Study setting
The prospective cohort study was conducted from January 1, 2021, to December 31, 2022, across 13 municipal tuberculosis-designated medical hospitals in Jiangsu Province, China. This study enrolled patients with drug susceptibility testing-confirmed MDR/RR-TB, who were subsequently allocated to one of four World Health Organization-recommended treatment regimens based on comprehensive clinical assessment, prior anti-tuberculosis treatment history, and second-line drug resistance profiles2,19,20. Short-term treatment regimens: 4–6 Am-Mfx-Pto-Cfz-E-Z-HINH/5 Mfx-Cfz-E-Z; New long-term oral regimen: 6 Lfx (Mfx)-Lzd-Cfz-Cs-Z (E, Pto)/12–14 Lfx (Mfx)-Cfz-Cs-Z (E, Pto); and new long-term injectable regimens: 6 Mfx (Lfx)-Lzd-Cfz (Cs)-Am-P-to-Z (E)/12 Mfx (Lfx)-Cfz (Cs)-Pto-Z (E); and traditional long-term regimens: 6 Cm (Am)-Lfx (Mfx)-Pto (PAS, E)-Cs (PAS, E)-Z/18 Lfx (Mfx) – Pto (PAS, E) – Cs (PAS, E) – Z21.
Study population
All eligible individuals meeting the following criteria were enrolled in this cohort: (1) diagnosis of MDR-TB or RR-TB; (2) age ≥ 15 years; (3) availability of sputum specimens for Mycobacterium tuberculosis (MTB) testing; (4) provision of written informed consent. Exclusion criteria comprised: (1) current hepatic, renal, metabolic, autoimmune, endocrine, or malignant diseases; (2) hematological dysfunction, long-term immunosuppressant use, or HIV/AIDS; (3) psychiatric or epilepsy history; (4) pregnancy or lactation; (5) refusal to provide informed consent, as previously described21; the research flowchart is presented in Fig. 1.
The flowchart of treatment outcomes for MDR/RR-TB patients.
Outcome definition
The primary outcome was treatment success versus adverse outcomes, defined per WHO guidelines22. Treatment success represents the composite of cured patients and those achieving treatment completion. Specifically, cured denotes pulmonary tuberculosis patients with bacteriologically confirmed TB at baseline who completed treatment per national policy while demonstrating bacteriological response without evidence of failure. Treatment completion describes patients who fulfilled the national treatment protocol without meeting criteria for either cure or failure. The sputum culture of successfully treated patients turns negative at least before the enhancement period (6 months). Conversely, adverse outcomes encompass four categories: treatment failure, meaning regimens requiring permanent termination or fundamental strategy alteration; death, covering mortality occurring Original treatment initiation or during therapy; loss to follow-up, defined as either never starting treatment or experiencing treatment interruption lasting two consecutive months or longer; and not evaluated, referring to patients lacking any outcome assignment. Patients underwent monthly follow-ups during the intensive treatment phase and bimonthly follow-ups during the continuation phase, with qualitative assessments conducted using structured questionnaires.
Study definitions
Patients were classified based on drug susceptibility testing results as either RR-TB or MDR-TB; RR-TB was defined as resistance to rifampicin alone, whereas MDR-TB was characterized by resistance to at least two first-line anti-tuberculosis drugs, including isoniazid and rifampicin, simultaneously. Additionally, patients were categorized according to treatment history as either primary or retreatment cases. Primary treatment cases included individuals who had never received anti-tuberculosis drug therapy or had undergone an incomplete course of a standard chemotherapy regimen (i.e., less than one month of irregular chemotherapy). Retreatment cases were defined as those who had either received inappropriate or irregular anti-tuberculosis treatment for ≥ 1 month, experienced treatment failure, or relapsed following prior therapy1,23.
Adverse reactions
Adverse events (AEs) were stratified by severity using the National Institute of Allergy and Infectious Diseases Division of AIDS (NIAID DAIDS) grading system, while serious adverse events (SAEs) were assessed using the Common Terminology Criteria for Adverse Events version, which defines severity as follows: Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe or medically significant but not immediately life-threatening), Grade 4 (Life-threatening; requiring urgent intervention), and Grade 5 (Death related to adverse event)23,24.
Cost evaluation
Direct cost, also known as total costs (TC) included direct medical expenses(DME) (registration, consultation, hospitalization, investigation, or medication) and non-medical (food, travel, and nutritional supplements). Indirect costs included overall loss of wages due to productivity loss, missed work, loss of time, loss of income, and caregiving work25. Medical expense reimbursement (MER) was the portion of DME covered by insurance or reimbursement schemes, and remaining DME was the out of pocket expenses (OOPs)21. Costs were primarily sourced from hospital billing records, supplemented by patient self-reports for out-of-pocket expenses. Self-reported data underwent cross-referencing with medical bills, consistency checks via follow-up calls.
The dependent and independent variables
The dependent variable was treatment outcome, categorized dichotomously as successful treatment or unsuccessful treatment. Independent variables encompassed demographic factors (age, sex, educational levels, BMI, registered residence); tuberculosis-related factors (treatment regimens, drug resistance results, adverse reaction, symptom, therapeutic category, delayed treatment); socioeconomic impacts (impact on life, subsistence, divorce or separation, unemployment, interruption of studies, social discrimination, other effects); along with economic burden measures (DME, MER, OOPs, direct non-medical expenses, TC).
Statistical analysis
Data were collected via structured questionnaires, collated in Microsoft Excel, and analyzed using SPSS 23.0. All patient identifiers were removed prior to analysis to ensure anonymization and protect patient privacy. Descriptive statistics were computed for all study variables. Categorical variables are presented as frequencies and percentages (n, %), while continuous variables—summarized using medians with interquartile range (IQR)—are reported as median (IQR). The Chi-square test or Fisher’s exact test was used for categorical data comparison, and the Mann-Whitney U test was applied to continuous data, according to the overall non-normal distribution. Correlation analysis was conducted using Pearson’s and Spearman’s correlation coefficients, and correlation heatmaps were generated using the ggcorrplot package in R. Multicollinearity was diagnosed based on correlation coefficients, tolerance values (> 0.1), and variance inflation factors (VIF P ≤ 0.05 considered statistically significant.
Ethical approval
The study involving human participants were conducted in accordance with the ethical standards of the Helsinki Declaration and received ethical approval from the Ethics Committee of Jiangsu Provincial Center for Disease Control and Prevention (Ethics Approval No. JSJK2023-B022-01). Financial support was provided by the Jiangsu Provincial Health Commission Scientific Research Project (Grant/Award Number: MQ2024008). Experimental protocols were performed in compliance with relevant institutional guidelines and regulatory requirements, with informed consent obtained from all participants.
