Phylogeography and transmission of M. tuberculosis in Moldova

Abstract

Background The incidence of multidrug-resistant tuberculosis (MDR-TB) remains critically high in countries of the former Soviet Union, where >20% of new cases and >50% of previously-treated cases have resistance to rifampin and isoniazid. Transmission of resistant strains, as opposed to resistance selected through inadequate treatment of drug-susceptible TB, is the main driver of incident MDR-TB in these countries. Methods We conducted a prospective, genomic analysis of all culture-positive TB cases diagnosed in 2018 and 2019 in the Republic of Moldova. We used phylogenetic methods to identify putative transmission clusters; spatial and demographic data were analyzed to further describe local transmission of M. tuberculosis. Results Of 2236 participants, 779 (36%) had MDR-TB, of whom 386 (50%) had never been treated previously for TB. 92% of MDR M. tuberculosis strains belonged to putative transmission clusters. Phylogenetic reconstruction identified three large clades that were comprised nearly uniformly of MDR-TB; two of these clades were of Beijing lineage and one of Ural lineage, and each had additional distinct clade-specific second-line drug resistance mutations and geographic distributions. Spatial and temporal proximity between pairs of cases within a cluster was associated with greater genomic similarity. Conclusions The MDR-TB epidemic in Moldova is the result of local transmission of multiple M. tuberculosis strains, including distinct clades of highly drug-resistant M. tuberculosis with varying geographic distributions and drug resistance profiles. This study demonstrates the role of comprehensive genomic surveillance for understanding the transmission of M. tuberculosis and highlights the urgency of interventions to interrupt transmission of highly drug-resistant M. tuberculosis.

Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis: a mathematical modeling analysis

“…tuberculosis whole genomic sequencing data from Moldova [30,35]. All those observations with rifampicin susceptibility were excluded, as per S3 Fig.…”

“…Exclusions made to the genomic sequencing drug susceptibility testing dataset are shown along with the number of observations. This dataset is described elsewhere [30,35]. The presence of a mutation conferring resistance to rifampicin was assumed to convey full resistance, and vice versa.…”

“…To estimate outcomes, we used a Markov microsimulation model parameterized with detailed genomic sequencing data describing specific patterns of initial drug resistance, and calculated the effect of each treatment strategy on length and quality of life, accounting for regimen effectiveness, risks of severe adverse events (SAEs) due to drug toxicity, and acquisition of resistance. We conducted the analysis for the setting of Moldova, a country with a high proportion of TB strains resistant to first-and second-line drugs, 16,17 and explored the generalizability of findings to settings with a different prevalence of initial fluoroquinolone resistance.…”

“…19 These data were collected in 2018-2019, and a full description has been provided by Yang and colleagues. 17 We assumed that there was only one strain of M. tuberculosis per individual (i.e., that there were no mixed infections) and that a mutation associated with resistance conferred full resistance to that drug. M. tuberculosis strains lacking relevant resistance mutations were assumed to be fully susceptible to the respective drugs.…”

“…We conducted the analysis for the setting of Moldova, an upper-middle income post-Soviet country where the incidence rate of RR-TB is among the highest in the world, and where an estimated 33% of individuals newly diagnosed with TB have RR-TB, ten times higher than the same proportion globally [29,30]. The reasons for this picture are not fully understood, but it is thought that economic shocks following the breakup of the Soviet Union contributed to this picture in the region, along with early treatment discontinuation [31] and mass incarceration [32].…”