Mathematical models of drug-resistant tuberculosis lack bacterial heterogeneity: A systematic review.

Drug-resistant tuberculosis (DR-TB) threatens progress in the control of TB. Mathematical models are increasingly being used to guide public health decisions on managing both antimicrobial resistance (AMR) and TB. It is important to consider bacterial heterogeneity in models as it can have consequences for predictions of resistance prevalence, which may affect decision-making. We conducted a systematic review of published mathematical models to determine the modelling landscape and to explore methods for including bacterial heterogeneity. Our first objective was to identify and analyse the general characteristics of mathematical models of DR-mycobacteria, including M. tuberculosis. The second objective was to analyse methods of including bacterial heterogeneity in these models. We had different definitions of heterogeneity depending on the model level. For between-host models of mycobacterium, heterogeneity was defined as any model where bacteria of the same resistance level were further differentiated. For bacterial population models, heterogeneity was defined as having multiple distinct resistant populations. The search was conducted following PRISMA guidelines in five databases, with studies included if they were mechanistic or simulation models of DR-mycobacteria. We identified 195 studies modelling DR-mycobacteria, with most being dynamic transmission models of non-treatment intervention impact in M. tuberculosis (n = 58). Studies were set in a limited number of specific countries, and 44% of models (n = 85) included only a single level of "multidrug-resistance (MDR)". Only 23 models (8 between-host) included any bacterial heterogeneity. Most of these also captured multiple antibiotic-resistant classes (n = 17), but six models included heterogeneity in bacterial populations resistant to a single antibiotic. Heterogeneity was usually represented by different fitness values for bacteria resistant to the same antibiotic (61%, n = 14). A large and growing body of mathematical models of DR-mycobacterium is being used to explore intervention impact to support policy as well as theoretical explorations of resistance dynamics. However, the majority lack bacterial heterogeneity, suggesting that important evolutionary effects may be missed.

The global impact of household contact management for children on multidrug-resistant and rifampicin-resistant tuberculosis cases, deaths, and health-system costs in 2019: a modelling study.

BACKGROUND: Estimates suggest that at least 30 000 children develop multidrug-resistant or rifampicin-resistant tuberculosis each year. Despite household contact management (HCM) being widely recommended, it is rarely done. METHODS: We used mathematical modelling to evaluate the potential country-level and global effects and cost-effectiveness of multidrug-resistant or rifampicin-resistant tuberculosis HCM for children younger than 15 years who are living with a person with newly diagnosed multidrug-resistant or rifampicin-resistant tuberculosis. We compared a baseline of no HCM with several HCM strategies and tuberculosis preventive therapy regimens, calculating the effect on multidrug-resistant or rifampicin-resistant tuberculosis cases, deaths, and health-system costs. All HCM strategies involved the screening of children for prevalent tuberculosis disease but with tuberculosis preventive therapy either not given or targeted dependent on age, HIV status, and result of tuberculin skin test. We evaluated the use of fluoroquinolones (ie, levofloxacin and moxifloxacin), delamanid, and bedaquiline as tuberculosis preventive therapy. FINDINGS: Compared with a baseline without HCM, HCM for all adults diagnosed with multidrug-resistant or rifampicin-resistant tuberculosis in 2019 would have entailed screening 227 000 children (95% uncertainty interval [UI]: 205 000-252 000) younger than 15 years globally, and averted 2350 tuberculosis deaths (1940-2790), costing an additional US$63 million (74-95 million). If all the children within the household who had been in contact with the person with multidrug-resistant or rifampicin-resistant tuberculosis received tuberculosis preventive therapy with levofloxacin, 5620 incident tuberculosis cases (95% UI 4540-6890) and an additional 1240 deaths (970-1540) would have been prevented. Incremental cost-effectiveness ratios were lower than half of per-capita gross domestic product for most interventions in most countries. Targeting only children younger than 5 years and those living with HIV reduced the number of incident cases and deaths averted, but improved cost-effectiveness. Tuberculosis preventive therapy with delamanid increased the effect, in terms of reduced incidence and mortality, compared with levofloxacin. INTERPRETATION: HCM for patients with multidrug-resistant or rifampicin-resistant tuberculosis is cost-effective in most settings and could avert a substantial proportion of multidrug-resistant or rifampicin-resistant tuberculosis cases and deaths in children globally. FUNDING: UK Medical Research Council.