Predicting the incidence of rifampicin resistant tuberculosis in Yunnan, China: a seasonal time series analysis based on routine surveillance data.

BACKGROUND: Rifampicin resistant tuberculosis (RR-TB) poses a growing threat to individuals and communities. This study utilized a seasonal autoregressive integrated moving average (SARIMA) model to quantitatively predict the monthly incidence of RR-TB in Yunnan Province which could guide government health administration departments and the centers for disease control and prevention (CDC) in preventing and controlling the RR-TB epidemic. METHODS: The study utilized routine surveillance reporting data from the infectious Disease Network Surveillance and Reporting System. Monthly incidence rates of RR-TB were collected from January 2019 to December 2022. A time series SARIMA model was used to predict the number of monthly RR-TB cases in Yunnan Province in 2023, and the model was validated using time series plots, seasonal and non-seasonal differencing, autocorrelation and partial autocorrelation analysis, and white noise tests. RESULTS: From 2019 to 2022, the incidence of RR-TB decreases as the incidence of all TB decreases (P < 0.05). There was no significant change in the proportion of RR-TB among all TB cases, which remained within 2.5% (P>0.05). The time series decomposition shows that it presented obvious seasonality, periodicity and randomness after being decomposed. Time series analysis was performed on the original series after 1 non-seasonal difference and 1 seasonal difference, the ADF test showed P < 0.05. According to ACF and PACF, the SARIMA (1, 1, 1) (1, 1, 0)12 model was chosen and statistically significant model parameter estimates (P < 0.05). The predicted seasonal trend of RR-TB incidence in 2019 to 2023 was similar to the actual data. The percentage accuracy in the prediction excesses 80% in 2019 to 2022 and is all within 95% CI. However there was a certain gap between the actual incidence and the predicted value in 2023, and the acutual incidence had increased by 12.4% compared to 2022. The percentage of accuracy in the prediction was only 70% in 2023. CONCLUSIONS: We found the incidence of RR-TB was based on that of all TB in Yunnan. The SARIMA model successfully predicted the seasonal incidence trend of RR-TB in Yunnan Province in 2019 to 2023, but the prediction precision could be influenced by factors such as new infectious disease outbreaks or pandemics, social issues, environmental challenges or other unknown risks. Hence CDCs should pay special attention to the post epidemic effects of new infectious disease outbreaks or pandemics, carry out monitoring and early warning, and better optimize disease prediction models.

Availability of drugs for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis in the World Health Organization European Region, October 2023.

The BPaLM regimen (bedaquiline, pretomanid, linezolid and moxifloxacin) recently recommended by the World Health Organization offers short, safe, and effective treatment for multidrug-resistant/rifampicin-resistant tuberculosis (TB). In a survey with national TB focal points in 18 central and western European countries to explore barriers for the implementation of BPaLM, only three reported full availability of pretomanid, a necessary component of this regimen. Implementation barriers included financing and procurement. Solutions on national and supranational level are needed to guarantee universal access.

Pharmacokinetics and Safety of Bedaquiline in Human Immunodeficiency Virus (HIV)-Positive and Negative Older Children and Adolescents With Rifampicin-Resistant Tuberculosis.

BACKGROUND: Pharmacokinetic data for bedaquiline in children are limited. We described the pharmacokinetics and safety of bedaquiline in South African children and adolescents receiving treatment for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in routine care. METHODS: In this observational cohort study, children aged 6-17 years receiving bedaquiline at recommended doses as part of MDR/RR-TB treatment underwent semi-intensive pharmacokinetic sampling. Bedaquiline and the M2 metabolite plasma concentrations were quantified, and nonlinear mixed-effects modeling performed. Pediatric data were described using a pre-established model of bedaquiline pharmacokinetics in adults. The exposure reference was 187 µg ⋅ h/mL, the median weekly area under the curve (AUC) of adults at week 24 of treatment with bedaquiline. Safety was assessed through monthly clinical, blood and electrocardiogram monitoring, and treatment outcomes described. RESULTS: Fifteen children (3 human immunodeficiency virus [HIV]-positive) with median age 13.3 years (range 6.5-16.3) were included. A bedaquiline pharmacokinetic model was adapted to be allometrically scaled in clearance and volume, centered in the median child population weight. Bedaquiline bioavailability was 57% of that in adults. Overall bedaquiline exposures were below target, and AUC reference attainment was achieved in only 3 (20%) children. Ten children experienced 27 adverse events at least possibly related to bedaquiline; no adverse events led to bedaquiline withdrawal. Two adverse events (arthritis and arthralgia) were considered severe, and 2 children had mild QT interval corrected for heart rate using Fridericia's formula (QT) prolongation. CONCLUSIONS: The evaluated doses of bedaquiline in children ≥ 6 years of age were safe but achieved slightly lower plasma concentrations compared to adults receiving the recommended dose, possibly due to delayed food intake relative to bedaquiline administration.

Evolution and spread of a highly drug resistant strain of Mycobacterium tuberculosis in Papua New Guinea.

BACKGROUND: Molecular mechanisms determining the transmission and prevalence of drug resistant tuberculosis (DR-TB) in Papua New Guinea (PNG) are poorly understood. We used genomic and drug susceptibility data to explore the evolutionary history, temporal acquisition of resistance and transmission dynamics of DR-TB across PNG. METHODS: We performed whole genome sequencing on isolates from Central Public Health Laboratory, PNG, collected 2017-2019. Data analysis was done on a composite dataset that also included 100 genomes previously sequenced from Daru, PNG (2012-2015). RESULTS: Sampled isolates represented 14 of the 22 PNG provinces, the majority (66/94; 70%) came from the National Capital District (NCD). In the composite dataset, 91% of strains were Beijing 2.2.1.1, identified in 13 provinces. Phylogenetic tree of Beijing strains revealed two clades, Daru dominant clade (A) and NCD dominant clade (B). Multi-drug resistance (MDR) was repeatedly and independently acquired, with the first MDR cases in both clades noted to have emerged in the early 1990s, while fluoroquinolone resistance emerged in 2009 (95% highest posterior density 2000-2016). We identified the presence of a frameshift mutation within Rv0678 (p.Asp47fs) which has been suggested to confer resistance to bedaquiline, despite no known exposure to the drug. Overall genomic clustering was significantly associated with rpoC compensatory and inhA promoter mutations (p < 0.001), with high percentage of most genomic clusters (12/14) identified in NCD, reflecting its role as a potential national amplifier. CONCLUSIONS: The acquisition and evolution of drug resistance among the major clades of Beijing strain threaten the success of DR-TB treatment in PNG. With continued transmission of this strain in PNG, genotypic drug resistance surveillance using whole genome sequencing is essential for improved public health response to outbreaks. With occurrence of resistance to newer drugs such as bedaquiline, knowledge of full drug resistance profiles will be important for optimal treatment selection.

Patient and health-care provider experience of a person-centred, multidisciplinary, psychosocial support and harm reduction programme for patients with harmful use of alcohol and drug-resistant tuberculosis in Minsk, Belarus.

BACKGROUND: Tuberculosis (TB) often concentrates in groups of people with complex health and social issues, including alcohol use disorders (AUD). Risk of TB, and poor TB treatment outcomes, are substantially elevated in people who have AUD. Médecins sans Frontières and the Belarus Ministry of Health have worked to improve treatment adherence in patients with multi-drug or rifampicin resistant (MDR/RR)-TB and harmful use of alcohol. In 2016, a person-centred, multidisciplinary, psychosocial support and harm reduction programme delivered by TB doctors, counsellors, psychiatrists, health-educators, and social workers was initiated. In 2020, we described patient and provider experiences within the programme as part of a wider evaluation. METHODS: We recruited 12 patients and 20 health-care workers, using purposive sampling, for in-depth individual interviews and focus group discussions. We used a participant-led, flexible, exploratory approach, enabling participants and the interviewer to shape topics of conversation. Qualitative data were coded manually and analysed thematically. As part of the analysis process, identified themes were shared with health-care worker participants to enable their reflections to be incorporated into the findings. RESULTS: Key themes related to the patients' and practitioners experience of having and treating MDRTB with associated complex health and social issues were: fragility and despair and guidance, trust and health. Prejudice and marginalisation were global to both themes. Counsellors and other health workers built a trusting relationship with patients, enabling guidance through a multi-disciplinary approach, which supported patients to achieve their vision of health. This guidance was achieved by a team of social workers, counsellors, doctors and health-educators who provided professional and individualised help for patients' illnesses, personal or interpersonal problems, administrative tasks, and job searches. CONCLUSIONS: Patients with MDR/RR-TB and harmful use of alcohol faced complex issues during treatment. Our findings describe how person-centred, multi-disciplinary, psychosocial support helped patients in this setting to cope with these challenges and complete the treatment programme. We recommend that these findings are used to: i) inform programmatic changes to further boost the person-centred care nature of this program; and ii) advocate for this type of person-centred care approach to be rolled out across Belarus, and in contexts that face similar challenges.

Distribution and Clonality of drug-resistant tuberculosis in South Africa.

BACKGROUND: Studies have shown that drug-resistant tuberculosis (DR-TB) in South Africa (SA) is clonal and is caused mostly by transmission. Identifying transmission chains is important in controlling DR-TB. This study reports on the sentinel molecular surveillance data of Rifampicin-Resistant (RR) TB in SA, aiming to describe the RR-TB strain population and the estimated transmission of RR-TB cases. METHOD: RR-TB isolates collected between 2014 and 2018 from eight provinces were genotyped using combination of spoligotyping and 24-loci mycobacterial interspersed repetitive-units-variable-number tandem repeats (MIRU-VNTR) typing. RESULTS: Of the 3007 isolates genotyped, 301 clusters were identified. Cluster size ranged between 2 and 270 cases. Most of the clusters (247/301; 82.0%) were small in size (< 5 cases), 12.0% (37/301) were medium sized (5-10 cases), 3.3% (10/301) were large (11-25 cases) and 2.3% (7/301) were very large with 26-270 cases. The Beijing genotype was responsible for majority of RR-TB cases in Western and Eastern Cape, while the East-African-Indian-Somalian (EAI1_SOM) genotype accounted for a third of RR-TB cases in Mpumalanga. The overall proportion of RR-TB cases estimated to be due to transmission was 42%, with the highest transmission-rate in Western Cape (64%) and the lowest in Northern Cape (9%). CONCLUSION: Large clusters contribute to the burden of RR-TB in specific geographic areas such as Western Cape, Eastern Cape and Mpumalanga, highlighting the need for community-wide interventions. Most of the clusters identified in the study were small, suggesting close contact transmission events, emphasizing the importance of contact investigations and infection control as the primary interventions in SA.

Direct detection of resistance to fluoroquinolones/SLIDs in sputum specimen by GenoType MTBDRsl v.2.0 assay A study from Eastern Uttar Pradesh, India.

BACKGROUND: According to World Health Organization (WHO), drug-resistant tuberculosis (DR-TB) is a major contributor to antimicrobial resistance globally and continues to be a public health threat. Annually, about half a million people fall ill with DR-TB globally. The gradual increase in resistance to fluoroquinolones (FQs) and second-line injectable drugs (SLIDs), poses a serious threat to effective TB control and adequate patient management. Therefore, WHO suggests the use of GenoType MTBDRsl v.2.0 assay for detection of multiple mutations associated with FQs and SLIDs. Hence, the study was conducted to determine the prevalence of resistance to FQs and SLIDs by comparing direct GenoType MTBDRsl v.2.0 assay with phenotypic drug susceptibility testing (DST). METHODS: The study was conducted on 1320 smear positive sputum samples from a total of 2536 RR-TB, confirmed by GeneXpert MTB/RIF. The smear positive specimens were decontaminated, and DNA extraction was performed. Furthermore, the extracted DNA was used for GenoType MTBDRsl v.2.0 assay. While 20% of the decontaminated specimens were inoculated in Mycobacterium growth indicator tube (MGIT) for drug susceptibility testing (DST). RESULTS: Out of 1320 smear positive sputum samples, 1178 were identified as Mycobacterium tuberculosis complex (MTBC) and remaining were negative by GenoType MTBDRsl v.2.0 assay. Of the 1178 MTBC positive, 26.6% were sensitive to both FQs and SLIDs, whereas 57.3% were only FQs resistant and 15.9% were resistant to both FQs and SLIDs. Further DST of 225 isolates by liquid culture showed that 17% were sensitive to both FQs and SLIDs, 61.3% were only FQs resistant and 21.3% were resistant to both. The specificity for FQs and SLIDs was 92.31% and 100% whereas sensitivity was 100% respectively by GenoType MTBDRsl v.2.0 assay in direct sputum samples. CONCLUSIONS: Our study clearly suggests that GenoType MTBDRsl v.2.0 assay is a reliable test for the rapid detection of resistance to second-line drugs after confirmation by GeneXpert MTB/RIF assay for RR-TB. Though, high rate FQ (ofloxacin) resistance was seen in our setting, moxifloxacin could be used as treatment option owing to very low resistance.

Improving Quality of Patient Data for Treatment of Multidrug- or Rifampin-Resistant Tuberculosis.

International policy for treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR TB) relies largely on individual patient data (IPD) from observational studies of patients treated under routine conditions. We prepared guidance on which data to collect and what measures could improve consistency and utility for future evidence-based recommendations. We highlight critical stages in data collection at which improvements to uniformity, accuracy, and completeness could add value to IPD quality. Through a repetitive development process, we suggest essential patient- and treatment-related characteristics that should be collected by prospective contributors of observational IPD in MDR/RR TB.

Prevalence and factors associated with multidrug/rifampicin resistant tuberculosis among suspected drug resistant tuberculosis patients in Botswana.

BACKGROUND: To investigate the prevalence and factors associated with the prevalence of multidrug/rifampicin-resistant tuberculosis among suspected drug resistant tuberculosis patients in Botswana. METHODS: A retrospective review of medical records of suspected drug resistant tuberculosis patients receiving care at public health facilities in Botswana was conducted from January, 2013 and December, 2014. Patient characteristics and drug susceptibility data were abstracted from 2568 medical records on to a pre-tested checklist form. The prevalence of multidrug/rifampicin resistance was computed. Bivariate and multivariate logistic regression was carried out to determine the factors associated with the prevalence of multidrug/rifampicin in the study population. RESULTS: Overall, multidrug/ rifampicin - resistance among suspected drug resistant tuberculosis patients in Botswana were found in 139 (5.4%) cases with 1.3% among new cases and 7.7% among previously treated tuberculosis patients. Being a previously treated tuberculosis patient and having a positive smear were found to be factors associated with the prevalence of multidrug/rifampicin-resistant tuberculosis (p < 0.05). However, age, sex, living in urban area and HIV status were not associated with this disease (p > 0.05). CONCLUSION: This study highlights a low burden of multidrug/rifampicin resistant tuberculosis among suspected drug resistant tuberculosis patients receiving care at public health facilities in Botswana. Strategies in controlling MDR/RR-TB should emphasize on effective implementation of Directly Observation Treatment - short course strategy, continuous surveillance of drug resistance cases, prevention of the development of new cases of MDR/RR-TB and to treat existing patients. Further interventions should focus on strengthening TB infection control activities.

Genetic polymorphism of human leucocyte antigen and susceptibility to multidrug-resistant and rifampicin-resistant tuberculosis in Han Chinese from Hubei Province.

We determined the high-resolution allele and haplotype frequencies at the human leucocyte antigen (HLA)A, B and DRB1 loci in the Han population of Hubei province, the TB endemic area of Central China, with pulmonary tuberculosis (PTB), and established the relationship between HLA-A, B and DRB1 alleles as well as haplotypes and susceptibility to multidrug-resistant and rifampicin-resistant tuberculosis (MDR/RR-TB). Blood samples were drawn from 174 patients with MDR/RR-TB and 838 patients with drug-susceptible PTB in ethnic Han population from Hubei province (central China). Four-digit allele genotyping of HLA- A, B and DRB1 loci was performed using polymerase chain reaction with sequence-specific oligonucleotide probes (PCR- SSOP). The allele and haplotype frequencies of HLA-A, B and DRB1 were determined and compared between patients with MDR/RR-TB and patients with drug-susceptible PTB. Statistical analysis of the generated data indicated no departure from expectation of Hardy-Weinberg equilibrium (HWE) at all loci of the control group. Multivariate analysis identified allele DRB1*08:01 (p < .0001; OR = 174.5, 95% CI 15.3-1987.2) as independent predictor of MDR/RR-TB, except for old age (p < .0001; OR = 10. 9, 95% CI 7.6-15.8), previous treatment history (p < .0001; OR = 11.0, 95% CI 7.2-16.7) and poor compliance to treatment (p < .0001; OR = 12.9, 95% CI 8.4-20.0). While in the subgroup of new TB cases, DRB1*08:01 (p < .0001; OR = 80.3, 95% CI 7.0-917.1) and older age (p < .0001; OR = 3.9, 95% CI 2.4-6.4) were independent susceptibility factors for primary MDR/RR-TB. Our results suggest that a combination of clinical and host genetic information about tuberculosis patients may contribute to prediction and early detection of MDR/RR-TB.

Determinant of catastrophic costs associated with treatment for rifampicin-resistant TB in households in the Republic of Moldova.

SETTING: The Republic of Moldova is a lower-middle-income country. Patients with TB face some barriers to accessing TB services. Welfare benefits are available during TB treatment. OBJECTIVES: We aimed to determine the proportion of rifampicin-resistant TB (RR-TB) households that experienced catastrophic costs due to TB at a threshold of ≥20% of household income and investigate the associated risk factors. DESIGN: A cross-sectional countrywide study comprised 430 patients with RR-TB who had received TB treatment as an inpatient or outpatient for at least 2 months. RESULTS: RR-TB patients lost 30% of their household income in inpatient and 70% in outpatient TB care. TB-related costs were associated with being unofficially employed or unemployed (aOR 1.9, 95% CI 1.1-3.3), having fewer household members (aOR 2.1, 95% CI 1.3-3.5), having an income that accounted for over 50% of household income (aOR 2.4, 95% CI 1.5-3.8), and being a poor household (aOR 2.2, 95% CI 1.2-3.9). CONCLUSION: Although TB health services are provided to patients free of charge, 26% of RR-TB households experienced catastrophic TB costs. The associated factors should be considered to improve patient-centred TB care, especially in vulnerable groups. Welfare payments mitigate TB costs.

CADRE: La République de Moldova est un pays à revenu intermédiaire de la tranche inférieure. Les patients atteints de TB se heurtent à certains obstacles pour accéder aux services de lutte contre la TB. Des prestations sociales sont disponibles pendant le traitement de la TB. OBJECTIFS: Nous avons cherché à déterminer la proportion de ménages atteints de TB résistant à la rifampicine (RR-TB) qui ont subi des coûts catastrophiques dus à la TB à un seuil de ≥20% du revenu du ménage et à étudier les facteurs de risque associés. MÉTHODE: Une étude transversale à l'échelle nationale a porté sur 430 patients atteints de RR-TB qui avaient reçu un traitement antituberculeux en hospitalisation ou en consultation externe pendant au moins 2 mois. RÉSULTATS: Les patients atteints de RR-TB ont perdu 30% du revenu de leur ménage en hospitalisation et 70% en soins ambulatoires. Les coûts liés à la TB étaient associés au fait d'avoir un emploi non officiel ou un chômeur (OR ajusté [ORa] 1,9 ; IC à 95% 1,1 à 3,3), d'avoir moins de membres du ménage (ORa 2,1 ; IC à 95% 1,3 à 3,5), d'avoir un revenu représentant plus de 50 % du revenu du ménage (ORa 2,4 ; IC à 95% 1,5 à 3,8) et d'être un ménage pauvre (ORa 2,2 ; IC à 95% 1,2 à 3,9). CONCLUSION: Bien que les services de santé liés à la TB soient fournis gratuitement aux patients, 26% des ménages atteints de RR-TB ont subi des coûts catastrophiques. Les facteurs associés doivent être pris en compte pour améliorer les soins de la TB centrés sur le patient, en particulier dans les groupes vulnérables. Les prestations sociales atténuent les coûts de la TB.

Efficacy and safety of the all-oral bedaquiline-containing regimen as treatment for pediatric multidrug/rifampicin-resistant tuberculosis: a multicenter, retrospective, cohort study.

OBJECTIVE: The study aimed to observe the efficacy and safety of an all-oral bedaquiline (BDQ)-containing regimen for pediatric multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) through a multicenter, retrospective study in China. METHODS: In the study, pediatric patients receiving all-oral BDQ-containing regimen (BDQ group) with clinical matched control group were included, the control group received an injection-containing regimen. The treatment outcomes and the incidence of adverse events (AEs) were compared and analyzed. RESULTS: 79 pediatric patients were enrolled, including 37 cases in BDQ group and 42 cases in the control group, the median age was 12 {8-16} and 11 {9-15} in both groups respectively. Favorable treatment outcome and cure rate in BDQ group were significantly higher than those in control group (100%vs 83.3%, p 0.03; 94.6%vs 63.3%, p 0.00). Median time of sputum culture conversion in BDQ group was significantly shorter than that in the control group (4 weeks vs 8 weeks, p 0.00). The incidence of AEs in the BDQ group was significantly less than that in the control group (48.6% vs 71.4%, p 0.03). No AEs leading to treatment discontinuation of BDQ occurred. CONCLUSIONS: The all-oral BDQ-containing regimens may be effective and safe in the Chinese pediatric population.

TB and poverty: the effect of rifampicin-resistant TB on household income.

SETTING: The Republic of Moldova, one of Europe's poorest countries, also bears one of the highest burdens of rifampicin-resistant TB (RR-TB). OBJECTIVES: To trace the patients' journey through TB in terms of the relationship with poverty and assess its determinants. DESIGN: This cross-sectional study used secondary data from a survey assessing catastrophic costs in RR-TB-affected households. RESULTS: Data were obtained from 430 RR-TB patients. The percentage of poor TB-affected households rose from 65% prior to TB to 86% after TB treatment completion (P < 0.001). Social factors leading to poverty were identified for each stage: diagnostic period (history of incarceration: cOR 2.3, 95% CI 1.1-5.2); treatment period (being unemployed or unofficially employed: cOR 6.7, 95% CI 4.3-10.0); and post-treatment (being married or cohabiting: cOR 5.7, 95% CI 2.9-11.0). Participants who had ≥3 members in their households were more likely to be poor at all TB stages: diagnostic period (cOR 5.7, 95% CI 3.7-8.8), treatment period (cOR 3.8, 95% CI 2.5-5.6) and post-treatment (cOR 7.2, 95% CI 3.6-14.3). CONCLUSION: The study identified risk factors associated with poverty at each stage of TB. These findings outline that innovative social protection policies are required to protect TB patients against poverty.

CONTEXTE: La République de Moldavie est l'un des pays les plus pauvres d'Europe et l'un des plus touchés par la TB résistante à la rifampicine (RR-TB). OBJECTIFS: Nous avons cartographié le parcours des patients atteints de TB en lien avec la pauvreté et évalué les déterminants associés. MÉTHODE: Cette étude transversale a analysé des données secondaires issues d'une enquête évaluant les coûts catastrophiques supportés par les ménages touchés par la RR-TB. RÉSULTATS: Des données ont été recueillies auprès de 430 patients atteints de RR-TB. Le taux de ménages pauvres touchés par la TB est passé de 65% avant le traitement à 86% après la fin du traitement de la TB (P < 0,001). Pour chaque stade de la TB, les facteurs sociaux conduisant à la pauvreté ont été identifiés : période de diagnostic (antécédents d'emprisonnement : rapport de cotes brut (cOR) 2,3, IC à 95% 1,1­5,2) ; période de traitement (être au chômage ou employé officieux : cOR 6,7 ; IC 95% 4,3­10,0) ; et post-traitement (être marié ou cohabitant : cOR 5,7, IC 95% 2,9­11,0). Les participants dont le ménage comptait ≥3 membres étaient plus susceptibles d'être pauvres à tous les stades de la TB : période de diagnostic (cOR 5,7 ; IC à 95% 3,7­8,8), période de traitement (cOR 3,8 ; IC à 95% 2,5­5,6) et post-traitement (cOR 7,2 ; IC à 95% 3,6­14,3). CONCLUSION: L'étude a permis d'identifier des facteurs de risque liés à la pauvreté à toutes les étapes de la TB. Ces résultats soulignent l'importance de mettre en place des politiques de protection sociale novatrices pour prévenir l'appauvrissement des patients atteints de TB.

Drug recommendation for optimization on treatment outcome for MDR/RR-TB based on a multi-center, large scale, retrospective cohort study in China.

OBJECTIVE: With the change in drug-resistant pattern, MDR/RR-TB was faced with underlying changes in regimens. A multi-center, large-scale, retrospective study performed aims to provide a recommendation of drug selection on optimization of outcome for the patients. METHOD: The study was conducted in six TB-specialized hospitals in China. Patients were included from 2018-2021 and followed up throughout the treatment. Using a multivarariable and propensity score-matched logistic regression analysis, we evaluated associations between outcomes and drug use, as well as clinical characteritics. RESULTS: Of 3112 patients, 74.29% had treatment sucess, 14.52% lost to follow-up, 9.67% failure, and 1.51% died. Treatment success was positively associated with Bedaquiline(Bdq), Linezolid(Lzd), and Cycloserin(Cs). Capreomycin(Cm) increased the risk of unfavorable outcomes. other drugs such as Amikacin(Amk) and clofazimine had no significant effect on outcomes. If isolates were susceptible to fluoroquinolones(FQs), FQs could decrease the risk of unfavorable outcomes. CONCLUSIONS: The recommendation order for the treatment of MDR/RR-TB is Bdq, Lzd, and Cs. FQs were decreased in use intensity. Injection drugs, whether Amk or Cm, are not recommended.

Availability of drugs and resistance testing for bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaL(M)) regimen for rifampicin-resistant tuberculosis in Europe.

OBJECTIVES: Multidrug-resistant/rifampicin-resistant tuberculosis is a major obstacle to successful tuberculosis control. The recommendation by the WHO to use bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaL(M)) for 6 months, based on results of two trials with high efficacy and low toxicity, has revolutionized treatment options. METHODS: In this study, representatives of the Tuberculosis Network European Trials group in 44 of 54 countries of the WHO Europe region documented the availability of the medicines and drug susceptibility testing (DST) of the BPaL(M) regimen through a structured questionnaire between September and November 2023. RESULTS: In total, 24 of 44 (54.5%), 42 of 44 (95.5%), 43 of 44 (97.7%), and 43 of 44 (97.7%) countries had access to pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, 23 of 44 (52.3%) countries had access to all the drugs composing the BPaL(M) regimen. In total, 21 of 44 (47.7%), 37 of 44 (84.1%), 40 of 44 (90.9%), and 41 of 44 (93.2%) countries had access to DST for pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, DST was available for all medicines composing the BPaL(M) regimen in 21 of 44 (47.7%) countries, including countries where pretomanid DST was available at specialized laboratories. The availability of DST for the drugs the countries had access to, varied from 87.5% to 95.3% (pretomanid 21 of 24 (87.5%), bedaquiline 37 of 42 (88.1%), linezolid 40 of 43 (93.1%) and moxifloxacin 41 of 43 (95.3%)). DISCUSSION: In only about half of the countries participating in the survey, clinicians had access to all the BPaL(M) regimen drugs. A complete DST for the BPaL(M) medicines was possible in less than half of the countries, because of the low accessibility of DST for pretomanid. Equal access to new regimens is urgently needed in Europe and a rapid scale up of DST, especially for pretomanid, is important to prevent unnoticed spread of drug resistance.

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

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.

The Safety and Efficacy of Prolonged Use of Bedaquiline for the Treatment of Patients with Pulmonary Multi-Drug Resistant/Rifampin-Resistant Tuberculosis: A Prospective, Cohort Study in China.

Objective: To evaluate the safety, tolerability, and efficacy of prolonged bedaquiline (Bdq) treatment in patients with multi-drug/rifampin-resistant tuberculosis (MDR/RR-TB). Methods: This prospective cohort study was performed from August 2018 to August 2021. Patients diagnosed with MDR/RR-TB who met the inclusion criteria were prospectively included. Patients were treated with individual regimens of 18-20 months containing Bdq for six months or a prolonged course of nine or 12 months according to treatment demands, and the efficacy and safety with a different course of Bdq-containing regimens were compared and evaluated. Results: A total of 159 MDR/RR-TB patients were included in the study, including 96 cases with six months of Bdq, 50 cases with nine months of Bdq, and 13 patients with 12 months of Bdq. The treatment success rates were 89.6%, 90%, and 84.6% in Bdq at six months, nine months, and 12 months, respectively, which were not statistically different (P = 0.85). The main adverse events (AEs) were anemia, thrombocytopenia, and liver dysfunction in all patients, with no significant difference among the three groups. Patients who had fewer drugs chosen, disseminated lesions or lesions that were slowly absorbed, and severe cavities were the common reasons for prolonged use of Bdq. Conclusion: Prolonged course use of Bdq from six months to 12 months clinically proved to be safe and efficient, and patients with severe or disseminated lesions had the chance to prolong the use of Bdq for more than six months to achieve optimal treatment outcomes.

Time to Treatment and Risk Factors for Unsuccessful Treatment Outcomes among People Who Started Second-Line Treatment for Rifampicin-Resistant or Multi-Drug-Resistant Tuberculosis in the Kyrgyz Republic, 2021.

The Kyrgyz Republic is a high-burden country for rifampicin resistant/multi-drug resistant tuberculosis (RR/MDR-TB). TB control efforts rely on early diagnosis and initiation of people on effective regimens. We studied the interval from diagnosis of RR-TB to starting treatment and risk factors for unsuccessful outcomes among people who started RR/MDR-TB treatment in 2021. We conducted a cohort study using country-wide programme data and used binomial regression to determine associations between unsuccessful outcomes and predictor variables. Of the 535 people included in the study, three-quarters were in the age category 18-59 years, and 68% had past history of TB. The median (IQR) time from onset of TB symptoms to diagnosis was 30 (11-62) days, 1 (0-4) days from diagnosis to starting treatment, and 35 (24-65) days from starting treatment to receipt of second-line drug susceptibility test (SL-DST) results. Overall, 136 (25%) had unsuccessful outcomes. Risk factors for unsuccessful outcomes were being homeless, fluroquinolone resistance, having unknown HIV status, past TB treatment, male gender and being unemployed. Treatment outcomes and the interval from diagnosis to starting treatment were commendable. Further reductions in unsuccessful outcomes by be achieved through ensuring timely diagnosis and access to SL-DSTs and by reducing the proportion of people who are lost to follow-up.

Multiplex LNA probe-based RAP assay for rapid and highly sensitive detection of rifampicin-resistant Mycobacterium tuberculosis.

Objectives: The World Health Organization (WHO) Global tuberculosis Report 2021 stated that rifampicin-resistant tuberculosis (RR-TB) remains a major public health threat. However, the in-practice diagnostic techniques for RR-TB have a variety of limitations including longer time, lack of sensitivity, and undetectable low proportion of heterogeneous drug resistance. Methods: Here we developed a multiplex LNA probe-based RAP method (MLP-RAP) for more sensitive detection of multiple point mutations of the RR-TB and its heteroresistance. A total of 126 clinical isolates and 78 sputum samples collected from the National Tuberculosis Reference Laboratory, China CDC, were tested by MLP-RAP assay. In parallel, qPCR and Sanger sequencing of nested PCR product assay were also performed for comparison. Results: The sensitivity of the MLP-RAP assay could reach 5 copies/µl using recombinant plasmids, which is 20 times more sensitive than qPCR (100 copies/µl). In addition, the detection ability of rifampicin heteroresistance was 5%. The MLP-RAP assay had low requirements (boiling method) for nucleic acid extraction and the reaction could be completed within 1 h when placed in a fluorescent qPCR instrument. The result of the clinical evaluation showed that the MLP-RAP method could cover codons 516, 526, 531, and 533 with good specificity. 41 out of 78 boiled sputum samples were detected positive by MLP-RAP assay, which was further confirmed by Sanger sequencing of nested PCR product assay, on the contrary, qPCR was able to detect 32 samples only. Compared with Sanger sequencing of nested PCR product assay, both the specificity and sensitivity of the MLP-RAP assay were 100%. Conclusion: MLP-RAP assay can detect RR-TB infection with high sensitivity and specificity, indicating that this assay has the prospect of being applied for rapid and sensitive RR-TB detection in general laboratories where fluorescent qPCR instrument is available.

Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial.

BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. METHODS: endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. DISCUSSION: This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.