Clinical profiles of multidrug-resistant and rifampicin-monoresistant tuberculosis in Korea, 2018-2021: a nationwide cross-sectional study.

BACKGROUND: This study aimed to identify the clinical characteristics of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) in the Republic of Korea. METHODS: Data of notified people with tuberculosis between July 2018 and December 2021 were retrieved from the Korea Tuberculosis Cohort database. MDR/RR-TB was further categorized according to isoniazid susceptibility as follows: (1) MDR-TB, (2) rifampicin-monoresistant tuberculosis (RMR-TB), and (3) RR-TB if susceptibility to isoniazid was unknown. Multivariable logistic regression analysis was conducted to identify the factors associated with MDR/RR-TB. RESULTS: Between 2018 and 2021, the proportion of MDR/RR-TB cases among all TB cases and TB cases with known drug susceptibility test results was 2.1% (502/24,447). The proportions of MDR/RR-TB and MDR-TB cases among TB cases with known drug susceptibility test results were 3.3% (502/15,071) and 1.9% (292/15,071), respectively. Among all cases of rifampicin resistance, 31.7% (159/502) were RMR-TB and 10.2% (51/502) were RR-TB. Multivariable logistic regression analyses revealed that younger age, foreigners, and prior tuberculosis history were significantly associated with MDR/RR-TB. CONCLUSION: Rapid identification of rifampicin resistance targeting the high-risk populations, such as younger generations, foreign-born individuals, and previously treated patients are necessary for patient-centered care.

Treatment Outcomes and Associated Influencing Factors Among Patients with Rifampicin-Resistant Tuberculosis: A Multicenter, Retrospective, Cohort Study in China.

Objective: Rifampin-resistant tuberculosis (RR-TB) remains a serious global public health concern. We assessed treatment outcomes and associated influencing factors among RR-TB patients in China. Methods: This research enrolled 1339 patients who started RR-TB treatment between May 2018 and April 2020 in China retrospectively. Data were collected from the electronic medical records. Multivariable logistic regression analysis was used to identify the influencing factors related to unfavorable outcomes. Results: Of the 1339 RR-TB patients, 78.8% (1055/1339) achieved treatment success (cured or treatment completed), 5.1% (68/1339) experienced treatment failure, 1.1% (15/1339) died during treatment, 10.1% (135/1339) were lost to follow-up, and 4.9% (66/1339) were not evaluated. About 67.7% (907/1339) of patients experienced at least one adverse event (AE). The most common AE was hypohepatia (507/1339, 37.9%), followed by hyperuricemia (429/1339, 32.0%), anemia (368/1339, 27.5%), electrolyte disturbance (318/1339, 23.7%), peripheral neuritis (245/1339, 18.3%), and gastrointestinal reactions (203/1339, 15.2%). Multivariate analysis showed that age ≥60 years [adjusted odds ratio (aOR): 1.96, 95% confidence interval (CI): 1.39-2.77], national minority (aOR: 2.36, 95% CI: 1.42-3.93), smoking (aOR: 1.50, 95% CI: 1.10-2.04), cardiopathy (aOR: 2.90, 95% CI: 1.33-6.31), tumors (aOR: 9.84, 95% CI: 2.27-42.67), immunocompromise (aOR: 2.17, 95% CI: 1.21-3.91), re-treated TB (aOR: 1.46, 95% CI: 1.08-1.97), and experienced gastrointestinal reactions (aOR: 2.27, 95% CI: 1.52-3.40) were associated with unfavorable outcomes. Body mass index (BMI) ≥18.5 kg/m2, regimens containing bedaquiline and experienced adverse events (AEs) such as hypohepatia, leukopenia, peripheral neuritis, and optic neuritis were associated with favorable outcomes. Conclusion: High rates of treatment success were achieved for RR-TB patients at tertiary tuberculosis hospitals in China. Age ≥60 years, national minority, smoking status, comorbidities, re-treated TB, and experienced gastrointestinal reactions were independent prognostic factors for unfavorable treatment outcomes.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

Tuberculosis Diagnosis and Preventive Monotherapy Among Children and Adolescents Exposed to Rifampicin-Resistant Tuberculosis in the Household.

Background: Children and adolescents with household exposure to multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) are at high risk of developing TB disease. Tuberculosis preventive therapy (TPT) is recommended, but programmatic experience is limited, particularly for adolescents. Methods: We conducted a prospective cohort study to describe MDR/RR-TB diagnosis and TPT provision for individuals aged <18 years with MDR/RR-TB exposure. Participants were assessed for TB either in homes or health facilities, with referral for chest x-ray or specimen collection at clinician discretion. The TPT regimens included levofloxacin, isoniazid, or delamanid monotherapy for 6 months, based on source patient drug-resistance profile. Results: Between March 1, 2020 and July 31, 2021, 112 participants were enrolled; median age was 8.5 years, 57 (51%) were female, and 6 (5%) had human immunodeficiency virus. On screening, 11 (10%) were diagnosed with TB: 10 presumptive MDR/RR-TB and 1 drug-susceptible TB. Overall, 95 (94% of 101) participants started TPT: 79 with levofloxacin, 9 with isoniazid, and 7 with delamanid. Seventy-six (80%) completed TPT, 12 (13%) were lost to follow up, and 7 (7%) stopped TPT early due to adverse events. Potential adverse events were reported for 12 (13%) participants; none were serious. There were no further TB diagnoses (200 days median follow up). Conclusions: Post-MDR/RR-TB exposure management for children and adolescents resulted in significant MDR/RR-TB detection and both high TPT initiation and completion. Tuberculosis preventive monotherapy was well tolerated and there were no further TB diagnoses after initial assessment. Key factors supporting these outcomes included use of pediatric formulations for young children, monotherapy, and community-based options for assessment and follow up.

Update of drug-resistant tuberculosis treatment guidelines: A turning point.

In December 2022 World Health Organization released a new treatment for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) guideline. The main novelty of this update is two new recommendations (i) a 6-month treatment regimen composed of bedaquiline, pretomanid, linezolid (600 mg), and moxifloxacin (BPaLM) is recommended in place of the 9-month or longer (18-month) regimens in MDR/RR-TB patients, now including extensive pulmonary TB and extrapulmonary TB (except TB involving central nervous system, miliary TB and osteoarticular TB); (ii) the use of the 9-month all-oral regimen rather than longer (18-months) regimen is suggested in patients with MDR/RR-TB and in whom resistance to fluoroquinolones has been excluded. Longer (18-month) treatments remain a valid option in all cases in which shorter regimens cannot be implemented due to intolerance, drug-drug interactions, extensively drug-resistant tuberculosis, extensive forms of extrapulmonary TB, or previous failure. The new guidelines represent a milestone in MDR/RR-TB treatment landscape, setting the basis for a shorter, all-oral, more acceptable, equitable, and patient-centered model for MDR/RR-TB management. However, some challenges remain to be addressed to allow full implementation of the new recommendations.

Diagnosis and Treatment Pathway of MDR/RR-TB in Taizhou, Zhejiang Province, China.

This study aims to understand MDR/RR-TB patients' experience from seeking TB-related health care to diagnosis and treatment completion, as well as the social determinants with the waiting time for DST and treatment, pre-treatment attrition, and treatment outcome based on a retrospective cohort study. Univariate and multi-variate logistic regressions were used to analyze the associated factors. The median time of waiting time for DST and treatment was 24.00 and 30.00 days, respectively. Non-residential patients (aOR: 2.89, 95% CI: 1.14-7.70), registered before 2018 (aOR: 19.93, 95% CI: 8.99-48.51), first visited a county-level hospital (aOR: 4.65, 95% CI: 1.08-21.67), sputum smear-negative (aOR: 3.54, 95% CI: 1.28-10.16), and comorbid with pneumoconiosis (aOR: 7.10, 95% CI: 1.23-47.98) had a longer DST delay. The pre-treatment attrition was 26.9% (82/305). Elderly, non-residential patients and patients registered before 2018 were more likely to refuse MDR/RR treatment. However, in housekeeping/unemployment and farmer/fisherman, recurrent patients tended to take therapeutic measures actively. The successful treatment rate was 62.1% (105/169). Elderly, comorbidity with diabetes and sputum smear conversion time >1 month may lead to poorer outcomes. Immediate interventions should be taken to smooth diagnosis and treatment pathways and improve the social protections further so as to encourage patients to cooperate with the treatment actively.