Global adoption of 6-month drug-resistant TB regimens: Projected uptake by 2026.

BACKGROUND: The WHO has issued a call to action urging countries to accelerate the rollout of new WHO-recommended shorter all-oral treatment regimens for drug-resistant TB (DR-TB), which remains a public-health crisis. The all-oral, 6-month BPaL/M regimen comprises 3-4 drugs: pretomanid used in combination with bedaquiline and linezolid, with or without moxifloxacin. This regimen has been recommended by the WHO for use in DR-TB patients instead of ≥9-month (up to 24-month) regimens. This study aims to project this regimen's use, along with its components bedaquiline, pretomanid and linezolid, and other treatments for DR-TB globally through 2026. It is intended to guide global health stakeholders in planning and budgeting for DR-TB interventions. Projected usage could help estimate cost of the individual components of DR-TB regimens over time. METHODS: Semi-structured interviews were conducted with national TB programme participants in key countries to gather intelligence on established plans and targets for use of various DR-TB treatment regimens from 2023 to 2026. These data informed development of projections for the global use of regimens and drugs. RESULTS: Consistent global growth in the use of shorter regimens in DR-TB treatment was shown: BPaLM reaching 126,792 patients, BPaL reaching 43,716 patients, and the 9-11-month all-oral bedaquiline-based regimen reaching 13,119 patients by 2026. By 2026, the longer all-oral regimen is projected to be used by 19,262 patients, and individualised treatment regimens by 15,344 patients. CONCLUSION: The study shows BPaL/M will be used in majority of DR-TB patients by 2024, reaching 78% by 2026. However, national efforts to scale-up, case-finding, monitoring, drug-susceptibility testing, and implementation of new treatments will be essential for ensuring they are accessible to all eligible patients in the coming years and goals for ending TB are met. There is an urgent need to engage communities in capacity building and demand generation.

Evaluation of the diagnostic efficacy of EC-Test for latent tuberculosis infection in ambulatory people with HIV.

BACKGROUND: Latent tuberculosis infection (LTBI) co-infected with human immunodeficiency virus (HIV) is more likely to develop into active tuberculosis (ATB), recombinant Mycobacterium tuberculosis fusion protein ESAT6/CFP10 (EC-Test) is a latest developed method for LTBI. Compared with the interferon γ release test assays (IGRAs), the diagnostic performance of EC-Test to LTBI screening in HIV needs to be evaluated. METHODS: A population-based multicenter prospective study was conducted in Guangxi Province, China. The baseline data was collected and LTBI were measured by QuantiFERON-TB Gold In-Tube (QFT-GIT), EC-Test and T-cell spot of the TB assay (T-SPOT.TB). RESULTS: A total of 1478 patients were enrolled. when taking T-SPOT.TB as reference, the value of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and consistency that EC-Test to diagnosis LTBI in HIV was 40.42, 97.98, 85.26, 85.04 and 85.06% respectively; when taking QFT-GIT as reference, the value was 36.00, 92.57, 55.10, 85.09 and 81.13%, respectively. When the CD4 + cell count was <200 cells/µl, the accuracies of EC-Test to T-SPOT.TB and QFT-GIT were 87.12 and 88.89%, respectively; when it was 200 ≤ CD4 + ≤ 500 cells/µl, the accuracies of EC-Test was 86.20 and 83.18%, respectively; when the CD4 + cell count >500 cells/µl, the accuracies of EC-Test were 84.29 and 77.94%, respectively. The incidence of adverse reactions in EC-Test was 34.23% and the serious adverse reactions were 1.15%. CONCLUSION: EC-Test has good consistency compared with IGRAs in detecting LTBI in HIV no matter in different immunosuppression status or different regions, and the safety of EC-Test is also well, suitable for LTBI screening in HIV in high prevalence settings.

Potential implementation strategies, acceptability, and feasibility of new and repurposed TB vaccines.

Recently, two Phase 2B tuberculosis vaccine trials reported positive efficacy results in adolescents and adults. However, experience in vaccinating these age groups is limited. We identified potential implementation strategies for the M72/AS01E vaccination and BCG-revaccination-like candidates and explored their acceptability and feasibility. We conducted in-depth semi-structured interviews among key decision makers to identify implementation strategies and target groups in South Africa, India, and China. Thematic and deductive analysis using a coding framework were used to identify themes across and within settings. In all three countries there was interest in novel TB vaccines, with school-attending adolescents named as a likely target group. In China and India, older people were also identified as a target group. Routine vaccination was preferred in all countries due to stigma and logistical issues with targeted mass campaigns. Perceived benefits for implementation of M72/AS01E were the likely efficacy in individuals with Mycobacterium tuberculosis (Mtb) infection and efficacy for people living with HIV. Perceived challenges for M72/AS01E included the infrastructure and the two-dose regimen required. Stakeholders valued the familiarity of BCG but were concerned about the adverse effects in people living with HIV, a particular concern in South Africa. Implementation challenges and opportunities were identified in all three countries. Our study provides crucial information for implementing novel TB vaccines in specific target groups and on country specific acceptability and feasibility. Key groups for vaccine implementation in these settings were identified, and should be included in clinical trials and implementation planning.

The impact of the COVID-19 epidemic on tuberculosis control in China.

BACKGROUND: In response to the COVID-19 epidemic, China implemented a series of interventions that impacted tuberculosis (TB) control in the country. METHODS: Based on routine surveillance data and questionnaires, the study analyzed TB notification, follow-up examinations, and treatment outcomes. The data were split into three phases in relation to outbreak, lockdown and reopen when the nationwide COVID-19 response started in 2020: control (11 weeks prior), intensive (11 weeks during and immediately after), and regular (4 additional weeks). Data from 2017-2019 were used as baseline. FINDINGS: The notified number of TB patients decreased sharply in the 1st week of the intensive period but took significantly longer to rebound in 2020 compared with baseline. The percentages of TB patients undergoing sputum examination within one week after 2 months treatment and full treatment course in the intensive period were most affected and decreased by 8% in comparison with control period. 75•2% (221/294) of counties reallocated CDC and primary health care workers to fight the COVID-19 epidemic, 26•9% (725/2694) of TB patients had postponed or missed their follow-up examinations due to travel restrictions and fear of contracting COVID-19. INTERPRETATION: In the short term, the COVID-19 epidemic mostly affected TB notification and follow-up examinations in China, which may lead to a surge of demand for TB services in the near future. To cope with this future challenge, an emergency response mechanism for TB should be established. FUNDING: National Health Commission of China-Bill & Melinda Gates Foundation TB Collaboration project (OPP1137180).

The development and verification of "Chinese Pathogenic Mycobacteria Mass Spectrometry Database" / 中华检验医学杂志

Objective@#To establish the domestic matrix assisted laser desorption/ionisation time of flight mass spectrometry database for identification of clinical mycobacteria and evaluate its accuracy with foreign counterpart. @*Methods@#The establishment of "Chinese Pathogenic Mycobacteria Mass Spectrometry Database" : nineteen American type culture collection strains from 19 species and 183 "standardized" isolates from 42 species were selected and extracted by modified ultrasonic extraction method for spectral acquisition and database establishment based on microTyper MS. Each extract was dropped onto 12 spots and tested twice to generate 24 spectrum, then at least 20 qualified spectrum according to the standard were selected. Subsequently they were composed into one main spectra (MSP) by setting peak number maximum, peak frequency minimum and mass tolerance. Verification of database: Totally 305 mycobacteria from different regions were used for comparison of accuracy and spectral features between microTyper MS based on domestic database and imported MALDI TOF MS base on Mycobacteria Library 3.0 database. @*Results@#The database composed of 202 stains from 42 species was constructed, with an average of 4.8 in each species. The top ten were M. Kansasii(16), M. intracellulare(16), M. gordonae(16), M. fortuitum(16), M. avium(16), M. abscessus(16), M. tuberculosis(15), M. marseillense(11), M. arupense(10), M. yongongens(8). A total of 305 isolates were confirmed belonging to 22 species by sequencing. The accuracy based on this database was 99.67% (304/305), which was better than the Mycobacteria Library 3.0 database (χ2=4.06, P<0.05). @*Conclusion@#The construction of the "Chinese Pathogenic Mycobacteria Mass Spectrometry Database" meets the requirement of routine clinical application and was more accurate than its counterpart in terms of domestic comment strains.(Chin J Lab Med, 2018, 41: 519-526)

Drug Resistance Pattern of the Mycobacterium tuberculosis among Retreantment and New Cases / 医学研究杂志

Objective To investigate the incidence of drug resistance among new and retreatment TB patients from special hospital.Methods Totally 500 smear positive TB patients from June 2013 to December 2014 in Beijing Chest Hospital were enrolled.Phenotypic susceptibilities to cultured isolates were analyzed in 15 anti tuberculosis drugs by MGIT 960,include Isoniazid (INH),Rifampicin (RFP),Streptomycin (STR),Ethambuto (EMB),Kanamycin (Km),Amikacin (Am),Capreomycin (Cm),Ofloxacin (Ofx),Levofloxacin (Lfx),Moxifloxacin (Mfx),Paza-aminosalicylate (PAS),Protionamide (Pto),Linezolid (Lzd),Ethionamide (Eto),Pyrazinamide (PZA).Results A total of 500 TB cases were enrolled.71 samples among these were NTM infection and 12 samples were contaminted.The rest of 417 of cases infected with Mycobacteriuma,and the rate of drug resistance was 47.2％ (192/417) and the MDR rate was 28.2％ (120/417).The retreatment was significantly higher than that of the new in any drug resistance rate and MDR rate (P =0.000).100 of the retreatment isolates and 50 of the new isolates with Mycobacteriuma were selected to do the drug susceptibility test in 11 subsequent anti tuberculosis drugs (include:PZA,Am,Km,Cm,Ofx,Lfx,Mfx,PAS,Pto,Lzd,Eto).Five cases were contaminated,and in the rest of the cases,48 was the new and 97was the retreatment.The rate of the drug resistance to PZA,Am,Km,Cm,Ofx,Lfx,Mfx for the retreatment were significantly higher than the new (P ＜ 0.05).The rate of drug resistance to PAS,Pto,Lzd and Eto for the new and reteartment were no markedly differential in statistics.Conclusion This study further confirmed the rate of drug resistance in retreatment cases is higher,and the management of tuberculosis patients should be further strengthened.

Analysis of drug-resistance to bedaquiline and relationships between phenotypes and genotypes in ;multidrug-resistant Mycobacterium tuberculosis strains / 中华微生物学和免疫学杂志

Objective To evaluate the resistance of multidrug-resistant Mycobacterium tuberculosis ( M. tb) strains to bedaquiline ( BDQ) and to analyze the relationships between their genotypes and BDQ-re-sistant phenotypes in order to provide a scientific basis for rational use of BDQ for the treatment of multidrug-resistant tuberculosis ( MDR-TB) in clinical practice. Methods A total of 387 clinical M. tb strains, inclu-ding 100 pan-susceptible strains and 287 strains isolated from patients with MDR ( MDR-TB strains) , were enrolled in this study. Of the 287 MDR-TB strains, 77 strains were collected in Chongqing in 2015 and the other strains were collected in a national drug-resistant tuberculosis survey conducted in China during 2007 to 2008. Minimum inhibitory concentrations (MIC) of BDQ against those strains were detected. Genotypes of those strains were analyzed by Spoligotyping. Differences in the resistant rates against BDQ between Beijing genotype and non-Beijng genotype MDR-TB strains were comparatively analyzed. Results MIC50 and MIC90 of BDQ against the 287 MDR-TB strains were 0. 03 μg/ml and 0. 25 μg/ml, respectively. Nineteen out of the 287 MDR-TB strains (6. 6%) were resistant to BDQ. Based on the Spoligotyping, 195 strains were clas-sified into Beijing genotype, and the other 92 strains belonged to non-Beijing genotype. Statistical analysis revealed that the BDQ-resistant rate in Being genotype strains (4. 6%, 9/195) was lower than that in non-Beijing genotype strains (10. 9%, 10/92, χ2=3. 955, P=0. 047). In addition, the MIC50 and MIC90 of BDQ against pan-susceptible strains were 0. 03 μg/ml and 0. 12 μg/ml, respectively. Sixty-three pan-sus-ceptible strains belonged to Beijing genotype and the other 37 strains belonged to non-Beijing genotype. None of the pan-susceptible strains was resistant to BDQ. Conclusion This study indicates that BDQ showed stronger in vitro antibacterial activity against the MDR-TB strains isolated in China. A correlation between non-Beijing genotype and BDQ resistance is observed in those MDR strains. MDR strains of Beijing genotype are more susceptible to BDQ than those of non-Beijing genotype.

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

OBJECTIVE: To investigate the cost-effectiveness of a comprehensive programme for drug-resistant tuberculosis launched in four sites in China in 2011. METHODS: In 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. FINDINGS: The 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. CONCLUSION: The 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.

Genotyping and drug resistance analysis of Mycobacterium tuberculosis from China / 中华检验医学杂志

Objective To study the genotypes of representative Mycobacterium tuberculosis (M.tuberculosis) strains from China with spacer oligonucleotide typing (spoligotyping),and to investigate the prevalence of different genotypes TB in China,and analyse the relationship between genotype and drug resistance.Methods 4017 clinical isolates were collected by Chinese Center for Disease Control and Prevention from 2007 to 2008 in 31 provinces in China according to sampling principle of epidemiology.Drug susceptibility testing was performed using proportion method,and spoligotyping was chosen to carry out genotyping of these M.tuberculosis.In addition,chi-square test was used to compare the differences among the detection rate of different genotypes.Results Among the 4017 M.tuberculosis isolates,2500 ( 62.2％ ) isolates belonged to Beijing genotype.The percentage of Beijing genotypes in the northern of China was higher than that in the southern of China ( 76.5％ vs.53.2％,x2 =219.69,P ＜ 0.05 ),while T1 genotypes were more common in the southern China,compared with that in northern China ( 13.3％ vs.4.3％,x2 =219.69,P ＜ 0.05 ).The differences were statistically significant.The proportions of Rifampinresistant (21.7％ vs.21.7％ ),Ofloxacin-resistant (4.9％ vs.2.4％ ) and Multidrug-resistant ( 11.3％vs.7.4％ ) isolates among Beijing genotype strains were significantly higher than those among non-Beijing strains (x2 =22.10,14.42 and 14.83,respectively,P ＜ 0.05 ).Conclusions Beijing genotype was still predominant epidemic genotypes.The percentage of Beijing genotype showed difference between distinct areas,and the percentage of Beijing genotypes in northern China was higher than that in southern China.Beijing genotype strains reveal correlation with Rifampin-resistance,Ofloxacin-resistance and Multidrug-resistance.

Analysis of current status and difficulties in tuberculosis laboratory diagnosis / 中华检验医学杂志

The early and effective diagnosis is crucial to efficacious treatment of pulmonary tuberculosis, especially for smear negative cases and MDR-TB, and is one of the priorities of global tuberculosis control and prevention. The traditional methods which have been used for decades of years, show many well-known drawbacks, in terms of fast speed and time consuming. Recently, some new promising diagnostic methods emerged, which have been expected to optimize the diagnosis of tuberculosis, especially for MDR-TB.

Evaluation of mycolic acid analysis in identification of Mycobacterium species through SMIS / 中华检验医学杂志

Objective To evaluate the usefulness of mycolic acid for identification of Mycobacterium species using SMIS. Methods One hundred and eighteen clinical Mycobacterium isolates collected from Beijing Tuberculosis and Thoracic Tumor Research Institute through whole year of 2007 were analyzed. The 118 isolates contain 25 isolates of Mycobacterium tuberculosis and 93 non tuberculosis Mycobacterium identified by PNB method. Mycolic acid analysis using SMIS is evaluated for identification of a broad range of Mycobacteria in comparison with 16S rDNA , 16-23S rDNA ITS sequencing to measure the concordance rate and agreement, and verify the concordance rate and agreement among results of mycolic acid, sequencing and PNB in identifying Mycobacterium tuberculosis and non tuberculosis Mycobacterium. Results The concordance rate between mycolic acid method analysis and DNA sequencing is 92% ( 108/118), of which concordance rate in Mycobacterium tuberculosis complex and non tuberculosis Mycobacterium are 95% (35/37) and 90% (73/81) respectively, agreement of both is great( agreement Kappa value is 0. 96). Through retrospective analysis, the concordance of results between SMIS and PNB method analysis is 90% (106/118)and agreement is well( agreement Kappa value is 0. 73 ), the concordance of results between sequencing and PNB method analysis is also 90% ( 106/118 ) and agreement is well (agreement Kappa value is 0. 74 ),despite the identification results of 11 isolates by PNB method are discordant. Conclusion Mycolic acid analysis by SMIS enables rapid identification of a broad range of clinical Mycobacterium species, which could play an important role in polyphasic identification of Mycobacterium species.

Regulatory T cells are increased in tuberculosis patients and closely correlate with its immunopathology / 中华微生物学和免疫学杂志

Objective To determine whether regulatory T cells(Tr)are increased in patients with tuberculosis and whether they are associated with its immunopathology.Meantime,to investigate the possibility of tuberculosis(TB)as a model for studying Tr functions.Methods The lymphocyte subsets were isolated from peripheral blood mononuclear cells by sorting with flow cytometry.Total cellular RNA was extracted and RT-PCR was performed to detect the Foxp3 mRNA in purified CD3+CIM+T cells,CD3+CD8+T cells and non-CD3+CD4+CD8+T cells.Using FACS analysis.we further investigated the distribution of Foxp3+ population in CD4+ CD25+T cells.Finally,we compared the percentage of CD4+CD25highFoxp3+T cells present in 51 active patients with tuberculosis and 40 uninfected healthy control subjects by FACS.The detection of Tr infiltration of Foxp3+ cells were performed with immunohistochemistry(IHC)method on tuberculosis pathological sections.Results Foxp3 was specific expressed in CD3+CD4+T cells,either in tuberculosis patients or healthy control subjects.Foxp3+ T cells took about 85%fraction of CD4+ CD25highpopulation.We used CD4+CD25high Foxp3+as a detective markers for Tr in the FACS analysis.The results showed that patients with active TB had a 4.4 fold higher percentage within the CD4+T cells in peripheral blood compared to healthy control group(modian,1.01%vs 0.23%,P<0.01).Much higher frequency of Tr were found along with T cells infiltration at the tuberculosis pathological tissues.A few individuals that we can followed indicated the expanded Tr was declined after curative treatment with operation.Conclusion Tr cells are increased in tuberculosis patients and closely correlate with its immunopathology.Tuberculosis should be a valuable model for Tr functional study.

Location of extracellular cysteine-rich domains of 4-1BB binding to murine 4-1BB ligand and analysis of its possible structure / 中华微生物学和免疫学杂志

ObJective To locate the cysteine-rich domains(CRD) of murine 4-1BB binding to its natural ligand. Methods A serial soluble extracellular CRDs of routine 4-1BB and 4-1BBL fusion proteins was constructed and prepared. The binding of purified 4-1BB-Igs to 4-1BBL and 4-1BB monoclonal antibody were tested using ELISA assay and Western blot analysis. Blocking experiment with 4-1BBL and 4-1BB mon-oclonal antibody was performed by ELISA assay. Results All truncated overlapped proteins containing ex-tracellular CRD Ⅱ of murine 4-1BB were able to bind to 4-1BBL by ELISA assay, excepting the CRD Ⅰ do-main alone. A 4-1BB monoclonal antibody proved to block the interaction of 4-1BB and 4-1BBI, was also able to bind to CRD Ⅱ. Conclusion Murine 4-1BBL whose specificity was mapped to CRD Ⅱ of 4-1BB ex-tracellular region with a possible conformational structure.