Drug-resistant Tuberculosis In China Research Articles

Transmission characteristics in Tuberculosis by WGS: nationwide cross-sectional surveillance in China

ABSTRACT China, with the third largest share of global tuberculosis cases, faces a substantial challenge in its healthcare system as a result of the high burden of multidrug-resistant and rifampicin-resistant tuberculosis (MDR/RR-TB). This study employs a genomic epidemiological approach to assess recent tuberculosis transmissions between individuals, identifying potential risk factors and discerning the role of transmitted resistant isolates in the emergence of drug-resistant tuberculosis in China. We conducted a population-based retrospective study on 5052 Mycobacterium tuberculosis (MTB) isolates from 70 surveillance sites using whole genome sequencing (WGS). Minimum spanning tree analysis identified resistance mutations, while epidemiological data analysis pinpointed transmission risk factors. Of the 5052 isolates, 23% (1160) formed 452 genomic clusters, with 85.6% (387) of the transmissions occurring within the same counties. Individuals with younger age, larger family size, new cases, smear positive, and MDR/RR were at higher odds for recent transmission, while higher education (university and above) and occupation as a non-physical workers emerged as protective factors. At least 61.4% (251/409) of MDR/RR-TB were likely a result of recent transmission of MDR/RR isolates, with previous treatment (crude OR = 2.77), smear-positive (cOR = 2.07) and larger family population (cOR = 1.13) established as risk factors. Our findings highlight that local transmission remains the predominant form of TB transmission in China. Correspondingly, drug-resistant tuberculosis is primarily driven by the transmission of resistant tuberculosis isolates. Targeted interventions for high-risk populations to interrupt transmission within the country will likely provide an opportunity to reduce the prevalence of both tuberculosis and drug-resistant tuberculosis.

Selecting an appropriate all-oral short-course regimen for patients with multidrug-resistant or pre-extensive drug-resistant tuberculosis in China: A multicenter prospective cohort study

ObjectivesLong, ineffective, and toxic regimens hinder the treatment of patients with multidrug-resistant tuberculosis (MDR-TB) and pre-extensive drug-resistant tuberculosis (pre-XDR-TB). MethodsWe conducted a multicenter cohort study to prospectively evaluate the safety and efficacy of three 9-month, all-oral, 5-drug regimens. Regimen A (bedaquiline [Bdq]+linezolid [Lzd]+moxifloxacin [Mfx]+cycloserine [Cs]+pyrazinamide [Pza]) and Regimen B (Lzd+Mfx+Cs+clofazimine [Cfz]+Pza) were used to treat MDR-TB patients (Groups A and B, respectively, assigned according to the patient's treatment preference), while Regimen C (Bdq+Lzd+Cs+Cfz+Pza) was used to treat pre-XDR-TB patients (Group C). The primary endpoint was the occurrence of an unfavorable outcome within 12 months of treatment completion, regardless of regimen. ResultsA total of 104 patients (34 in Group A, 46 in Group B, and 24 in Group C), with a median age of 35.5 (29.0-54.0) years, were included in the analysis population. At 12 months after treatment completion, five patients were deemed non-assessable. Of the remaining 99 participants, seven (7.1%) had an unfavorable outcome (including two deaths from any cause, four with treatment failure, and one loss to follow-up) and 92 (92.9%) had a favorable outcome. Culture conversion was achieved in 82.5% (80/97) of participants at month 2 and in 97.9% (94/97) of participants at month 6. Adverse events (AEs) resulting in drug adjustment occurred in 69.2% (72/104) of participants, mainly due to Lzd and Pza use. A QT interval prolongation of ≥ 500 ms occurred in 5.8% (6/104) of participants. ConclusionThe primary outcome of the three tailored, 9-month, all-oral, 5-drug regimens was satisfactory in the vast majority of MDR-TB and pre-XDR-TB patients, with manageable and reversible AEs.

Factors associated with treatment outcomes of patients with drug-resistant tuberculosis in China: A retrospective study using competing risk model.

ObjectivesDrug-resistant tuberculosis remains a serious public health problem worldwide, particularly in developing countries, including China. This study determined treatment outcomes among a cohort in Guangzhou, China, and identified factors associated with them.MethodsWe initiated a retrospective study using drug-resistant TB data in Guangzhou from 2016 to 2020, managed by Guangzhou Chest Hospital. A competing risk model was used to identify the factors associated with treatment failure and death, as well as loss to follow-up (LTFU).ResultsA total of 809 patients were included in the study, of which 281 were under treatment. Of the remaining 528 who had clear treatment outcomes, the number and proportion of treatment success, treatment failure, death, and LTFU were 314 (59.5%), 14 (2.7%), 32 (6.0%), and 168 (31.8%), respectively. Being older and having cavities involving the upper lungs were risk factors for treatment failure and death, while non-Guangzhou household registration and interprovincial mobility were risk factors associated with LTFU.ConclusionTreatment failure and death were significantly associated with cavitation in the lungs, and LTFU was significantly associated with household registration and geographical mobility. Early identification of factors associated with different treatment outcomes is extremely important for policymakers, health experts, and researchers to implement appropriate strategies and measures to treat and manage the TB-infected population in China.

Linezolid for patients with multidrug-resistant tuberculosis/extensively drug-resistant tuberculosis in China

Linezolid has been one of the key anti-tuberculosis agents for the treatment of multidrug-resistant tuberculosis (MDR-TB)/extensively drug-resistant tuberculosis (XDR-TB). It used to be very expensive and was not covered by social insurance from local governments. Nevertheless, a growing number of patients in China received linezolid in their anti- MDR/XDR TB regimens over the past decade. Many scholars in China have reported their experience using linezolid to treat patients with MDR/XDR-TB. In view of this, existing evidence of the efficacy and safety of linezolid and problems faced by Chinese patients with MDR/XDR-TB are summarized here.

Prediction of different interventions on the burden of drug-resistant tuberculosis in China: a dynamic modelling study

Tuberculosis (TB) is one of the top 10 causes of death worldwide. The World Health Organization adopted the 'End TB Strategy' to end the global TB epidemic by 2035. However, achieving this goal will be difficult using current measures. A Susceptible-Exposed-Infectious-Recovered (SEIR) model that distinguishes drug-sensitive (DS) and drug-resistant (DR) TB in the entire Chinese population was established. Goodness-of-fit tests and sensitivity analyses were used to assess model performance. Predictive analysis was performed to assess the effect of different prevention and control strategies on DR-TB. We used parameter fitting to determine the basic reproduction number of the model as R0 = 0.6993. The predictive analysis led to two major projections that can achieve the goal by 2035. First, if the progression rate of latently infected people reaches 10%, then there will be 92.2% fewer cases than in 2015. Second, if the cure rate of DR-TB increases to 40%, then there will be 91.5% fewer cases than in 2015. A combination of five interventions could lead to earlier achievement of the 2035 target. We found that reducing the probability of transmission and the rate of disease progression in patients with DR-TB and improving treatment compliance and the cure rate of patients with DR-TB can contribute to attaining the goal of the End TB Strategy.

Impacts of a comprehensive tuberculosis control model on the quality of clinical services and the financial burden of treatment for patients with drug-resistant tuberculosis in China: a mixed-methods evaluation

BackgroundThe China National Health Commission-Gates TB Project Phase III implemented a comprehensive TB control model including multiple interventions to address the burden of drug-resistant TB (DRTB). This study aims to evaluate the quality of DRTB clinical services and assess the financial burden of DRTB patients during the intervention period.MethodsA mixed-methods approach was used to evaluate the effectiveness of interventions in the three project provinces: Zhejiang, Jilin and Ningxia Hui Autonomous Region. The quantitative data included de-identified DRTB registry data during 2015–2018 in project provinces from China CDC, medical records of DRTB patients registered in 2018 (n = 106) from designated hospitals, and a structured DRTB patient survey in six sample prefectures in 2019. The quality of clinical services was evaluated using seven indicators across patient screening, diagnosis and treatment. Logistic regression was conducted to explore factors associated with the extremely high financial burden. Semi-structured in-depth interviews with policymakers and focus group discussions with physicians and DRTB patients were conducted to understand the interventions implemented and their impacts.ResultsThe percentage of bacterially confirmed patients taking a drug susceptibility test (DST) increased significantly between 2015 and 2018: from 57.4 to 93.6% in Zhejiang, 12.5 to 86.5% in Jilin, and 29.7 to 91.4% in Ningxia. The treatment enrollment rate among diagnosed DRTB patients also increased significantly and varied from 73 to 82% in the three provinces in 2018. Over 90% of patients in Zhejiang and Jilin and 75% in Ningxia remained in treatment by the end of the first six months’ treatment. Among all survey respondents 77.5% incurred extremely high financial burden of treatment. Qualitative results showed that interventions on promoting rapid DST technologies and patient referral were successfully implemented, but the new financing policies for reducing patients’ financial burden were not implemented as planned.ConclusionsThe quality of DRTB related clinical services has been significantly improved following the comprehensive interventions, while the financial burden of DRTB patients remains high due to the delay in implementing financing policies. Stronger political commitment and leadership are required for multi-channel financing to provide additional financial support to DRTB patients.

Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis in China.

BACKGROUND: Multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB) continues to be a challenge in China. Bedaquiline (BDQ) is associated with accelerated sputum culture conversion and favourable treatment outcomes when added to a preferred background regimen. This post-hoc study aimed to assess the outcomes of BDQ treatment in Chinese patients with MDR/XDR-TB.METHODS: Data from 51 Chinese patients who participated in a global Phase 2, open-label, single-arm study (TMC207-C209) were analysed for effectiveness and safety of the BDQ-containing regimen.RESULTS: During the 24-week BDQ treatment, adverse events (AEs) occurred in 48 patients (94.1%), with the most common AE being hyperuricemia. Drug-induced liver injury (DILI) was reported in 13 patients (25.5%); serious DILI was reported in one patient (2.0%). Seven (13.7%) AEs were considered to be possibly related to BDQ by the investigators. Only one Grade 1 QTc prolongation was reported; no QTcF >500 ms was reported. One death occurred after BDQ treatment due to progressive TB. The median time to sputum culture conversion was 85 days based on the 24-week data. The sputum culture conversion rate was 82% at 24 weeks and 78% at 120 weeks; 66% of patients achieved a cure.CONCLUSIONS: BDQ was well-tolerated and effective for treating MDR-TB among Chinese patients.

Long-term impact of the adoption of bedaquiline-containing regimens on the burden of drug-resistant tuberculosis in China

BackgroundCurrently available injectable agents are inadequate to address the high drug-resistant tuberculosis (DR-TB) burden in China. Regimens including the oral agent bedaquiline have been shown to be efficacious and safe, leading to its incorporation into multiple national TB treatment programs. This analysis evaluated the impact of increased adoption of bedaquiline-containing regimens on the DR-TB burden in China.MethodsA state-transition model was developed that permits movement and interaction between susceptible, latent, and active TB disease states, while distinguishing between drug-sensitive (DS) and DR-TB. Model inputs were obtained from the published literature or derived such that model metrics approximated those published by the WHO. Expected improvements in infrastructure were built into the model to forecast the epidemiology of DR-TB in China through 2040 in the absence of bedaquiline (baseline forecast). The impact of higher utilization of bedaquiline-containing regimens (85% peak share) was then assessed in two scenarios that differed with regard to treatment success rates of the regimens: 61% (reflecting findings of clinical trials) and 80% (reflecting data from observational studies), versus the 44% success rate associated with standard-of-care treatment.ResultsIn the baseline scenario, the model predicted increases in annual incidence of DR-TB by 6–8% during each five-year period between 2020 and 2040, with an increase of 30% over the entire study duration. Adoption of bedaquiline-based regimens limits the incidence increases to only 1–3% in each five-year period and to 8% over the study duration in the 61% success rate scenario. Incidence declines by 1–6% during each five-year period and by 12% over the study duration in the 80% success rate scenario. Similar effects on DR-TB prevalence (4–5% increase in baseline, 0–7% decline in scenario 1, and 4–19% decline in scenario 2) and mortality (5–7% increase in baseline, 0–16% decline in scenario 1, and 6–40% decline in scenario 2) were seen following bedaquiline adoption.ConclusionsIncorporation of bedaquiline into DR-TB treatment regimens will significantly reduce the DR-TB burden in China, helping to counter the expected increase in burden in the absence of bedaquiline. The study will provide valuable information to public health policy planners.

Primary drug resistance of mycobacterium tuberculosis in Shandong, China, 2004\u20132018

BackgroundPrimary drug-resistant tuberculosis (DR-TB) has contributed to a significant health and economic burden on a global scale, especially in China. we sought to estimate epidemiological characteristics of primary DR-TB in China from 2004 to 2018.MethodsEleven thousand four hundred sixty-seven newly diagnosed and 1981 retreated TB cases with drug susceptibility data were included. Chi-Square test for trends, linear regression, a joinpoint regression model and temporal trend in proportions of the different resistance patterns were carried out.ResultsThe proportion of primary DR-TB and mono-resistant TB (MR-TB) in China had reduced by more than 12% since 2004, and were 21.38%, 13.35% in 2018 respectively. Among primary DR-TB cases (2173,18.95%), the percentage of multiresistant TB (MDR-TB, from 5.41 to 17.46%), male (from 77.03 to 84.13%), cavity (from 13.51 to 43.92%), rifampicin(RFP)-resistant TB (from 8.11 to 26.98%), streptomycin(SM)-resistant TB (from 50.00 to 71.43%) increased significantly (P < 0.05). On the contrary, the proportion of female, non-cavity, isoniazide(INH)-resistant TB (from 55.41 to 48.15%) and MR-TB (from 82.43 to 62.43%) decreased significant (P < 0.05). The primary drug resistance rate among female, cavity, smoking, drinking, 15 to 44 year-old TB subgroups increased by 0.16, 6.24, 20.95, 158.85, 31.49%, respectively. The percentage of primary DR-TB, RFP-resistant TB dropped significantly during 2004–2007 in Joinpoint regression model.ConclusionThe total rate of drug resistance among new TB cases showed a downward trend in Shandong, China, from 2004 to 2018. Primary drug resistance patterns were shifting from female, non-cavity, INH-resistant TB, and MR-TB groups to male, cavity, RFP/SM-resistant TB, and MDR-TB groups. Considering the rising drug resistance rate among some special population, future control of primary DR-TB in China may require an increased focus on female, cavity, smoking, drinking, or 15 to 44 year-old TB subgroups.

Prevalence, risk and genetic characteristics of drug-resistant tuberculosis in a tertiary care tuberculosis hospital in China.

ObjectivesTo explore the prevalence, risk and genetic characteristics of drug-resistant tuberculosis (TB) from a tertiary care TB hospital in China.Patients and methodsWe carried out a retrospective study including isolates from 189 patients with pulmonary TB at Fuzhou Pulmonary Hospital. All isolates from these patients were subjected to drug susceptibility testing and genotyping. For drug-resistant isolates, DNA sequencing was used to investigate mutations in 12 loci, including katG, inhA, oxyR–ahpC, rpoB, rpsL, rrs1 (nucleotides 388–1084 of rrs), embB, tlyA, eis, rrs2 (nucleotides 1158–1674 of rrs), gyrA and gyrB.ResultsAmong 189 isolates, 28.6% were resistant to at least one of the seven anti-TB drugs, including isoniazid (INH), rifampin (RIF), streptomycin (STR), ethambutol (EMB), capreomycin (CAP), kanzmycin (KAN) and ofloxacin (OFX). The proportion of multidrug-resistant TB and extensively drug-resistant TB isolates was 9.5% and 1.1%, respectively. Patients in rural areas as well as previously treated patients showed a significantly increased risk of developing drug resistance. In addition, among these isolates, 111 (58.7%) were Beijing genotype strains, 84 (75.7%) of which belonged to modern Beijing sublineage. There was no association between genotype and drug resistance. The most common mutations were katG315, rpoB531 rpsL43, embB306, rrs1401 and gyrA94. ConclusionThese findings provided additional information of drug-resistant TB in China. Previously treated patients and patients in rural areas should receive greater attention owing to their higher risk of developing drug resistance.

Consideration on the use of injectable anti-tuberculosis drufgs in the treatment of drug-resistant tuberculosis in china

随着世界卫生组织新治疗指南的发布及越来越多口服抗结核药物临床数据的产生，从不良反应、患者的依从性、治疗方式的改变等方面考虑，注射剂将逐渐被口服药物取代，这是历史进步、科学发展的必然趋势。但考虑到当前新指南中部分A、B组药物在我国的可及性、氟喹诺酮类药物在我国的耐药率较高、大部分A、B组药品价格昂贵且尚未全面纳入医保且建议的"理想"全口服方案费用较高，患者难以承受，故认为注射剂在我国耐药结核病治疗中仍有一定的作用，在一段时间内将会出现含注射剂方案和口服药物方案并行的情况。.

Diagnostic accuracy of line probe assays for drug-resistant tuberculosis: a Meta-analysis

Objective: To evaluate the diagnostic accuracy of line probe assays for drug- resistant tuberculosis (TB) in China. Methods: Chinese databases (CNKI, Wanfang, SinoMed, VIP Information) and English databases (PubMed, Embase, Cochrane Library) were used to retrieve the literatures regarding the accuracy of line probe assays in the diagnosis of drug-resistant tuberculosis in China between January 1, 2000 and September 1, 2017. Quality Assessment of Diagnostic Accuracy Studies-2 was used to evaluate the quality of the included studies. Sensitivity and specificity in different studies (using drug sensitivity test or gene sequencing as gold standard) were combined by Meta-analysis using bivariate or univariate model. In addition, subgroup analysis (GenoType MTBDRplus, GenoType MTBDRsl and Reverse dot blot hybridization) and sensitivity analysis were also carried out. Results: A total of 24 literatures involving 82 studies were included in the final analysis. The sensitivity and specificity of line probe assays for rifampicin resistant TB were 0.91(0.88-0.94) and 0.98 (0.97-0.99), respectively. The sensitivity and specificity of line probe assays for isoniazid resistant TB were 0.80 (0.77-0.83) and 0.98 (0.96-0.99), respectively. The sensitivity and specificity of line probe assays for multidrug-resistant TB were 0.81 (0.76-0.85) and 0.99 (0.99-1.00), respectively. The sensitivity and specificity of line probe assays for quinolone resistant TB were 0.92(0.88-0.95) and 0.94 (0.91-0.97), respectively. The sensitivity and specificity of line probe assays for second-line injectable drug resistant TB (including kanamycin, Capreomycin, amikacin) were 0.79(0.58-0.91) and 0.98 (0.90-1.00), respectively. The sensitivity and specificity of line probe assays for extensively drug-resistant TB were 0.46 (0.19-0.75) and 1.00 (0.98-1.00), respectively. Subgroup analysis showed that the overall diagnostic accuracy of GenoType MTBDRplus and GenoType MTBDRsl was higher than that of Reverse dot blot hybridization. According to the results of sensitivity analysis, the results of this study were robust. Conclusion: The diagnostic accuracy of line probe assays for drug-resistant TB is high.

Trends in drug-resistant tuberculosis in China: data from a clinical tuberculosis centre.

To describe the trends in prevalence of drug-resistant tuberculosis (TB) among in-patients in Beijing Chest Hospital, Beijing, China, using a 10-year retrospective study. From 2005 to 2014, 18 310 in-patients with TB were recruited for the study, most of whom were referrals; no distinction was made between new and previously treated cases. Drug susceptibility testing (DST) was performed in culture-positive cases using the proportion method to determine multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). Risk factors associated with drug resistance were identified. A total of 5141 (28.0%) samples were culture-positive. DST results showed that 860 (16.7%) cases were MDR-TB and 176 (3.4%) were XDR-TB. MDR-TB and XDR-TB were detected in respectively 21.2% and 12.5% of new cases. The rate of MDR-TB and XDR-TB gradually increased from 2005, with MDR-TB reaching a peak in 2008 and XDR-TB in 2009. These data closely mirror national survey data on this region, patient age and occupation. Trends in MDR-TB and XDR-TB prevalence during the past decade and their inflection points were determined, which complemented reports from previous national surveys. This information is useful for fighting TB in China.

Epidemic spread of multidrug-resistant tuberculosis in China

An estimated 10·4 million people worldwide developed tuberculosis in 2015. Tuberculosis is the leading infectious cause of death worldwide, with 1·8 million deaths, more than HIV/AIDS and malaria combined. 1 WHOGlobal tuberculosis report 2016. http://www.who.int/tb/publications/global_report/en/ Google Scholar In 2015, 580 000 (5·7%) patients with tuberculosis had rifampicin-resistant or multidrug-resistant (MDR; resistant to isoniazid and rifampicin) disease, with India and China having the greatest number of these cases. 1 WHOGlobal tuberculosis report 2016. http://www.who.int/tb/publications/global_report/en/ Google Scholar Improved living standards in China have led to global gains in tuberculosis control in the past 20 years, particularly in the western Pacific region. 2 Raviglione M Marais B Floyd K et al. Scaling up interventions to achieve global tuberculosis control: progress and new developments. Lancet. 2012; 379: 1902-1913 Summary Full Text Full Text PDF PubMed Scopus (264) Google Scholar However, a survey 3 Zhao Y Xu S Wang L et al. National survey of drug-resistant tuberculosis in China. N Engl J Med. 2012; 366: 2161-2170 Crossref PubMed Scopus (515) Google Scholar done in 2007 showed MDR tuberculosis in 6% of new cases and in 26% of cases with a tuberculosis treatment history. Rates of concurrent fluoroquinolone resistance in these patients were also high. 4 Zhang Z Lu J Wang Y Pang Y Zhao Y Prevalence and molecular characterization of fluoroquinolone-resistant Mycobacterium tuberculosis isolates in China. Antimicrobial Agents Chemother. 2014; 58: 364-369 Crossref PubMed Scopus (66) Google Scholar Initial assumptions were that most cases of MDR tuberculosis represented acquired drug resistance, 5 Marais BJ The global tuberculosis situation and the inexorable rise of drug-resistant disease. Adv Drug Deliv Rev. 2016; 102: 3-9 Crossref PubMed Scopus (28) Google Scholar but a 2015 analysis 6 Wei-wei Jiao W Liu Z Han R et al. Prevalence of drug resistant Mycobacterium tuberculosis among children in China. Tuberculosis. 2015; 95: 315-320 Summary Full Text Full Text PDF PubMed Scopus (18) Google Scholar of 100 children with culture-confirmed tuberculosis showed high rates of drug resistance suggesting active transmission of MDR tuberculosis within China. Transmission of multidrug-resistant Mycobacterium tuberculosis in Shanghai, China: a retrospective observational study using whole-genome sequencing and epidemiological investigationRecent transmission of MDR tuberculosis strains, with increasing drug-resistance, drives the MDR tuberculosis epidemic in Shanghai, China. Whole-genome sequencing can measure of the heterogeneity of drug-resistant mutations within and between hosts and help to determine the transmission patterns of MDR tuberculosis. Full-Text PDF

Prevalence and Risk Factors of Primary Drug-Resistant Tuberculosis in China

ObjectiveTo investigate the prevalence of primary drug-resistant tuberculosis (TB) and associated risk factors in China. We also explored factors contributing to the transmission of multidrug-resistant tuberculosis (MDR-TB). MethodsA total of 2794 representative, Mycobacterium tuberculosis isolates from treatment-naive patients were subjected to drug susceptibility testing, and risk factors for drug-resistant TB were analyzed. We also analyzed MDR-TB strain sublineages, drug-resistance-conferring mutations, and risk factors associated with clustered primary MDR strains. ResultsAmong 2794 Mycobacterium tuberculosis isolates from treatment-naive patients, the prevalence of any resistance to first-line drugs was 33.2% and the prevalence of MDR-TB was 5.7%. We did not find any risk factors significantly associated with resistance to first-line drugs. The 93 primary MDR-TB isolates were classified into six sublineages, of which, 75 (80.6%) isolates were the RD105-deleted Beijing lineage. The largest sublineage included 65 (69.9%) isolates with concurrent deletions of RD105, RD207, and RD181. Twenty-nine (31.2%) primary MDR strains grouped in clusters; MDR isolates in clusters were more likely to have S531L rpoB mutation. ConclusionThis study indicates that primary drug-resistant TB and MDR-TB strains are prevalent in China, and multiple measures should be taken to address drug-resistant TB.

Status of drug-resistant tuberculosis in China: A systematic review and meta-analysis

We conducted a systematic review and meta-analysis on drug-resistant tuberculosis in China to provide useful data for tuberculosis (TB) surveillance and treatment. Several databases, including PubMed, Embase, and the Chinese Biological Medical Database, were systematically searched between January 1, 1999, and August 31, 2015, using strict inclusion and exclusion criteria. The corresponding drug-resistant TB prevalence between the new and previously treated cases was significantly different in almost all of the economic regions. The Eastern coastal region is the most developed economic region with the lowest total drug-resistant TB prevalence (any drug resistance: 28%; 95% confidence interval [CI], 25%-32%; multidrug resistance: 9%; 95% CI, 8%-12%) and the lowest number of new cases (any drug resistance: 21%; 95% CI, 19%-23%; multidrug resistance: 4%; 95% CI, 3%-5%). The Northwest is the least developed area with the lowest drug-resistant TB prevalence for previously treated cases (any drug resistance: 45%; 95% CI, 36%-55%; multidrug resistance: 17%; 95% CI, 11%-26%). The prevalence (multidrug and first-line drug resistance) exhibited a downward trend from 1996-2014. The extensively drug-resistant prevalence in China was 3% (95% CI, 2%-5%) in this review. Overall, the status of drug-resistant tuberculosis in China is notably grim and exhibits regional epidemiologic characteristics. We are in urgent need of several comprehensive and effective control efforts to reverse this situation.

Prevalence of mutations conferring resistance among multi- and extensively drug-resistant Mycobacterium tuberculosis isolates in China.

To identify the mutations in multi- and extensively drug-resistant tuberculosis isolates and to evaluate the use of molecular markers of resistance, we analyzed 257 multi- and extensively drug-resistant isolates and 64 pan-sensitive isolates from 23 provinces in China. Seven loci associated with drug resistance, including rpoB for rifampin (RIF), katG, inhA and oxyR-ahpC for isoniazid (INH), gyrA and gyrB for ofloxacin (OFX), and rrs for kanmycin (KAN), were examined by DNA sequencing. Compared with the phenotypic data, the sensitivity and specificity for DNA sequencing were 91.1% and 98.4% for RIF, 80.2% and 98.4% for INH, 72.2% and 98.3% for OFX and 40% and 98.2% for KAN, respectively. The most common mutations found in RIF, INH, OFX and KAN resistance were Ser531Leu (48.2%) in rpoB, Ser315Thr (49.8%) in katG, C(-15)T (10.5%) in inhA, Asp94Gly (20.3%), Asp94Ala (12.7%) and Ala90Val (21.5%) in gyrA, and A1401G (40%) in rrs. This molecular information will be helpful to establish new molecular biology-based methods for diagnosing multi- and extensively drug-resistant tuberculosis in China.

Cost-effectiveness of a comprehensive programme for drug-resistant tuberculosis in China.

ObjectiveTo investigate the cost–effectiveness of a comprehensive programme for drug-resistant tuberculosis launched in four sites in China in 2011.MethodsIn 2011–2012, we reviewed the records of 172 patients with drug-resistant tuberculosis who enrolled in the comprehensive programme and we collected relevant administrative data from hospitals and China’s public health agency. For comparison, we examined a cohort of 81 patients who were treated for drug-resistant tuberculosis in 2006−2009. We performed a cost–effectiveness analysis, from a societal perspective, that included probabilistic uncertainty. We measured early treatment outcomes based on three-month culture results and modelled longer-term outcomes to facilitate estimation of the comprehensive programme’s cost per disability-adjusted life-year (DALY) averted.FindingsThe comprehensive programme cost 8837 United States dollars (US$) per patient treated. Low enrolment rates meant that some fixed costs were higher, per patient, than expected. Although the comprehensive programme appeared 30 times more costly than the previous one, it resulted in greater health benefits. The comprehensive programme, which cost US$ 639 (95% credible interval: 112 to 1322) per DALY averted, satisfied the World Health Organization’s criterion for a very cost–effective intervention.ConclusionThe comprehensive programme, which included rapid screening, standardized care and financial protection, improved individual outcomes for MDR tuberculosis in a cost-effective manner. To support post-2015 global heath targets, the comprehensive programme should be expanded to non-residents and other areas of China.

Pulmonary tuberculosis caused by Mycobacterium bovis in China.

The epidemiology of Mycobacterium bovis infection in humans in China is unknown. In this study, pulmonary tuberculosis caused by M. bovis in China was studied. A total of 4069 clinical strains isolated from sputa during the 2007–2009 nationwide surveillance of drug-resistant tuberculosis in China were analyzed. M. bovis was identified by para-nitrobenzoic acid and thiophen-2-carboxylic acid hydrazide growth tests, spoligotyping and multiplex PCR amplification. In addition, a total of 1828 clinical specimens were recruited from Beijing Chest Hospital (Beijing, China) for Löwenstein-Jensen (LJ) culture, both on standard LJ medium and LJ medium containing 4.5 mg/ml(W/V) sodium pyruvate, the latter being the preferred medium for M. bovis growth. The isolates which demonstrated more vigorous on pyruvate containing medium than on standard LJ medium were then identified by multiplex PCR amplification. Only 1 isolate from the nationwide surveillance was confirmed as M. bovis-BCG. The isolate belonged to a predominant spoligotype SB0120 (ST482). In addition, no M. bovis isolate was acquired by the continuous screening step in Beijing Chest Hospital. M. bovis has a negligible contribution to pulmonary tuberculosis in China, so neither laboratory identification nor clinical treatment of M. bovis infection need be considered in routine work.

Accessibility of bacteriological-based diagnosis and prevalence of drug resistant tuberculosis in previously treated tuberculosis patients

Aims and objectivesMultidrug-resistant tuberculosis (MDR-TB) has become a major public health problem worldwide, which lays a heavy burden on low- and middle-income countries. Compared with newly diagnosed tuberculosis (TB) patients, patients with a history of anti-TB treatment have increased mortality and a higher prevalence of drug resistance. However, these patients are neglected by both global and national TB control programs and have met barriers to access to medical care for potential drug resistance. This study aims to understand the drug-resistance status of patients with previous treatment history and to determine the factors associated with the accessibility of bacteriological-based TB diagnosis. MethodsA cross-sectional study was conducted in 8 county/district TB clinics in three provinces (Jiangsu, Shandong and Sichuan) of China, where a global fund-supported MDR-TB control project had been initiated. TB patients who had at least one previous treatment episode were interviewed using a structured questionnaire. Information on demographics, socioeconomic status of patients, and their experiences on seeking TB diagnosis and treatment were collected. ResultsA total of 196 smear-positive TB patients were recruited, of which 78% (153/196) were male and the average age of these patients was 57years old. About 70% (137/196) of the subjects were farmers, and 63% (121/195) had less than 6years’ education. Among these patients, 120 cases (61.22%) received culture-based TB diagnosis in this treatment episode, while patients from Jiangsu province (versus Shandong/Sichuan aOR: 8.10/36.42, 95% CI: 2.70–24.25/12.20–108.66) and patients with a higher annual income per capita (aOR: 3.35, 95% CI: 1.26–8.92) were found to be more likely to reach culture tests after adjusting for gender and age. MTB complex and non-tuberculosis mycobacteria (NTM) strains were isolated from 92 and 10 patients, respectively, and the remaining 18 patients were negative to bacteria culture. Drug sensitivity testing (DST) for first-line anti-TB drugs, and kanamycin and ofloxacin, was completed for the 92 MTB isolates. The total proportion of drug-resistant tuberculosis was 52.48% (47/92), while the prevalence for resistance to a single drug, multidrug-resistant and other combinations of drug resistance were 16.30% (95% CI: 9.78–23.91%), 30.43% (95% CI: 21.74–40.22%), and 4.35% (95% CI: 1.09–8.70%), respectively. Resistance to isoniazid, rifampicin, streptomycin, ethambutol, kanamycin and ofloxacin was 36.96%, 35.87%, 23.91%, 10.87%, 4.35% and 6.52%, respectively. ConclusionsPatients with a previous treatment history are at extremely high risk of drug-resistant tuberculosis in China. The poor accessibility of bacteriological-based diagnosis may aggravate the difficulty of detection and control for drug-resistant TB patients. The next step of the anti-TB strategy should be focused on how to make bacteriological-based diagnosis cheaper, safer and more maneuverable and on how to assure the DST-guided treatment for these high-risk TB patients.