Research Article: Treatment of latent infection to achieve tuberculosis elimination in low-incidence countries

Date Published: June 6, 2019

Publisher: Public Library of Science

Author(s): Jonathon R. Campbell, David Dowdy, Kevin Schwartzman

Abstract: In a Perspective for the Tuberculosis Special Issue, Kevin Schwartzman and colleagues discuss the choices and implications for personal versus public health benefits when pursuing tuberculosis elimination in low-incidence countries.

Partial Text: Tuberculosis (TB) remains an important public health problem in every country of the world. The World Health Organization (WHO) has developed the End TB strategy, which sets ambitious global goals: 95% decline in TB mortality and 90% reduction in TB incidence by 2035, compared to 2015 [1]. In high-incidence countries, reaching these goals will require much better access to timely diagnosis and treatment, as well as improvements in socioeconomic conditions and health systems. Low-incidence countries have already benefited from these improvements, reflected in marked decreases in TB-related morbidity and mortality over the last century: in Canada, incidence declined from a high of 103 per 100,000 in 1946 to less than 5 per 100,000 from 2000 onward. Similarly, TB-related mortality declined from 80 per 100,000 in 1924 to 0.4 per 100,000 by 2000 [2]. However, TB incidence has now leveled off in many low-incidence countries, and ongoing transmission now accounts for a minority of new cases [3,4]. This stagnation largely reflects the challenge of preventing ongoing reactivation of latent TB infection (LTBI), which causes most active TB in low-incidence countries [4,5].

The current WHO framework for TB elimination in low-incidence countries advocates an individual-level approach to LTBI screening and treatment [5]. This is motivated by the principle that an intention to screen an individual for LTBI is an intention to treat if positive, so that risks of treatment should be outweighed by anticipated benefits before screening is performed. Relying on robust epidemiologic evidence, WHO recommends LTBI screening when there is high certainty of substantial benefit (for example, close contacts of persons with active TB; human immunodeficiency virus [HIV]-infected persons). In low-incidence countries, this population of individuals is small. In Canada, for example, individuals recommended for screening by WHO criteria represent 2 of every 49 TB cases that must be prevented to eliminate TB. For the most part, these persons are already routinely screened and treated as part of standard clinical care [2,8,15,16].

The primary benefit of LTBI treatment is reduced risk of TB disease with related morbidity and mortality, including both acute and longer-term complications such as chronic respiratory impairment [22]. Importantly, these benefits often accrue well into the future and are generally not detectable by persons with LTBI, their families, or their communities. Patient and community valuation of these potential benefits is critical to sustaining political and financial support for LTBI diagnosis and treatment programs. In formal terms, this valuation incorporates patient time preference, often described as a discount rate. For example, the commonly used discount rate of 3% [23] implies that preventing a TB case 10 years from now is valued 26% less than preventing a TB case tomorrow. Importantly, the discount rate varies considerably between individuals [24]. This means that faced with identical short-term risks and long-term benefits, some persons may choose LTBI treatment and others may decide against it, based on varying time preference. More generally, after understanding their personal risks and benefits associated with LTBI treatment, some individuals with LTBI will reasonably make an informed decision against treatment, based on rational preferences.

Providing LTBI treatment to individuals ≥65 years of age is a clinical challenge since they carry both the highest age-related risk of adverse events and highest age-related risk of TB [33,34]. In both Canada and the United States, this age group accounts for approximately one-quarter of TB cases [6,35]. If we are to reach the aspirational goal of TB elimination, persons in this age group must be included in screening and treatment initiatives [8]. A brief case study (Fig 2) examines two perspectives on this decision, demonstrating the risk–benefit considerations clinicians and their patients will increasingly face if we maintain the target of TB elimination.

We argue that approaching LTBI treatment from an individual perspective is the most patient-centered and equitable way to proceed. The uncertainty inherent to LTBI testing among persons at lower risk of infection and disease, and the limited net individual benefit to most patients even in the era of shortened rifamycin-based regimens, likely justifies a more risk-averse approach as opposed to the more utilitarian public health framework. Yet, taking this approach implies an acceptance that—absent a new intervention (for example, vaccine) with a substantially lower risk profile—TB elimination will not be achieved within any of our lifetimes, let alone by the WHO target date of 2050. Additional quantitative research could be helpful in developing a TB incidence goal that could be achieved without subjecting any individual to an unfavorable balance of risks and benefits.



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