Transmission of rifampicin-resistant tuberculosis in Ho Chi Minh City, Viet Nam: a prospective genomic epidemiology study

Summary Background Rifampicin-resistant tuberculosis (RR-TB) is a major threat to public health in Viet Nam, with nearly 10,000 incident cases estimated annually. It is uncertain whether these cases are driven by transmission of resistant strains or de novo resistance acquisition during treatment. Methods We undertook dense, city-wide sampling of adults newly diagnosed with pulmonary RR-TB in Ho Chi Minh City, Viet Nam’s largest city, between March 2020 and April 2024. Participants provided sputum for culture and whole-genome sequencing (WGS), and demographic and clinical data were collected at enrolment. Phylogenetic analyses were combined with clinical histories to infer transmitted versus acquired rifampicin resistance. Estimates were corrected for sampling coverage using simulation-extrapolation (SIMEX). Temporal emergence of rifampicin resistance was reconstructed by lineage using Bayesian phylogenetic dating, and the geographic and demographic structure of transmission networks was assessed using geocoded residential data and commute time-based analyses. Findings Among 2,319 RR-TB cases diagnosed during the study period, 1,491 (64%) isolates were successfully sequenced. After accounting for sampling and phylogenetic uncertainty, we estimated that between 72% and 87% of all RR-TB arose through transmission of already-resistant strains with the remainder due to de novo acquired resistance. Bayesian dating analyses revealed that resistance emergence events occurred repeatedly from the 1980s to the present, with early events seeding long-lived, city-wide transmission networks. Transmission networks were geographically dispersed across the city, with limited household clustering, and only weakly structured by host demographics, consistent with diffuse, city-wide transmission rather than localised or assortative spread. Interpretation RR-TB in Ho Chi Minh City is driven predominantly by ongoing transmission, but a substantial minority of cases arise from newly acquired resistance. Alongside promoting early diagnosis and treatment to interrupt transmission, the main drivers of acquired resistance need to be identified to control RR-TB. Funding The Rhodes Trust, Wellcome. Research in context Evidence before this study We searched PubMed from database inception up to November 2025 for studies describing the transmission and acquisition of multidrug /rifampicin-resistant tuberculosis (MDR/RR-TB), using terms including “tuberculosis”, “rifampicin resistance”, “multidrug resistance”, “genomic epidemiology”, “whole-genome sequencing”, “transmission” and “acquired resistance”. We additionally added terms “Ho Chi Minh City” and “Viet Nam” to identify results specific our study setting. Previous studies from high burden settings typically reported that MDR/RR-TB isolates clustered with high proportions, suggesting transmission is the major contributor to MDR/RR-TB burden. However, estimates varied widely across settings, study designs and analytic approaches. Many studies relied on SNP-based clustering thresholds and did not account for incomplete sampling. Few studies integrated treatment history and homoplasy-aware phylogenetic inference or accounted for uncertainty in their estimates of the population-level contribution of de novo rifampicin resistance acquisition. No studies from Viet Nam addressed this question and the extent to which transmitted and acquired resistance contribute to the burden of MDR/RR-TB remains unknown. Added value of this study We combined dense, city-wide sampling of RR-TB in a high-burden metropolitan setting with whole-genome sequencing, historic genomic context and phylogenetic analyses to quantify the contributions of transmission and de novo acquisition to MDR/RR-TB burden. By integrating phylogenetic placement of resistance mutations with individual treatment history, we provide robust population-level estimates of transmission and independent resistance emergence while explicitly accounting for phylogenetic and sampling uncertainty. Acknowledging the potential effect of sampling coverage on these estimates, we further provide estimates extrapolated to complete coverage using a simulation-extrapolation framework. We show that the majority of RR-TB in Ho Chi Minh City is attributable to transmission, but that a substantial minority of cases reflect de novo acquisition of rifampicin resistance. Our findings demonstrate that de novo resistance acquisition continues to occur notwithstanding improvements in programmatic TB control, treatment success rates, and diagnostic capacity. Implications of all of the available evidence Our findings emphasise that MDR/RR-TB in Ho Chi Minh City is overwhelmingly driven by transmission and that controlling it requires a transmission-focused response. Intensified efforts to interrupt transmission through earlier case detection and rapid treatment initiation should be programmatic priorities. Concurrently, further investigation into the precise drivers of acquired drug resistance, which represents a potentially preventable fraction of the RR-TB burden, remains warranted