations is either a poorly implemented intervention (5) or a fully neglected area (6), due to low political commitment and the limited availability of financial and material resources hindering implementation on a large scale.
The new END-TB strategy aims at changing radically this picture. By including LTBI management among the essential components of its biomedical interventions, and by setting a global indicator on coverage of LTBI treatment initiation in the above-mentioned groups, the strategy claims for a key role for this intervention on a global scale (7).
In high and upper-middle income countries with TB incidence below 100 per 100,000 population a substantial proportion of new TB cases are due to progression from recent or remote LTBI (2). In this setting TB elimination is stated as a realistic target within 2050 (8), and a list of eight priority actions has been proposed, including systematic screening and treatment of LTBI. WHO issued a guidance document for a public health approach to LTBI management in this context in 2014 (9).
Several at-risk populations, in addition to PLHIV and child contacts were strongly recommended for systematic testing and treatment of LTBI in this setting. These include persons with silicosis and those requiring treatment with tumour necrosis factor-alfa inhibitors, solid organ or bone marrow transplantation, or haemodialysis. For other risk groups, like prisoners, homeless people, injection drug users, migrants originating from high-TB burden areas, and health care workers, the decision to embark in LTBI testing and treatment should be taken locally based on prevailing epidemiology and resource availability (9). Candidates to treatment should be identified through immunological tests such as tuberculin skin tests (i.e. Mantoux test) and IGRAs (Interferon-gamma Release Assays) and those who yield a positive result should be systematically offered treatment, after exclusion of active TB. In such a context, treatment options go beyond isoniazid, and include short-course rifamycin-based regimens which may favour good patient adherence: 3 months of weekly rifapentine plus isoniazid; 3 months of daily rifampicin plus isoniazid; 4 months of daily rifampicin alone (9).
The existence of two different policies for rich and resource-constrained countries might look embarrassing. However, it stands on solid scientific basis. LTBI testing and treatment, even when considered under a public health perspective, must provide more potential benefits than potential harms to each single individual who is candidate to treatment. Wherever TB transmission is intense (high TB-burden countries) the occurrence of reinfections hampers the durability of LTBI treatment and significantly reduces the benefits, while the harms remain the same. Wherever resources are limited, LTBI activities cannot compete, in terms of cost-effectiveness, with diagnosis and care of active TB, since treatment of LTBI has an indirect effect on incidence.
The END-TB strategy has set a target of 90% LTBI treatment coverage (among PLHIV and children under five) within 2025: this may look unrealistic (7). Indeed, national TB Programs or their equivalent at ministerial level must face an incredible challenge as they virtually start from scratch in terms of LTBI testing and treatment interventions. Nevertheless, this very ambitious target can have a pulling effect on activities implementation and bring us close to the final goal, provided that substantial investment will be made in human resources and infrastructures.
- Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA. 1999;282(7):677-86.
- Getahun H, Matteelli A, Chaisson RE, Raviglione M. Latent Mycobacterium tuberculosis infection. N Engl J Med. 2015;372(22):2127-35.
- Intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings. Geneva: World Health Organization 2011.
- Guidance for national tuberculosis programmes on the management of tuberculosis in children. Geneva: World Health Organization, 2014.
- Global Tuberculosis Report 2014. Geneva: World Health Organization, 2014.
- Acosta CD, Rusovich V, Harries AD, Ahmedov S, van den Boom M, Dara M. A new roadmap for childhood tuberculosis. Lancet Glob Health. 2014;2(1):e15-7.
- Uplekar M, Weil D, Lonnroth K, Jaramillo E, Lienhardt C, Dias HM, et al. WHO’s new end TB strategy. Lancet. 2015;385(9979):1799-801.
- Lonnroth K, Migliori GB, Abubakar I, D’Ambrosio L, de Vries G, Diel R, et al. Towards tuberculosis elimination: an action framework for low-incidence countries. Eur Respir J. 2015;45(4):928-52.
- Guidelines on the Management of Latent Tuberculosis Infection. Geneva: World Health Organization 2015.; 2015.
Giorgia Sulis (Resident in Infectious Diseases since August 2013), was born in Italy in 1986. After graduating from the University of Pavia as a medical doctor in July 2011, she earned a postgraduate research fellowship on HIV/AIDS infection among migrants at the University of Brescia. She also holds a diploma in tropical medicine and international health with TropEd accreditation issued by the University of Brescia in 2013. In 2014 she performed an internship at the Global Tuberculosis Programme of the World Health Organization in Geneva, working with the TB/HIV team.
Lucia Urbinati was born in Italy in 1982. After graduating from the University of Bologna as a medical doctor, she attended a TropEd Course in Tropical Medicine and International Health held in Brescia. In June 2014 she completed her residency training in Tropical Medicine at University of Pavia. She is currently research fellow at the University of Brescia.
Alberto Matteelli was born in Italy in 1960. After graduating from the University of Pavia as a medical doctor he got his first job as WHO Junior Professional Officer in 1988 to work in Tanzania. He is employed by the Spedali Civili di Brescia since 1991. Currently he is the head of the Community Infections Unit, head of the Hospital STI centre, and co-Director of the WHO collaborating Center for TB/HIV co-infection.