Preventive Therapy for Multidrug Resistant Latent Tuberculosis Infection: An Ethical Imperative with Ethical Barriers to Implementation?

Abstract

Multidrug resistant tuberculosis (MDR-TB) has a substantial impact on individuals and communities globally, including lengthy, expensive and burdensome therapy with high rates of treatment failure and death. Strategies to prevent disease are well established for those who acquire latent tuberculosis infection (LTBI) after exposure to drug susceptible TB (DS-TB). However, there has been limited research or programmatic experience regarding the prevention of MDR-TB. Accordingly, while global recommendations strongly emphasize the need to deliver LTBI therapy after TB exposure, most programs do not do so where MDR LTBI is identified. The paucity of prospective randomized trial evidence for the effectiveness of MDR LTBI therapy, and concerns regarding its adverse effects, have been used to justify a reluctance to scale up programmatic interventions to prevent MDR-TB, or to participate in research evaluating such strategies. However, such a response fails to adequately balance potential risks of therapy with the substantial harms associated with inaction. Furthermore, the cost of inaction falls disproportionately on the most vulnerable members of society, including children. Delays in implementing proven preventive strategies may also mask hidden programmatic concerns, particularly regarding the financial cost and other burdens of treating drug resistant infection. Reticence to engage with preventative therapy for MDR-TB, even in the absence of high-level evidence, may run counter to the best interests of individuals who have been exposed to MDR-TB. This chapter will explore ethical tensions raised by expanding access to preventative therapies for MDR-TB, and consider how ethically optimal responses to this adverse condition may be evaluated. An ethical perspective on evidentiary burden will be addressed, emphasizing how MDR LTBI research may both offer, and be shaped by, paradigmatic insights into human research ethics more generally. Emerging research and illustrations from the authors programmatic engagement in Vietnam are offered as case examples, because social and community expectations and norms may challenge, or support, implementation of therapy for drug-resistant infection. Such circumstances prompt consideration of the broader questions of social impact, such as the potential for widespread preventive therapy to accelerate the development of antimicrobial resistance.

Treatment of Infection as a Core Strategy to Prevent Rifampicin-Resistant/Multidrug-Resistant Tuberculosis

“…The principles of what has traditionally been called preventive therapy but what should more accurately be referred to as the treatment of infection for drug-susceptible TB and RR/MDR-TB are essentially the same [ 21 ]. The goal is identifying individuals when they are harboring only a small population of mycobacteria in the lungs—and thus are usually asymptomatic—so that they can be treated with fewer medications (often just one or two) and for shorter periods of time (ranging from one to six months) than are needed for people with active TB disease.…”

Invisible epidemics: ethics and asymptomatic infection

“…Globally rising tides of drug resistance make the problem of asymptomatic infection increasingly urgent—in part because certain highly resistant pathogens have become impossible to cure with existing antimicrobial drugs. For example, drug-resistant TB is a key threat to global public health, increasing numbers of people now asymptomatically carry multi-drug resistant TB (Nguyen et al 2020 ), and some even carry “extensively” resistant strains which are virtually incurable. When, or if, such persons eventually develop active illness and thereby become contagious, the danger to others they might infect is significantly greater than would otherwise be the case.…”