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Implementing tuberculosis preventive treatment in high-prevalence settings

Open AccessPublished:March 11, 2021DOI:https://doi.org/10.1016/j.ijid.2021.02.094

      Highlights

      • Tuberculosis preventive treatment is effective and feasible in high-prevalence settings.
      • Successful scale-up of tuberculosis preventive treatment requires attention to all steps in the ‘cascade of care’.
      • The greatest drop-out typically occurs prior to commencement of therapy.
      • Programs should adopt a patient-centred approach.
      • Shorter-course regimens promise to improve treatment completion.
      • Operational research can help to localise the use of preventive therapy.

      Abstract

      Latent tuberculosis infection affects one quarter of the world’s population, and effective therapies are available. However, scale-up of tuberculosis preventive treatment (TPT) remains limited. We describe strategies to support scale-up of TPT in high-prevalence settings, where the potential benefit for affected individuals is considerable. Patients must be at the centre of policies to scale-up TPT. Addressing the health system requirements for scale-up will ensure that programs can deliver treatment safely, efficiently and sustainably. Further research is required to adapt TPT to local contexts, and develop new shorter treatments that will be suitable for wide-scale deployment.

      Keywords

      Latent tuberculosis infection (LTBI) affects an estimated two billion people worldwide (
      • Houben R.M.
      • Dodd P.J.
      The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling.
      ), and is a driver of the global tuberculosis (TB) pandemic (
      • World Health Organization
      Global Tuberculosis Report. World Health Organization.
      ). This asymptomatic condition caused by Mycobacterium tuberculosis confers an increased risk of progression to tuberculosis disease (TB) (
      • de Martino M.
      • Lodi L.
      • Galli L.
      • Chiappini E.
      Immune Response to Mycobacterium tuberculosis: A Narrative Review.
      ), which is most likely to occur in the period soon after infection (
      • Trauer J.M.
      • Moyo N.
      • Tay E.L.
      • Dale K.
      • Ragonnet R.
      • McBryde E.S.
      • et al.
      Risk of Active Tuberculosis in the Five Years Following Infection. . . 15%?.
      ,
      • Martinez L.
      • Cords O.
      • Horsburgh C.R.
      • Andrews J.R.
      • Pediatric T.B. Contact Studies Consortium
      The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis.
      ) or with immune compromise. Treatment of LTBI – also referred to as tuberculosis preventive treatment (TPT) – has been a core strategy for TB control in many low-prevalence settings for decades. Recent World Health Organization (WHO) recommendations have established the importance of targeted LTBI screening and TPT in high-prevalence countries (
      • World Health Organization
      WHO consolidated guidelines on tuberculosis. Module 1: Prevention. Tuberculosis preventive treatment.
      ). However, in most countries only a small proportion of people with LTBI are identified, evaluated and treated. A recent meta-analysis estimated that just 18.8% of people eligible for screening actually completed TPT (
      • Alsdurf H.
      • Hill P.C.
      • Matteelli A.
      • Getahun H.
      • Menzies D.
      The cascade of care in diagnosis and treatment of latent tuberculosis infection: a systematic review and meta-analysis.
      ).

      Rationale for preventive treatment among high-risk populations

      TPT offers the greatest benefit to infected individuals with a high risk of future progression to TB. In most settings, TPT focuses upon close contacts of patients with known pulmonary TB, and people with immunological impairment such as HIV infection, or young children (<5 years) – who are particularly vulnerable (
      • World Health Organization
      WHO consolidated guidelines on tuberculosis. Module 1: Prevention. Tuberculosis preventive treatment.
      ). This approach reduces the risk of disease progression for individuals with LTBI, and also averts future M. tuberculosis transmission in their immediate communities. Widespread treatment of high-risk populations could have a measurable impact upon TB incidence (
      • Havumaki J.
      • Cohen T.
      • Zhai C.
      • Miller J.C.
      • Guikema S.D.
      • Eisenberg M.C.
      • et al.
      Protective impacts of household-based tuberculosis contact tracing are robust across endemic incidence levels and community contact patterns.
      ). However, targeted TPT is unlikely to have a substantial population-wide impact, given that a relatively small proportion of the incident TB cases occurring in a population will occur in recognised high-risk groups (
      • Rangaka M.X.
      • Cavalcante S.C.
      • Marais B.J.
      • Thim S.
      • Martinson N.A.
      • Swaminathan S.
      • et al.
      Controlling the seedbeds of tuberculosis: diagnosis and treatment of tuberculosis infection.
      ). Hence, the important benefit to vulnerable contacts provides the main motivation (
      • Sloot R.
      • Schim van der Loeff M.F.
      • Kouw P.M.
      • Borgdorff M.W.
      Risk of tuberculosis after recent exposure. A 10-year follow-up study of contacts in Amsterdam.
      ).
      Globally, implementation of TPT remains sub-optimal, particularly in many low- and middle-income countries where TB remains a serious public health problem. Barriers to TPT scale-up include insufficient awareness of the importance of TPT by healthcare workers, limited engagement of TB control programmes in preventive strategies, a limited capacity to diagnose LTBI and excluding TB disease, as well as insufficient availability and duration of treatment options. New advances promise to overcome many of these limitations. Importantly, shorter and more acceptable TPT regimens using less toxic drugs have recently been recommended by WHO (
      • World Health Organization
      WHO consolidated guidelines on tuberculosis. Module 1: Prevention. Tuberculosis preventive treatment.
      ). However, for these shorter duration TPT regimens to substantially alter the current TB epidemic trajectory, robust operational research is required to guide its implementation in different settings. National TB programmes are encouraged to develop tailored strategies to screen and treat high-risk populations such as close contacts (
      • World Health Organization
      Latent tuberculosis infection. Updated and consolidated guidelines for programmatic management.
      ).

      The ‘cascade-of-care’ framework to strengthen LTBI treatment

      A patient’s journey from infection with M. tuberculosis to completion of treatment can be presented as a ‘cascade-of-care’ (Figure 1) . Such a framework enables health services to quantify where attrition occurs, and monitor the progress of interventions to strengthen each step. While safer and shorter rifamycin-based regimens have increased TPT completion rates, losses occurring before treatment commencement represent the biggest drop-out (occurring up to 70% of contacts) and presents the biggest barrier. The greatest losses occur during the early steps of contact identification, initial testing for LTBI and medical evaluation (
      • Alsdurf H.
      • Hill P.C.
      • Matteelli A.
      • Getahun H.
      • Menzies D.
      The cascade of care in diagnosis and treatment of latent tuberculosis infection: a systematic review and meta-analysis.
      ). The reasons for pre-treatment fall-out in the care cascade are manifold and context-specific. Efforts to expand TPT must recognise and address the factors that impede progression through this cascade.
      Figure 1
      Figure 1Overview of the ‘cascade of care’ for latent tuberculosis infection.
      Tailored interventions to reduce drop-out prior to treatment initiation based have been the focus of a recent randomised trial conducted in five low- and high-prevalence countries (
      • Oxlade O.
      • Benedetti A.
      • Adjobimey M.
      • Alsdurf H.
      • Anagonou S.
      • Cook V.J.
      • et al.
      Effectiveness and cost-effectiveness of a health systems intervention for latent tuberculosis infection management (ACT4): a cluster-randomised trial.
      ). Study sites received a three-phase public health intervention, which strengthened local health capacity and monitored the cascade-of-care for treating LTBI. The interventions substantially increased initiation of TPT at intervention sites. Benefit was seen primarily in low- and middle-income countries, and provide the evidence required to justify scale-up in comparable settings.
      Despite exemplars of effective scale-up of TPT, the adoption of international recommendations remains limited. In 2019, less than 20% of contacts over five years were provided TPT globally (
      • World Health Organization
      Global Tuberculosis Report. World Health Organization.
      ), reflecting the continuing barriers to scale-up and ubiquitous ambivalence towards preventive treatment. Overcoming this inertia will require TB control programmes to develop the experience required to support scale-up. When TB control programmes first introduce TPT, they typically begin with close contacts of patients with TB. This high-risk group is readily identifiable and may be motivated to participate in screening, due to their recognised exposure and perceived personal benefits. Contacts also benefit from the recency of their exposure – increasing the chance to interrupt disease progression soon after infection. However, significant barriers to participation must be overcome (
      • Yanes-Lane M.
      • Trajman A.
      • Bastos M.L.
      • Oxlade O.
      • Valiquette C.
      • Rufino N.
      • et al.
      Effects of programmatic interventions to improve the management of latent tuberculosis: a follow up study up to five months after implementation.
      ). Once programmes have developed experience in delivering TPT to close contacts, they can expand treatment to other high-risk populations.

      Strategies to strengthen TB prevention

      Patient engagement is critical to the successful scale-up of TPT. Adopting a patient-centred approach will ensure that programs are attuned to the needs of patients. Empowerment of patient representatives to provide input into TPT programmes will enhance the quality of care and ultimately improve participation. For example, patients’ interaction with the health care systems should be designed to minimise the number of visits that patients have with healthcare providers. A so-called ‘one-stop shop’ approach involves all steps in enrolment and screening being conducted in the minimum number of visits – orienting the health service to patient’s needs.
      The growing number of therapeutic options available to patients also enable a more patient-centred approach to TPT. The availability of multiple effective treatments for LTBI offer patient greater choice (
      • World Health Organization
      Latent tuberculosis infection. Updated and consolidated guidelines for programmatic management.
      ). Digital patient decision aids, Smartphone Apps and online risk calculators can provide individual risk-benefit estimates, explore personal priorities, and consider individual risks of toxicity. Examples of decision aids include tstin3d.com and PERISKOPE-TB (
      • Gupta R.K.
      • Calderwood C.J.
      • Yavlinsky A.
      • Krutikov M.
      • Quartagno M.
      • Aichelburg M.C.
      • et al.
      Discovery and validation of a personalized risk predictor for incident tuberculosis in low transmission settings.
      ). However, further research is required to guide the adoption of digital tools in a range of settings.
      A health system approach can help programmes to identify the structural changes required to deliver TPT at scale. The six elements of the WHO Health Systems framework include service delivery, health workforce, health information systems, access to preventive treatment, financing and leadership/governance (
      • World Health Organization
      Monitoring the building blocks of health systems.
      ). Developing a local plan that addresses each of these elements, accompanied by adequate investment, will help to ensure TPT programs are sustainable.

      Future directions and next seps

      Many research questions remain. These include the optimal algorithms for detecting LTBI and excluding active TB in relevant risk groups, and the development of biomarkers that accurately detect likely disease progressors (incipient disease). Better predictors of the risk of disease progression would dramatically reduce the number of individuals requiring treatment, and avert adverse effects in those at a lower risk of progression. Operational research to apply the ‘cascade-of-care’ approach will help programmes to evaluate scale-up. Research is also required to develop shorter duration, safer and more cost-effective TPT, in order to increase treatment completion. Effective TPT regimens for drug-resistant TB are also urgently needed.
      In conclusion, the tools for diagnosing and treating LTBI are already available. Ambitious public health action is now required to generate new implementation models, scale-up evidence-based practices and expand the benefits of preventive treatment to many more people living in high-burden settings.

      Conflict of interest

      No conflicts of interest were declared.

      Funding source

      GJF was supported by an Australian National Health and Medical Research Council Career Development Fellowship ( APP 1148372 ).

      Ethical approval

      This narrative review did not involve participant recruitment, and did not require ethical approval.

      Transparency declaration

      This article is part of a supplement entitled Commemorating World Tuberculosis Day March 24th, 2021: “The Clock is Ticking” published with support from an unrestricted educational grant from QIAGEN Sciences Inc.

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