Cost-Effectiveness of Targeted Next-Generation Sequencing for Diagnosing Pre-XDR and XDR Tuberculosis in Rifampicin-Resistant Patients Across High-Burden Settings

Objectives To evaluate whether targeted next-generation sequencing (tNGS)-alone or in combination with phenotypic drug susceptibility testing (pDST)-is cost-effective for diagnosing pre-extensively drug-resistant and extensively drug-resistant tuberculosis (pre-XDR/XDR-TB) in rifampicin-resistant tuberculosis (RR-TB) patients across South Africa, India, and Georgia, and to quantify mortality reduction from earlier treatment initiation enabled by rapid molecular diagnostics. Methods We developed a decision-analytic model combining a short-term decision tree with a 10-year Markov model to simulate outcomes in a hypothetical RR-TB cohort. Three diagnostic strategies were compared: pDST, tNGS, and tNGS+pDST. Outcomes included costs, quality-adjusted life years (QALYs), early treatment initiation, TB-related mortality, and incremental cost-effectiveness ratios (ICERs). Cost-effectiveness was assessed against country-specific willingness-to-pay (WTP) thresholds. Sensitivity analyses were conducted to characterize uncertainty. Results Tngs-based strategies improved early treatment initiation (South Africa: +9.8%; India: +19.1%; Georgia: +29.6%) and reduced mortality across all settings. In South Africa, tNGS was cost-effective (ICER, $2805/QALY). In Georgia, the combination strategy was cost-effective (ICER, $6361/QALY). In India, neither tNGS (ICER, $4453/QALY) nor the combination strategy (ICER, $6198/QALY) met the WTP threshold; tNGS would require cost reduction to ≤$116/test. The HR, for delayed treatment and tNGS cost were primary ICER drivers. Probabilistic analysis confirmed robustness, with tNGS cost-effective in 58% of simulations in South Africa and the combination strategy in 42% in Georgia. Conclusions Tngs is cost-effective in South Africa and Georgia when the survival benefit of earlier treatment initiation is accounted for. In India, tNGS pricing exceeds affordability thresholds, necessitating cost reductions and targeted deployment. These findings provide context-specific guidance for national TB programs.