High rates of multidrug-resistant and rifampicin-resistant tuberculosis among re-treatment cases: where do they come from?

Abstract

Background: Globally 3.9% of new and 21% of re-treatment tuberculosis (TB) cases are multidrug-resistant or rifampicin-resistant (MDR/RR), which is often interpreted as evidence that drug resistance results mainly from poor treatment adherence. This study aims to assess the respective contributions of the different causal pathways leading to MDR/RR-TB at re-treatment.

Methods: We use a simple mathematical model to simulate progression between the different stages of disease and treatment for patients diagnosed with TB. The model is parameterised using region and country-specific TB disease burden data reported by the World Health Organization (WHO). The contributions of four separate causal pathways to MDR/RR-TB among re-treatment cases are estimated: I) initial drug-susceptible TB with resistance amplification during treatment; II) initial MDR/RR-TB inappropriately treated as drug-susceptible TB; III) MDR/RR-TB relapse despite appropriate treatment; and IV) re-infection with MDR/RR-TB.

Results: At the global level, Pathways I, II, III and IV contribute 38% (28-49, 95% Simulation Interval), 44% (36-52, 95% SI), 6% (5-7, 95% SI) and 12% (7-19, 95% SI) respectively to the burden of MDR/RR-TB among re-treatment cases. Pathway II is dominant in the Western Pacific (74%; 67-80 95% SI), Eastern Mediterranean (68%; 60-74 95% SI) and European (53%; 48-59 95% SI) regions, while Pathway I makes the greatest contribution in the American (53%; 40-66 95% SI), African (43%; 28-61 95% SI) and South-East Asian (50%; 40-59 95% SI) regions.

Conclusions: Globally, failure to diagnose MDR/RR-TB at first presentation is the leading cause of the high proportion of MDR/RR-TB among re-treatment cases. These findings highlight the need for contextualised solutions to limit the impact and spread of MDR/RR-TB.

Keywords: Causal pathway; Drug resistance amplification; Inappropriate therapy; Misdiagnosis; Multidrug-resistant tuberculosis; Re-treatment; Tuberculosis.

Fig. 1

Presentation of the model structure and parameters. Parameters correspond to the probability of a patient transitioning to the state at the end of the corresponding arrow if initially in the state at the start of this arrow. The coloured boxes correspond to the outputs that we observe for quantifying the respective contributions of the different pathways to MDR/RR-TB at re-treatment. *‘new TB case’ stands for a patient presenting primary TB disease and who undergoes therapy against TB. Parameter a is the rate of MDR/RR-TB among new TB-cases. Parameter b is the DST coverage in new TB-cases while parameter h stands for the proportion of notified MDR/RR-TB cases that start on second-line regimen. Parameters c and d are the treatment success rates for new DS-TB cases and new MDR/RR-TB cases respectively. Parameter e represents the treatment success rate for MDR/RR-TB treated with first-line regimen. Parameter f is the risk of drug-resistance amplification for a DS-TB patient failing therapy. Parameter g is the proportion of recovered individual who get re-infected with TB. Parameters m and k are the death rate during treatment for DS-TB and MDR/RR-TB patients respectively

Fig. 2

Rates of MDR/RR-TB at re-treatment by WHO region. Blue crosses show the estimates presented in the WHO Global Tuberculosis Report 2015 and vertical blue bars represent the associated 95% confidence intervals. Orange dots show the average model outputs while vertical orange bars represent the 95% central ranges obtained from the uncertainty analysis. WHO regions are designated as following: African region (AFR), American region (AMR), Eastern Mediterranean region (EMR), European region (EUR), South East Asian region (SEAR), Western Pacific region (WPR) and Global region (GLOBAL)

Fig. 3

Contributions of the different causal pathways leading to MDR/RR-TB at re-treatment in the seven WHO regions. Results are expressed as percentages of the total burden of MDR/RR-TB at re-treatment. For each region, the mean values and the intervals containing 95% of the values obtained from simulation of 1,000,000 sets of parameters are presented by the bars and the lines respectively. WHO regions are designated as following: African region (AFR), American region (AMR), Eastern Mediterranean region (EMR), European region (EUR), South East Asian region (SEAR), Western Pacific region (WPR) and Global region (GLOBAL)

Fig. 4

Representation of the leading pathway to MDR/RR-TB at re-treatment around the world. Only countries with TB-incidence ≥50 new cases/100,000/year and for which sufficient data was available (see the Methods section for a full description) are represented