MDR-TB treatment as prevention: The projected population-level impact of expanded treatment for multidrug-resistant tuberculosis

Abstract

Background: In 2013, approximately 480,000 people developed active multidrug-resistant tuberculosis (MDR-TB), while only 97,000 started MDR-TB treatment. We sought to estimate the impact of improving access to MDR-TB diagnosis and treatment, under multiple diagnostic algorithm and treatment regimen scenarios, on ten-year projections of MDR-TB incidence and mortality.

Methods: We constructed a dynamic transmission model of an MDR-TB epidemic in an illustrative East/Southeast Asian setting. Using approximate Bayesian computation, we investigated a wide array of potential epidemic trajectories consistent with current notification data and known TB epidemiology.

Results: Despite an overall projected decline in TB incidence, data-consistent simulations suggested that MDR-TB incidence is likely to rise between 2015 and 2025 under continued 2013 treatment practices, although with considerable uncertainty (median 17% increase, 95% Uncertainty Range [UR] -38% to +137%). But if, by 2017, all identified active TB patients with previously-treated TB could be tested for drug susceptibility, and 85% of those with MDR-TB could initiate MDR-appropriate treatment, then MDR-TB incidence in 2025 could be reduced by 26% (95% UR 4-52%) relative to projections under continued current practice. Also expanding this drug-susceptibility testing and appropriate MDR-TB treatment to treatment-naïve as well as previously-treated TB cases, by 2020, could reduce MDR-TB incidence in 2025 by 29% (95% UR 6-55%) compared to continued current practice. If this diagnosis and treatment of all MDR-TB in known active TB cases by 2020 could be implemented via a novel second-line regimen with similar effectiveness and tolerability as current first-line therapy, a 54% (95% UR 20-74%) reduction in MDR-TB incidence compared to current-practice projections could be achieved by 2025.

Conclusions: Expansion of diagnosis and treatment of MDR-TB, even using current sub-optimal second-line regimens, is expected to significantly decrease MDR-TB incidence at the population level. Focusing MDR diagnostic efforts on previously-treated cases is an efficient first-step approach.

Fig 1. Model structure.

Simplified diagram of modeled compartments. Separate compartments for never-treated and previously-treated individuals and for DS and MDR-TB at each stage are included in the model but not shown here. Also not shown: mortality (occurs at an increased rate during active disease) and spontaneous self-cure (can occur from any active disease or treatment compartment).

Fig 2. Model projections for East/Southeast Asian TB epidemic assuming continuation of current practice.

Simulations are fitted to notification data for Vietnam through year 2013. Median and uncertainty ranges among the data-consistent projections are shown through year 2025, assuming unchanged diagnostic and treatment practices. The model assumes decline over time in the number of transmissions per infectious person-year, and therefore total TB incidence falls (panel A), but the fraction of both new and previously-treated patients who present to care with MDR-TB continues to rise (panel B), and MDR-TB incidence (panel C) and mortality (panel D) also rise until at least 2025 in the majority of data-consistent simulations.

Fig 3. Impact of expanded drug-resistance diagnosis and second-line treatment availability.

Under the intervention, use of drug susceptibility testing for previously-treated patients increases linearly from current levels in 2015 to 100% in 2017, and individuals found to have MDR-TB start second-line treatment, with allowance for 15% initial loss to follow up. Median and 95% uncertainty range values of MDR-TB incidence are shown, with continued current practice (gray) and under the intervention of expanded MDR-TB diagnosis and treatment (black with dotted 95% uncertainty range); their values in 2025 indicated numerically on the right. The outcome of this intervention in year 2025 is compared in Fig 4 with outcomes of other modeled interventions.

Fig 4. Impacts of primary and alternative interventions on multidrug-resistant tuberculosis (MDR-TB) epidemic in 2025.

Drug susceptibility testing is performed either at current levels, or in all retreatment patients implemented (the primary intervention, shown in bold; linear scale-up completed by 2017), or in all patients prior to initial treatment (linear scale-up completed by 2020). Enrollment on appropriate MDR-TB treatment occurs either at current levels, or in 85% of diagnosed patients (allowing typical initial loss to follow up), or in 100% of diagnosed patients. For the “improved second-line regimen”, for MDR-TB patients’ adherence, cure, relapse, and time to non-infectiousness are equivalent to the standard first-line regimen outcomes for drug-susceptible TB patients. Error bars represent 95% uncertainty ranges among model simulations.

Fig 5. Multivariable sensitivity analysis.

Partial rank correlation coefficients > 0 indicate that as the parameter of interest increases (after correction for the other parameters), the projected absolute MDR-TB incidence in 2025 under current practice increases (panel A), or the magnitude of the reduction in MDR-TB incidence under the primary intervention (85% MDR treatment coverage among retreatment patients) increases (panel B). Negative values likewise reflect negative correlation between parameter and output. “Relative rate of decline in MDR strain transmission” refers to the decrease in MDR-TB transmissions per infectious person-time, as DS-TB transmissions decrease to model declining TB incidence (methods are described further in S1 Text).