Multidrug-resistant Tuberculosis In China Research Articles

A pragmatic randomized controlled trial to evaluate the efficacy and safety of an oral short-course regimen including bedaquiline for the treatment of patients with multidrug-resistant tuberculosis in China: study protocol for PROSPECT

IntroductionThe lack of safe, effective, and simple short-course regimens (SCRs) for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment has significantly impeded TB control efforts in China.MethodsThis phase 4, randomized, open-label, controlled, non-inferiority trial aims to assess the efficacy and safety of a 9-month all-oral SCR containing bedaquiline (BDQ) versus an all-oral SCR without BDQ for adult MDR-TB patients (18–65 years) in China. The trial design mainly mirrors that of the “Evaluation of a Standardized Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB” (STREAM) stage 2 study, while also incorporating programmatic data from South Africa and the 2019 consensus recommendations of Chinese MDR/RR-TB treatment experts. Experimental arm participants will receive a modified STREAM regimen C that replaces three group C drugs, ethambutol (EMB), pyrazinamide (PZA), and prothionamide (PTO), with two group B drugs, linezolid (LZD) and cycloserine (CS), while omitting high-dose isoniazid (INH) for confirmed INH-resistant cases. BDQ duration will be extended from 6 to 9 months for participants with Mycobacterium tuberculosis-positive sputum cultures at week 16. The control arm will receive a modified STREAM regimen B without high-dose INH and injectable kanamycin (KM) that incorporates experimental arm LZD and CS dosages, treatment durations, and administration methods. LZD (600 mg) will be given daily for ≥ 24 weeks as guided by observed benefits and harm. The primary outcome measures the proportion of participants with favorable treatment outcomes at treatment completion (week 40), while the same measurement taken at 48 weeks post-treatment completion is the secondary outcome. Assuming an α = 0.025 significance level (one-sided test), 80% power, 15% non-inferiority margin, and 10% lost to follow-up rate, each arm requires 106 participants (212 total) to demonstrate non-inferiority.DiscussionPROSPECT aims to assess the safety and efficacy of a BDQ-containing SCR MDR-TB treatment at seventeen sites across China, while also providing high-quality data to guide SCRs administration under the direction of the China National Tuberculosis Program for MDR-TB. Additionally, PROSPECT will explore the potential benefits of extending the administration of the 9-month BDQ-containing SCR for participants without sputum conversion by week 16.Trial registrationClinicalTrials.gov NCT05306223. Prospectively registered on 16 March 2022 at https://clinicaltrials.gov/ct2/show/NCT05306223?term=NCT05306223&draw=1&rank=1 {2}.

Transmission of Fluoroquinolones Resistance among Multidrug-Resistant Tuberculosis in Shanghai, China: A Retrospective population-based Genomic Epidemiology Study

ABSTRACT Fluoroquinolones (FQ) are essential for the treatment of multidrug-resistant tuberculosis (MDR-TB). The FQ resistance (FQ-R) rate in MDR-TB in China and its risk factors remain poorly understood. We conducted a retrospective, population-based genomic epidemiology study of MDR-TB patients in Shanghai, China, from 2009 to 2018. A genomic cluster was defined as strains with genetic distances ≤ 12 single nucleotide polymorphisms. The transmitted FQ-R was defined as the same FQ resistance-conferring mutations shared by ≥ 2 strains in a genomic cluster. We used multivariable logistic regression analysis to identify the risk factors for drug resistance. Among the total 850 MDR-TB patients included in the study, 72.8% (619/850) were male, the median age was 39 (interquartile range 28, 55) years, 52.7% (448/850) were migrants, and 34.5% (293/850) were previously treated patients. Most of the MDR-TB strains belong to the Beijing lineage (91.7%, 779/850). Overall, the genotypic resistance rate of FQ was 34.7% (295/850), and 47.1% (139/295) FQ-R patients were in genomic clusters, of which 98 (33.2%, 98/295) were presumed as transmitted FQ-R. Patients with treatment-naïve (aOR = 1.84; 95% CI: 1.09, 3.16), diagnosed in a district-level hospital (aOR = 2.69; 95% CI: 1.56, 4.75), and streptomycin resistance (aOR = 3.69; 95% CI: 1.65, 9.42) were significantly associated with the transmission of FQ-R. In summary, the prevalence of FQ-R among MDR-TB patients was high in Shanghai, and at least one-third were transmitted. Enforced interventions including surveillance of FQ drug susceptibility testing and screening among MDR-TB before initiation of treatment were urgently needed.

Insight into the drug-resistant characteristics and genetic diversity of multidrug-resistant Mycobacterium tuberculosis in China.

Multidrug-resistant tuberculosis (MDR-TB) has a severe impact on public health. To investigate the drug-resistant profile, compensatory mutations and genetic variations among MDR-TB isolates, a total of 546 MDR-TB isolates from China underwent drug-susceptibility testing and whole genome sequencing for further analysis. The results showed that our isolates have a high rate of fluoroquinolone resistance (45.60%, 249/546) and a low proportion of conferring resistance to bedaquiline, clofazimine, linezolid, and delamanid. The majority of MDR-TB isolates (77.66%, 424/546) belong to Lineage 2.2.1, followed by Lineage 4.5 (6.41%, 35/546), and the Lineage 2 isolates have a strong association with pre-XDR/XDR-TB (P < 0.05) in our study. Epidemic success analysis using time-scaled haplotypic density (THD) showed that clustered isolates outperformed non-clustered isolates. Compensatory mutations happened in rpoA, rpoC, and non-RRDR of rpoB genes, which were found more frequently in clusters and were associated with the increase of THD index, suggesting that increased bacterial fitness was associated with MDR-TB transmission. In addition, the variants in resistance associated genes in MDR isolates are mainly focused on single nucleotide polymorphism mutations, and only a few genes have indel variants, such as katG, ethA. We also found some genes underwent indel variation correlated with the lineage and sub-lineage of isolates, suggesting the selective evolution of different lineage isolates. Thus, this analysis of the characterization and genetic diversity of MDR isolates would be helpful in developing effective strategies for treatment regimens and tailoring public interventions. IMPORTANCE Multidrug-resistant tuberculosis (MDR-TB) is a serious obstacle to tuberculosis prevention and control in China. This study provides insight into the drug-resistant characteristics of MDR combined with phenotypic drug-susceptibility testing and whole genome sequencing. The compensatory mutations and epidemic success analysis were analyzed by time-scaled haplotypic density (THD) method, suggesting clustered isolates and compensatory mutations are associated with MDR-TB transmission. In addition, the insertion and deletion variants happened in some genes, which are associated with the lineage and sub-lineage of isolates, such as the mpt64 gene. This study offered a valuable reference and increased understanding of MDR-TB in China, which could be crucial for achieving the objective of precision medicine in the prevention and treatment of MDR-TB.

Cost-Effectiveness Analysis of Combined Chemotherapy Regimen Containing Bedaquiline in the Treatment of Multidrug-Resistant Tuberculosis in China*

ObjectiveThis study aims to estimate the cost-effectiveness of the combined chemotherapy regimen containing Bedaquiline (BR) and the conventional treatment regimen (CR, not containing Bedaquiline) for the treatment of adults with multidrug-resistant tuberculosis (MDR-TB) in China. MethodsA combination of a decision tree and a Markov model was developed to estimate the cost and effects of MDR patients in BR and CR within ten years. The model parameter data were synthesized from the literature, the national TB surveillance information system, and consultation with experts. The incremental cost-effectiveness ratio (ICER) of BR vs. CR was determined. ResultsBR (vs. CR) had a higher sputum culture conversion rate and cure rate and prevented many premature deaths (decreased by 12.8%), thereby obtaining more quality-adjusted life years (QALYs) (increased by 2.31 years). The per capita cost in BR was as high as 138,000 yuan, roughly double that of CR. The ICER for BR was 33,700 yuan/QALY, which was lower than China’s 1× per capita Gross Domestic Product (GDP) in 2020 (72,400 yuan). ConclusionBR is shown to be cost effective. When the unit price of Bedaquiline reaches or falls below 57.21 yuan per unit, BR is expected to be the dominant strategy in China over CR.

Treatment outcomes of multidrug-resistant tuberculosis patients receiving ambulatory treatment in Shenzhen, China: a retrospective cohort study.

WHO recommended multidrug-resistant tuberculosis (MDR-TB) should be treated mainly under ambulatory model, but outcome of ambulatory treatment of MDR-TB in China was little known. The clinical data of 261 MDR-TB patients treated as outpatients in Shenzhen, China during 2010-2015 were collected and analyzed retrospectively. Of 261 MDR-TB patients receiving ambulatory treatment, 71.1% (186/261) achieved treatment success (cured or completed treatment), 0.4% (1/261) died during treatment, 11.5% (30/261) had treatment failure or relapse, 8.0% (21/261) were lost to follow-up, and 8.8% (23/261) were transferred out. The culture conversion rate at 6 months was 85.0%. Although 91.6% (239/261) of patients experienced at least one adverse event (AE), only 2% of AEs caused permanent discontinuation of one or more drugs. Multivariate analysis showed that previous TB treatment, regimens containing capreomycin and resistance to FQs were associated with poor outcomes, while experiencing three or more AEs was associated with good outcomes. Good treatment success rates and early culture conversions were achieved with entirely ambulatory treatment of MDR-TB patients in Shenzhen, supporting WHO recommendations. Advantageous aspects of the local TB control program, including accessible and affordable second-line drugs, patient support, active monitoring and proper management of AEs and well-implemented DOT likely contributed to treatment success rates.

Population pharmacokinetics and model-based dosing evaluation of bedaquiline in multidrug-resistant tuberculosis patients.

Aims: Bedaquiline is now recommended to all patients in the treatment of multidrug-resistant tuberculosis (MDR-TB) using standard dosing regimens. As the ability to measure blood drug concentrations is very limited, little is known about drug exposure and treatment outcome. Thus, this study aimed to model the population pharmacokinetics as well as to evaluate the currently recommended dosage. Methodology: A bedaquiline population pharmacokinetic (PK) model was developed based on samples collected from the development cohort before and 1, 2, 3, 4, 5, 6, 8, 12, 18, and 24h after drug intake on week 2 and week 4 of treatment. In a prospective validation cohort of patients with MDR-TB, treated with bedaquiline-containing standardized regimen, drug exposure was assessed using the developed population PK model and thresholds were identified by relating to 2-month and 6-month sputum culture conversion and final treatment outcome using classification and regression tree analysis. In an exploratory analysis by the probability of target attainment (PTA) analysis, we evaluated the recommended dosage at different MIC levels by Middlebrook 7H11 agar dilution (7H11). Results: Bedaquiline pharmacokinetic data from 55 patients with MDR-TB were best described by a three-compartment model with dual zero-order input. Body weight was a covariate of the clearance and the central volume of distribution, albumin was a covariate of the clearance. In the validation cohort, we enrolled 159 patients with MDR-TB. The 7H11 MIC mode (range) of bedaquiline was 0.06mg (0.008-0.25mg/L). The study participants with AUC0-24h/MIC above 175.5 had a higher probability of culture conversion after 2-month treatment (adjusted relative risk, aRR:16.4; 95%CI: 5.3-50.4). Similarly, those with AUC0-24h/MIC above 118.2 had a higher probability of culture conversion after 6-month treatment (aRR:20.1; 95%CI: 2.9-139.4), and those with AUC0-24h/MIC above 74.6 had a higher probability of successful treatment outcome (aRR:9.7; 95%CI: 1.5-64.8). Based on the identified thresholds, simulations showed that the WHO recommended dosage (400mg once daily for 14 days followed by 200mg thrice weekly) resulted in PTA >90% for the majority of isolates (94%; MICs ≤0.125mg/L). Conclusion: We established a population PK model for bedaquiline in patients with MDR-TB in China. Based on the thresholds and MIC distribution derived in a clinical study, the recommended dosage of bedaquiline is sufficient for the treatment of MDR-TB.

A meta-analysis of risk factors for multidrug-resistant tuberculosis in China

Objective: To explore the main risk factors of multidrug-resistant tuberculosis (MDR-TB) in China and to provide evidence-based evidence for MDR-TB preventon and control. Methods: All relevant literatures were searched in thedatabases, such as Pubmed, Web of Science and CNKI, Wanfang, VIP and SinoMed from 2000 to 2021. Quality evaluation and data extraction were carried out, and then a meta-analysis was performed using Stata 16.0 software. Results: A total of 59 literatures (36 cross-sectional and 23 case-control) including 75 793 participants were included in this study, and meta-analysis results showed age (OR=1.27, 95%CI: 1.05-1.54), education level (OR=1.29, 95%CI: 1.02-1.65), positive sputum smear (OR=2.56, 95%CI: 1.09-6.04), pulmonary cavity (OR=1.99, 95%CI: 1.57-2.52), course of disease (OR=4.25, 95%CI: 1.95-9.30), history of tuberculosis treatment (OR=6.42,95%CI:5.40-7.63), treatment interruption (OR=2.81, 95%CI: 1.50-5.29), irregular medication (OR=5.02, 95%CI: 2.95-8.54), adverse drug reactions (OR=4.27, 95%CI: 2.22-8.19), combined chronic obstructive pulmonary disease (COPD) (OR=2.21, 95%CI: 1.45-3.37), tuberculosis exposure history (OR=1.99, 95%CI: 1.36-2.91), smoking history (OR=1.35, 95%CI: 1.09-1.66) and floating population (OR=1.60, 95%CI: 1.04-2.44) were associated with the occurrence of MDR-TB. Conclusions: The high risk groups were farmer, low education level, pulmonary cavity, long course of disease, history of tuberculosis treatment, treatment interruption, irregular medication, adverse drug reaction, co-COPD, contact history of tuberculosis, smoking history, rural residence, and floating population. We should pay attention to high-risk groups, strengthen management and take effective measures such as early screening, knowledge education on tuberculosis, standardized and personalized treatment and whole-course supervision.

Emergence of additional drug resistance during treatment of multidrug-resistant tuberculosis in China: a prospective cohort study

ObjectivesLittle is known about how additional second-line drug resistance emerges during multidrug-resistant tuberculosis (MDR-TB) treatment. The present study aimed to investigate the influence of microevolution, exogenous reinfection and mixed infection on second-line drug resistance during the recommended 2-year MDR-TB treatment. MethodsIndividuals with MDR-TB were enrolled between 2013 and 2016 in a multicentre prospective observational cohort study and were followed up for 2 years until treatment completion. Whole-genome sequencing (WGS) was applied for serial Mycobacterium tuberculosis isolates from study participants throughout the treatment, to study the role of microevolution, exogenous reinfection and mixed infection in the development of second-line drug resistance. ResultsOf the 286 enrolled patients with MDR-TB, 63 (22.0%) M. tuberculosis isolates developed additional drug resistance during the MDR-TB treatment, including 5 that fulfilled the criteria of extensively drug-resistant TB. By comparing WGS data of serial isolates retrieved from the patients throughout treatment, 41 (65.1%) of the cases of additional second-line drug resistance were the result of exogenous reinfection, 18 (28.6%) were caused by acquired drug resistance, i.e. microevolution, while the remaining 4 (6.3%) were caused by mixed infections with drug-resistant and drug-susceptible strains. In multivariate analysis, previous TB treatment (adjusted hazard ratio (aHR) 2.51, 95% CI 1.51–4.18), extensive disease on chest X-ray (aHR 3.39, 95% CI 2.03–5.66) and type 2 diabetes mellitus (aHR 4.00, 95% CI 2.22–7.21) were independent risk factors associated with the development of additional second-line drug resistance. ConclusionsA large proportion of additional second-line drug resistance emerging during MDR-TB treatment was attributed to exogenous reinfection, indicating the urgency of infection control in health facilities as well as the need for repeated drug susceptibility testing throughout MDR-TB treatment.

Molecular characterization of multidrug-resistant tuberculosis against levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, and delamanid in southwest of China

ObjectivesTo explore the drug susceptibility of levofloxacin (LFX), moxifloxacin (MFX), bedaquiline (BDQ), linezolid (LZD), clofazimine (CFZ) and delamanid (DLM) against multidrug resistant tuberculosis (MDR-TB) isolates from drug resistance survey of southwest China, and to illustrate the genetic characteristics of MDR-TB isolates with acquired drug resistance.MethodsA total of 339 strains were collected from smear-positive TB patients in the drug resistance survey of southwest China between January 2014 and December 2016. The MICs for the above mentioned drugs were determined for MDR-TB by conventional drug susceptibility testing. Genes related to drug resistance were amplified with their corresponding pairs of primers.ResultsMDR was observed in 88 (26.0%; 88/339) isolates. LFX had the highest resistance rate (50.0%; 44/88), followed by MFX (38.6%; 34/88). The resistance rate to LZD, CFZ, and DLM was 4.5% (4/88), 3.4% (3/88), and 4.5% (4/88), respectively, and the lowest resistance rate was observed in BDQ (2.3%; 2/88). Of the 45 isolates resistant to LFX and MFX, the most prevalent resistance mutation was found in gyrA with the substitution of codon 94 (34/45, 75.6%). Two strains with CFZ - BDQ cross resistance had a mutation in the Rv0678 gene. Of the four LZD resistant isolates, two carried mutations in rplC gene. For the four isolates resistant to DLM, one isolate had mutations in codon 318 of fbiC gene, and two isolates were with mutations in codon 81 of ddn gene.ConclusionThis study provided evidence of the usefulness of new anti-TB drugs in the treatment of MDR-TB in China.

Bedaquiline-containing regimens in patients with pulmonary multidrug-resistant tuberculosis in China: focus on the safety

BackgroundWorld Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis (DR-TB) should develop and implement a system for active pharmacovigilance that allows for detection, reporting and management of adverse events. The aim of the study is to evaluate the frequency and severity of adverse events (AEs) of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-TB based on active drug safety monitoring (aDSM) system of New Drug Introduction and Protection Program (NDIP).MethodsAEs were prospectively collected with demographic, bacteriological, radiological and clinical data from 54 sites throughout China at patient enrollment and during treatment between February, 2018 and December, 2019. This is an interim analysis including patients who are still on treatment and those that have completed treatment. A descriptive analysis was performed on the patients evaluated in the cohort.ResultsBy December 31, 2019, a total of 1162 patients received bedaquiline-containing anti-TB treatment. Overall, 1563 AEs were reported, 66.9% were classified as minor (Grade 1–2) and 33.1% as serious (Grade 3–5). The median duration of bedaquiline treatment was 167.0 [interquartile range (IQR): 75–169] days. 86 (7.4%) patients received 36-week prolonged treatment with bedaquiline. The incidence of AEs and serious AEs was 47.1% and 7.8%, respectively. The most frequently reported AEs were QT prolongation (24.7%) and hepatotoxicity (16.4%). There were 14 (1.2%) AEs leading to death. Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 3.1% (32/1044) experienced a post-baseline QTcF ≥ 500 ms, and 15.7% (132/839) had at least one change of QTcF ≥ 60 ms from baseline. 49 (4.2%) patients had QT prolonged AEs leading to bedaquiline withdrawal. One hundred and ninety patients reported 361 AEs with hepatotoxicity ranking the second with high occurrence. Thirty-four patients reported 43 AEs of hepatic injury referred to bedaquiline, much lower than that referred to protionamide, pyrazinamide and para-aminosalicylic acid individually.ConclusionsBedaquiline was generally well-tolerated with few safety concerns in this clinical patient population without any new safety signal identified. The mortality rate was generally low. These data inform significant positive effect to support the WHO recent recommendations for the wide use of bedaquiline.

Prevalence and molecular characterizations of seven additional drug resistance among multidrug-resistant tuberculosis in China: A subsequent study of a national survey

The drug resistance prevalence data facilitates selection of the initial drug for treating multidrug-resistant tuberculosis (MDR-TB). The aim of this study was to investigate the prevalence and molecular characterization of seven additional types of drug resistances among MDR-TB isolates collected from the first/only nationwide drug resistance surveillance in China. A total of 391 out of the 401 MDR-TB strains were successfully recovered by Löwenstein-Jensen medium. Drug susceptibility testing was performed against moxifloxacin (Mfx), bedaquiline (Bdq), linezolid (Lzd), clofazimine (Cfz), cycloserine (Cs), delamanid (Dlm) and pyrazinamide (PZA). The strains were subjected to whole-genome sequencing for the analysis corresponding drug resistant genes and their profiles. 269 (68.80%) were simple MDR-TB, 28 (7.16%) were extensively drug-resistant tuberculosis (XDR-TB) and 94 (24.04%) were pre-XDR-TB. Dlm, Lzd, Cfz and Bdq presented the lowest drug resistant rates i.e. 3.32% (13/391), 3.84% (15/391),6.65% (26/391) and 7.16% (28/391), respectively. Mfx (17.39%, 68/391) and CS (13.55%, 53/391) also demonstrated strong potencies against the MDR strains, whereas PZA (38.36%, 150/391) presented much higher resistant rate. 54.41% (37/68) Mfx-resistant strains carried mutations located within gyrA or gyrB. 70.15% (94/134) PZA-resistant strains had pncA mutations. Two of the 26 Cfz-resistant isolates had mutation in Rv0678 were also resistant to Bdq. Dlm, Lzd, Cfz and Bdq exhibited excellent activity against MDR-TB, including XDR-TB. These data highlighted the necessity of a timely, feasible and reliable DST, while genotypic DST for Mfx and PZA is promising at this moment.

Analysis of Serial Multidrug-Resistant Tuberculosis Strains Causing Treatment Failure and Within-Host Evolution by Whole-Genome Sequencing.

The cure rate of multidrug-resistant tuberculosis (MDR-TB) is relatively low in China. The reasons for the treatment failure and within-host evolution during treatment have not been sufficiently studied. All MDR-TB patients receiving standard treatment from January 2014 to September 2016 at a designated TB Hospital in Zhejiang Province were retrospectively included and grouped according to their known treatment outcome. Clinical information was collected. Baseline strains of all patients and serial strains of treatment-failure patients were revived. Drug susceptibility tests (DSTs) of 14 drugs and single nucleotide polymorphism (SNP) analysis based on whole-genome sequencing (WGS) were performed. The genetic distance and within-host evolution were investigated based on SNPs. In total, 20 treatment failure patients and 74 patients who succeeded in treatment were included. The number of effective drugs for patients who failed treatment was no more than three. Eighteen (90.0%) treatment-failure patients were characterized by a continuous infection of the primary strain, of which 14 patients (77.8%) developed phenotypic or genotypic acquired drug resistance under ineffective treatment. Acquired resistance to amikacin and moxifloxacin (2.0 mg/ml) was detected most frequently, in 5 and 4 patients, respectively. The insufficient number of effective drugs in the combined treatment regimen was the main reason for MDR-TB treatment failure. The study emphasizes the importance of DST for second-line drugs when implementing the second-line drug regimen in MDR-TB patients. For patients with risk factors for MDR-TB, DST of second-line antituberculosis drugs should be performed at initiation of treatment. Second-line drugs should be selected based on the results of DST to avoid acquired resistance. WGS detects low-frequency resistance mutations and heterogeneous resistance with high sensitivity, which is of great significance for guiding clinical treatment and preventing acquired resistance.IMPORTANCE Few studies have focused on the reasons for the low cure rate of multidrug-resistant tuberculosis in China and within-host evolution during treatment, which is of great significance for improving clinical treatment regimens. Acquired resistance events were common during the ineffective treatment, among which resistance to amikacin and high-level moxifloxacin were the most common. The main reason for the treatment failure of MDR-TB patients was insufficient effective drugs, which may lead to higher levels of drug resistance in MDR-TB strains. Therefore, the study emphasizes the importance of DST in the development of second-line treatment regimen when there is a risk of MDR. By performing whole-genome sequencing of serial strains from patients with treatment failure, we found that WGS can detect low-frequency resistance mutations and heterogeneous resistance with high sensitivity. It is thus recommended to conduct drug susceptibility tests at the beginning of treatment and repeat the DST when the sputum bacteria remain positive.

Challenge of the Rising Multidrug-Resistant Tuberculosis in China: A Predictive Study Using Markov Modeling

Background: Multidrug-resistant tuberculosis (MDR-TB) is emerging in China. We used a dynamic Markov model to predict the longitudinal trends of MDR-TB in China by 2050, and assess the effects of alternative control measures. Methods Eight states of TB transmission were set up in the Markov model using a hypothetical cohort of 100,000 people. Prevalence of MDR-TB and bacteriological confirmed drug-susceptible TB (DS-TB+) were simulated. MDR-TB was stratified into being treated with the recommended regimen or not. Findings: Under the current China’s TB control conditions, by 2050, prevalence of DS-TB+ could be estimated to decrease to 39 per 100,000 people, a 37·1% reduction from 2019 , whereas MDR-TB would increase by three times to 58/100,000. Furthermore, by the year of 2050, 86·2% of the MDR-TB cases would be left untreated. If the detection rate of MDR-TB could reach 50% or 70% at 5% per year, the decline of MDR-TB prevalence would be 25·9% and 36·2% respectively. If treatment coverage was improved to 70% or 100% by 5% yearly , MDR-TB prevalence in 2050 would gain a reduction of 13·8% and 24·1%, respectively. If both detection rate and treatment coverage could reach 70%, the prevalence of MDR-TB would be reduced to 28/100, 000, a 51·7% reduction by 2050. Interpretation: MDR-TB, especially untreated MDR-TB, would rise rapidly under current MDR-TB control strategies in China. Interventions on promoting effective detection and treatment of MDR-TB are imperative in the fights against MDR-TB epidemics. Funding Statement: The Sweden-China (VR-NSFC) joint project (PI, Biao Xu, 81361138019 and Sven Hoffner, 540-2013-8797). Declaration of Interests: The authors stated: None declared. Ethics Approval Statement: Not required.

The epidemic of multidrug resistant tuberculosis in China in historical and phylogenetic perspectives

ObjectivesFor the past decade, the epidemic of multidrug resistance tuberculosis (MDR-TB) stays high in China. We investigated the possible driving forces behind the epidemics from phylogenetic and historical perspectives. Methods420 representative strains were selected from the first national drug resistance survey based on their genotypes, drug susceptibility patterns and geographic information. We reconstructed the phylogeny by whole genome sequencing and compared it to the global phylogeny including MDR outbreaks reported in other settings. We estimated the historical trajectory of population dynamics by Bayesian Skygrid plot for all strains and MDR-TB alone. Integrating geographic information and mutations in drug resistance related genes, we investigated the spatial scale of transmission, recent selection of drug resistant mutant, and mechanism for fitness restoration. ResultsThree new subgroups within Beijing clade are described for the first time, but none of the MDR-TB outbreak strains reported in other high MDR-TB burden settings is identified. The overall epidemics experienced two successive phases of expansion at different rates between 1660s and 1950s, followed by a sharp decline till today. Four fifths of the clustered MDR-TB strains suggest transmission of DR strains and nearly half suggest recent selection of (additional) mutations in rpoB. Among all identified transmission events, about one fifth occurred between far distant locations. Possible intergenic and intragenic compensatory mutations both presented in our dataset at comparable frequencies. ConclusionsMDR-TB epidemic in China is not yet driven by the spread of a few highly successful clonal expansions but by repeated emergence of smaller and currently less successful clusters. However, internal migration and undertreatment could escalate MDR-TB epidemic. To prevent generating of drug resistance and restoration of fitness as well as to stop transmission of MDR-TB at early stage, national TB control program needs to strengthen management of floating populations and promote universal drug susceptibility testing in China.

Is rifampin resistance a reliable predictive marker of multidrug-resistant tuberculosis in China: A meta-analysis of findings

Systematic review of multidrug-resistant tuberculosis (MDR-TB) prevalence among rifampicin (RIF)-resistant tuberculosis (RR-TB) patients in 34 provinces of China was conducted to correlate RIF resistance with concurrent isoniazid (INH) resistance. Database searches (PubMed, Embase, China National Knowledge Infrastructure, Chinese Scientific Journal, Wanfang), identified drug resistance surveillance studies conducted between January 1, 2000 and June 30, 2018. Of 1554 records, random-effects meta-analysis of 34 studies of adequate methodological quality yielded 108,366 TB cases for MDR-TB prevalence analysis of RR-TB cases. MDR-TB prevalence among RR-TB cases varied from 57% (Xinjiang; 95% CI 47%, 67%) to 95% (Taiwan; 95% CI 92%, 98%), for a pooled national rate of 77% (95% CI 75%, 80%). Subgroup and meta-regression analyses revealed greater MDR-TB prevalence in previously treated versus new RR-TB cases (P < 0.001), with no significant differences of regional initial drug resistance rates or sampling methods. Regional MDR-TB prevalence among RR-TB cases was lowest (69%) in the Northeast Region (95% CI 65%, 73%) and highest (90%) in Hong Kong, Macao and Taiwan (95% CI 81%, 98%). In China, ∼77% of RR-TB cases are MDR-TB. Thus, RIF resistance cannot effectively predict MDR-TB. Highly variable RR-TB prevalence across China warrants improved TB management.

Risk factors of multidrug-resistant tuberculosis in China: A meta-analysis.

Multidrug-resistant tuberculosis (MDR-TB) brings major challenges to the health care workers (HCWs). This study is to determine the risk factors for MDR-TB, latent tuberculosis infection (LTBI), and tuberculosis (TB) disease among HCWs in China. A meta-analysis was conducted to evaluate the risk factors for MDR-TB, LTBI, and TB disease among HCWs using a random-effects model, and the pooled odds ratios (ORs) with 95% confidence interval (CI) were used as effect indicators. We identified 46 eligible studies and found eight factors were associated with MDR. The ORs with 95% CI are migrant population 1.96 (95% CI, 1.50-2.57), low family income 2.23 (95% CI, 1.74-2.85), retreatment 7.22 (95% CI, 5.63-9.26), anti-TB treatment history 5.65 (95% CI, 4.80-6.65), multiple episodes of treatment 3.28 (95% CI, 2.60-4.13), adverse reactions 3.48 (95% CI, 2.54-4.76), interrupted treatment 3.18 (95% CI, 2.60-3.89), and lung cavities 1.42 (95% CI, 1.14-1.77). Work duration as a HCW for 5years and above increased the risk of LTBI and TB. HCWs aged 30years and above were more susceptible to TB (OR=1.70, 95% CI: 1.37-2.09). The risk factors for MDR-TB in China are possibly migrant population, low family income, retreatment, anti-TB treatment history, adverse reactions, interrupted treatment, and lung cavities. Longer work duration and greater age are risk factors for LTBI and TB among HCWs.

Cross-sectional Whole-genome Sequencing and Epidemiological Study of Multidrug-resistant Mycobacterium tuberculosis in China.

BackgroundThe increase in multidrug-resistant tuberculosis (MDR-TB) severely hampers tuberculosis prevention and control in China, a country with the second highest MDR-TB burden globally. The first nationwide drug-resistant tuberculosis surveillance program provides an opportunity to comprehensively investigate the epidemiological/drug-resistance characteristics, potential drug-resistance mutations, and effective population changes of Chinese MDR-TB.MethodsWe sequenced 357 MDR strains from 4600 representative tuberculosis-positive sputum samples collected during the survey (70 counties in 31 provinces). Drug-susceptibility testing was performed using 18 anti-tuberculosis drugs, representing the most comprehensive drug-resistance profile to date. We used 3 statistical and 1 machine-learning methods to identify drug-resistance genes/single-nucleotide polymorphisms (SNPs). We used Bayesian skyline analysis to investigate changes in effective population size.ResultsEpidemiological/drug-resistance characteristics showed different MDR profiles, co-resistance patterns, preferred drug combination/use, and recommended regimens among 7 Chinese administrative regions. These factors not only reflected the serious multidrug co-resistance and drug misuse but they were also potentially significant in facilitating the development of appropriate regimens for MDR-TB treatment in China. Further investigation identified 86 drug-resistance genes/intergenic regions/SNPs (58 new), providing potential targets for MDR-TB diagnosis and treatment. In addition, the effective population of Chinese MDR-TB displayed a strong expansion during 1993–2000, reflecting socioeconomic transition within the country. The phenomenon of expansion was restrained after 2000, likely attributable to the advances in diagnosis/treatment technologies and government support.ConclusionsOur findings provide an important reference and improved understanding of MDR-TB in China, which are potentially significant in achieving the goal of precision medicine with respect to MDR-TB prevention and treatment.

Protective immune mechanisms of Yifei Tongluo, a Chinese herb formulation, in the treatment of mycobacterial infection.

Yifei Tongluo (YFTL) is a traditional Chinese medicine (TCM) formulation which has been shown clinical efficacy in treatment of patients with multidrug-resistant tuberculosis in China. However, the underlying mechanisms of the effects of YFTL are lacking. This study investigated the effects of YFTL on immune regulation with a mouse lung infection model with Bacille Calmette-Guérin (BCG). We found that compared with untreated mice, the lung mycobacterial load in YFTL-treated mice was significantly reduced, accompanied by alleviated pulmonary inflammation with reduction of pro-inflammatory cytokines and increase of prostaglandin E2 (PGE2). Flow cytometry analyses showed that Th1 cells were significantly higher in the lungs of YFTL-treated mice at early infection time. The results suggest that YFTL-treatment down-regulates pulmonary inflammation, which facilitates a rapid infiltration of Th1 cells into the lungs. Moreover, the Th1 cells in the lungs were resolved faster at later time concomitant with increased the regulatory T cells (Tregs). The reduction of mycobacterial burden associated with improved tissue pathology, faster Th1 cell trafficking, and accelerated resolution of Th1 cells in the lungs of YFTL-treated mice indicates that YFTL improves mycobacterial clearance by maintaining lung homeostasis and dynamically regulating T cells in the lung parenchyma, and suggests that YFTL can be used as host-directed therapies that target immune responses to mycobacterial infection.

Factors affecting time to sputum culture conversion and treatment outcome of patients with multidrug-resistant tuberculosis in China

BackgroundFew prospective cohort studies, none in China, have investigated the relationship between treatment outcomes of multidrug-resistant tuberculosis (MDR-TB) patients and sputum culture conversion. Factors affecting the time of the culture conversion throughout the whole course of the treatment have rarely been investigated.MethodsThis study was performed in four cities in Jiangsu province, China. MDR-TB patients were consecutively enrolled between December 2011 and March 2014. Rates of sputum culture conversion were calculated and Cox proportional-hazards model was performed. Factors contributing to sputum culture conversion were investigated.ResultsIn all, 139 MDR-TB patients with treatment outcomes were enrolled. Median time to culture conversion among those who converted was 91.5 days (interquartile range, 34.0–110.8 days). After multivariable analysis, smoking (HR = 0.44; 95% CI: 0.23–0.83), drinking (HR = 0.41; 95% CI: 0.21–0.81), ofloxacin resistance (HR = 0.43; 95% CI: 0.24–0.76) and sputum smear grade > 1 (HR = 0.51; 95% CI: 0.31–0.83) were less likely to have culture conversion.ConclusionsMDR-TB patients who smoke, drink, have ofloxacin resistance, or a high smear grade are less likely to respond to treatment and should be meticulously followed up.

Prognostic factors for treatment success in patients with multidrug-resistant tuberculosis in China.

To examine the clinical outcomes and associated prognostic factors among patients with multidrug-resistant tuberculosis (MDR-TB) in China. This retrospective study involved 243 patients with MDR-TB. All patients received standard regimens containing para-amino salicylic acid (PAS) and/or cycloserine (CS). The demographic, social and clinical characteristics of patients were recorded and the patients were followed up for 24 months. Treatment success was closely associated with young age, non-farming occupations, shorter history or smoking, normal urine results, initial MDR-TB treatment regimen, increased haemoglobin, direct bilirubin, uric acid and thyroid stimulating hormone (TSH) levels, and lower white blood cell, neutrophil and blood platelet counts (all P < 0.05). On multivariable analysis, increased haemoglobin (hazard ratio [HR] 1.019, 95%CI 1.007-1.032, P = 0.002) and TSH levels (HR 1.002, 95%CI 1.006-1.039, P = 0.008), normal urine results (HR 1.541, 95%CI 1.008-2.358, P = 0.046) and initial MDR-TB treatment regimen (HR 2.238, 95%CI 1.090-4.597, P = 0.028) were prognostic factors for treatment success in MDR-TB. Higher haemoglobin and TSH levels, normal urine results and initial MDR-TB treatment regimen might predict successful treatment of MDR-TB.