Abstract
Transmitted drug resistance (TDR) poses a growing challenge to HIV control, particularly in highly mobile urban settings with complex transmission dynamics. We analyzed HIV-1 pol sequences from 7,538 newly diagnosed, treatment-naïve individuals in Shanghai (2018-2024), integrating genotypic resistance testing, molecular transmission network analysis, and time-scaled discrete phylogeographic inference. Individuals with Shanghai hukou were classified as Shanghai residents, whereas those without Shanghai hukou were categorized by residence as resident migrants (residing in Shanghai) or temporary migrants (residing outside Shanghai). Overall TDR prevalence was 5.1% (95% CI: 4.6%-5.6%), and was higher among individuals with recent infections (7.3%, 95% CI: 5.6%-9.5%; P = 0.004). Non-nucleoside reverse transcriptase inhibitors (NNRTIs)-associated resistance increased significantly over the study period (adjusted P = 0.009) driven primarily by K103N/S. In multivariable analysis, TDR was independently associated with recent infection (AOR = 1.66) and resident migrant status (AOR = 1.31). TDR sequences exhibited significant non-random clustering across transmission networks (P < 0.001), with 59.2% of networked TDR sequences concentrated in 2.7% of transmission clusters. Phylogeographic analyses indicated substantial cross-population linkages of TDR-associated lineages, with both temporary and resident migrants contributing disproportionately to TDR introduction. Resident migrants showed substantial network participation (44.1%), were overrepresented in TDR transmission clusters (78.9%), and disproportionately involved in TDR-TDR edges (74.3%), suggesting they may facilitate connectivity between non-local and local transmission networks. These findings support a structured pattern of TDR dissemination and highlight the role of population mobility in cross-population TDR dynamics, informing targeted surveillance in highly mobile urban settings.