Modelling tuberculosis drug resistance amplification rates in high-burden settings

Background: Antimicrobial resistance develops following the accrual of mutations in the bacterial genome, and may variably impact organism fitness and hence, transmission risk. Classical representation of tuberculosis (TB) dynamics using a single or two strain (DS/MDR-TB) model typically does not capture elements of this important aspect of TB epidemiology. To understand and estimate the likelihood of resistance spreading in high drug-resistant TB incidence settings, we used molecular understanding to develop a compartmental epidemiological model of Mycobacterium tuberculosis (Mtb) transmission. Methods: A four-strain (drug-susceptible (DS), isoniazid mono-resistant (INH-R), rifampicin mono-resistant (RIF-R) and multidrug-resistant (MDR)) compartmental deterministic Mtb transmission model was developed to explore the progression from DS- to MDR-TB. The model incorporated strain-specific fitness costs and was calibrated using data from national tuberculosis prevalence surveys and drug resistance surveys from Philippines and Viet Nam. Using an adaptive Metropolis algorithm, we estimated drug resistance amplification and transmission rates. Results: The posterior estimates for the proportion of isoniazid mono-resistant amplification among treatment failure was 0.75 (0.64 - 0.85) for Philippines and 0.55 (0.39 - 0.63) for Viet Nam. The proportion of rifampicin mono-resistant amplification among treatment failure was 0.05 (0.04 - 0.06) for Philippines and 0.011 (0.010 - 0.012) for Viet Nam. In Philippines, the estimated proportion of primary resistance resulting from transmission was 56% (42 - 68) for INH-R, 48% (34 - 62) for RIF-R and 42% (34 - 50) for MDR-TB. For Viet Nam, the estimated proportion of drug resistance due to transmission was 79% (70 - 86) for INH-R, 68% (58 - 75) for RIF-R and 50% (45 - 53) for MDR-TB. Discussion: RIF-R strains were more likely to be transmitted than acquired through amplification, while both mechanisms of acquisition were important contributors in the case of INH-R. These findings highlight the complexity of drug resistance dynamics in high-incidence settings, and emphasize the importance of prioritizing testing algorithms which also allow for early detection of INH-R.