Loss to follow-up among adults with drug-resistant TB in Papua New Guinea.

SETTING: Multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB) is now endemic in the National Capital District (NCD), Papua New Guinea. Loss to follow-up (LTFU) is a challenge. OBJECTIVE: To evaluate and identify risk factors for LTFU, including pre-treatment LTFU, in adults with MDR/RR-TB at Port Moresby General Hospital (PMGH). DESIGN: A retrospective analysis of treatment initiation in adults diagnosed with MDR/RR-TB (2018-2022) and outcomes for a cohort treated for MDR/RR-TB (2014-2019). We assessed the factors associated with LTFU using multivariate logistic regression. RESULTS: Of 95 patients diagnosed with MDR/RR-TB at PMGH from 2018 to 2022, 21 (22%) were lost to follow-up before treatment. Of the 658 adults who initiated treatment for MDR/RR-TB at PMGH from 2014 to 2019, 161 (24%) were lost to follow-up during treatment. A higher proportion of patients on injectable-containing long regimens (110/404, 27%) were lost to follow-up than those on the all-oral regimen containing bedaquiline (13/66, 12%). Treatment loss to follow-up was associated with age (35-54 years age group: aOR 0.49, 95% CI 0.32-0.77; 55-75 years age group: aOR 0.42, 95% CI 0.19-0.90; compared to the 15-34 years age group), residence outside of NCD (aOR 1.79, 95% CI 1.04-3.06), and year of treatment initiation. CONCLUSION: Pre-treatment LTFU requires programmatic focus. Shorter oral regimens and decentralised services may address the reasons for higher LTFU in younger people and people living outside NCD.

CONTEXTE: La TB multirésistante/résistante à la rifampicine (MDR-TB/RR-TB, pour l'anglais « multidrug/rifampicin-resistant TB ¼) est maintenant endémique dans le district de la capitale nationale (NCD, pour l'anglais « National Capital District ¼), en Papouasie-Nouvelle-Guinée. La perte de suivi (LTFU, pour l'anglais « loss to follow-up ¼) est un défi. OBJECTIF: Évaluer et identifier les facteurs de risque de LTFU, y compris le LTFU avant le traitement, chez les adultes atteints de MDR-TB/RR-TB à Port Moresby General Hospital (PMGH). CONCEPTION: Une analyse rétrospective de l'initiation du traitement chez les adultes diagnostiqués avec une MDR-TB/RR-TB (2018­2022) et des résultats pour une cohorte traitée pour la MDR-TB/RR-TB (2014­2019). Nous avons évalué les facteurs associés au LTFU à l'aide d'une régression logistique multivariée. RÉSULTATS: Sur les 95 patients diagnostiqués avec une MDR-TB/RR-TB à PMGH de 2018 à 2022, 21 (22%) ont été perdus de vue avant le traitement. Sur les 658 adultes qui ont commencé un traitement pour la MDR-TB/RR-TB à PMGH entre 2014 et 2019, 161 (24%) ont été perdus de vue pendant le traitement. Une proportion plus élevée de patients recevant des régimes longs contenant des injectables (110/404 ; 27%) ont été perdus de vue que ceux recevant un régime entièrement oral contenant de la bédaquiline (13/66 ; 12%). La perte de traitement au suivi était associée à l'âge (groupe d'âge de 35 à 54 ans : aOR 0,49 ; IC à 95% 0,32 à 0,77 ; groupe d'âge de 55 à 75 ans : aOR 0,42 ; IC à 95% 0,19 à 0,90 ; par rapport au groupe d'âge de 15 à 34 ans), à la résidence en dehors des NCD (aOR 1,79 ; IC à 95% 1,04 à 3,06) et à quelques années de début de traitement. CONCLUSION: Le LTFU avant le traitement nécessite une orientation programmatique. Des régimes oraux plus courts et des services décentralisés peuvent s'attaquer aux raisons de l'augmentation du LTFU chez les jeunes et les personnes vivant en dehors des NCD.

Exploring the therapeutic and prophylactic potential of bedaquiline in leprosy.

Leprosy remains a significant public health concern despite major strides in treatment and control efforts. The Global Leprosy Strategy 2021-2030 and the National Strategic Plan for Leprosy 2023-2027 majorly focus on facilitating action to reach the goal of zero leprosy. Exploration of new treatment regimens is emphasized as one of the verticals of the multipronged approach for reaching the aforementioned goals. This becomes particularly pertinent in the wake of growing evidence for resistance to the drugs currently being used in the management of leprosy. Repurposed molecules present a very good approach in this direction. The present review aims to explore the potential of bedaquiline, a drug used for multidrug-resistant tuberculosis, as a potential addition to the therapeutic armamentarium of leprosy. Through this narrative review, the authors attempt to look into the available proof of concept, clinical evidence, potential risks, and possible ways forward with bedaquiline in leprosy.

Establishing the Safety and Efficacy of Bedaquiline-Containing Regimen for the Treatment of Drug-Resistant Tuberculosis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

The risks and benefits of bedaquiline (BDQ) for treatment of drug-resistant tuberculosis (DR-TB) have not been firmly established. We aimed to assess the safety and efficacy of BDQ-containing regimens for the treatment of DR-TB as evidenced in available randomized controlled trials (RCTs). In this systematic review and meta-analysis, five databases (i.e., ClinicalTrials.gov, Cochrane CENTRAL, PubMed, ScienceDirect, and SinoMed) were searched. RCTs among DR-TB patients that had a control arm were eligible. The safety endpoints were all-cause mortality and serious adverse effects (SAEs). Efficacy outcomes were sputum culture conversion rate at 8-12 weeks and 24-26 weeks, treatment success, and time to culture conversion. A total of 476 records were screened; 18 met the eligibility criteria. The pooled analysis included 2520 participants (55.8% received BDQ-containing regimens, n = 1408). Pooled safety outcomes showed no significant reduction in all-cause mortality (relative risk [RR] [95%confidence interval (CI)] = 0.94 [0.41-2.20]) or SAEs (RR [95%CI] = 0.91 [0.67-1.23]) in the BDQ-regimen group. Pooled efficacy outcomes showed significantly superior culture conversion rates at 8-12 weeks (RR [95%CI] = 1.35 [1.10-1.65]) and 24-26 weeks (RR [95%CI] = 1.25 [1.15-1.36]), more treatment success (RR [95%CI] = 1.30 [1.17-1.44]), and a 17-day reduction in the time to culture conversion (standardized mean difference [SMD] [95%CI] = -17.46 [-34.82 to -0.11]) in the BDQ-regimen group (reference: non-BDQ regimen). Overall, BDQ regimens showed significant treatment effect against DR-TB but did not reduce mortality or SAEs.

Factors associated with mortality among laboratory-diagnosed drug-resistant tuberculosis patients on treatment, KwaZulu-Natal Province, 2017-2019.

Introduction: tuberculosis (TB) remains a leading cause of death in South Africa. KwaZulu-Natal (KZN) is one of the provinces with a high burden of TB/drug-resistant TB cases and deaths. We determined predictors for mortality among drug-resistant TB patients on treatment in KZN province. Methods: we conducted a retrospective cohort study using secondary data from the Electronic Drug-Resistant Tuberculosis Register. We used a modified Poisson regression model with robust standard errors to determine predictors for drug-resistant TB mortality. Results: of the 7,692 eligible patients, 1,234 (16.0%) died. Males predominated (707, 57.3%) and the median age was 36 years (Interquartlile Range: 29-45 years). The majority (978, 79.2%) were HIV-TB co-infected with 911 (93%) on antiretroviral treatment (ART). The predictors included HIV-TB co-infection without ART (aIRR 3.4; 95% CI: 2.3-5.1), unknown ART status (aIRR: 1.8; 95% CI: 1.4-2.3), aged ≥60 years (aIRR: 2.1; 95% CI: 1.6-2.7), previous drug-resistant TB (aIRR: 1.5; 95% CI: 1.2-1.8) and exposure to second-line drugs (aIRR: 1.7; 95% CI: 1.4-2.0). Other predictors were hospitalization during treatment initiation (aIRR 2.5; 95% CI 2.0-3.1), initiation in other treatment facilities (aIRR: 2.2; 95% CI: 1.6-2.9) and rifampicin-resistant (aIRR: 1.2; 95% CI: 1.1-1.4). Bedaquiline fumarate was a significant protective factor against death (aIRR: 0.5; 95% CI: 0.4-0.5). Conclusion: older age, HIV co-infection without ART, hospitalization for treatment initiation, exposure to second-line drugs and a previous episode of drug-resistant TB were predictors for DR-TB mortality. Early treatment initiation and provision of antiretroviral treatment for all co-infected patients may reduce DR-TB mortality in the Province.

Multidrug-resistant Mycobacterium abscessus infection in an anophthalmic socket treated with bedaquiline on a compassionate use basis: A case report.

Purpose: To explore the management of a rare ophthalmic infection caused by a multi-resistant strain of Mycobacterium abscessus in the anophthalmic cavity of a patient with a history of multiple eye surgeries. Observations: A 60-year-old woman with a history of multiple ocular complications, culminating in the enucleation of the eye and subsequent dermograft implant, developed a resistant infection in the anophthalmic cavity. The infection persisted despite various local interventions and broad-spectrum systemic antibiotic treatments. Resolution of the infection was only achieved after precise diagnosis and the implementation of intensive treatment, which included a specific combination of antibiotics and appropriate surgical debridement of the anophthalmic cavity. Conclusions and importance: This case highlights the complexity in managing ophthalmic infections caused by non-tuberculous mycobacteria. It underscores the importance of a multidisciplinary and personalized treatment approach, as well as the need to develop specific guidelines for ophthalmic infections caused by rapidly growing mycobacteria.

Pharmacology of emerging drugs for the treatment of multi-drug resistant tuberculosis.

Mycobacterium tuberculosis (TB) remains the leading cause of infection-related mortality worldwide. Drug resistance, need for multiple antimycobacterial agents, prolonged treatment courses, and medication-related side effects are complicating factors to TB cure. The introduction of treatment regimens containing the novel agents bedaquiline, pretomanid, and linezolid, with or without moxifloxacin (BPaL-M or BPaL, respectively) have substantially reduced TB-related morbidity and mortality and are associated with favorable rates of treatment completion and cure. This review summarizes key information on the pharmacology and treatment principles for moxifloxacin, bedaquiline, delamanid, pretomanid, linezolid, and tedizolid in the treatment of multi-drug resistant TB, with recommendations provided to address and attenuate common adverse effects during treatment.

Effectiveness of bedaquiline containing all oral longer regimens in treating multidrug/rifampicin resistant tuberculosis in Pakistan.

BACKGROUND: Despite the introduction of bedaquiline (Bdq) containing all-oral regimens for treating patients with rifampicin resistant/multidrug resistant tuberculosis (MDR/RR-TB) in 2019, data on its effectiveness in Pakistan, which has the fifth highest MDR-TB burden, is lacking. This study evaluates treatment outcomes and identifies factors associated with unsuccessful outcomes among MDR/RR-TB patients treated with an all-oral longer treatment regimen (LTR). METHODS: This retrospective record review included all microbiologically confirmed pulmonary MDR/RR-TB patients treated with an all-oral LTR between August 2019 and February 2021 across nine PMDT centres in Pakistan. Sociodemographic and clinical data were retrieved from the Electronic Nominal Recording and Reporting System. Treatment outcomes, defined by WHO criteria, were analysed using SPSS and multivariate binary logistic regression to identify factors associated with unsuccessful outcomes. A p-value < 0.05 was considered statistically significant. RESULTS: The final analysis included 644 MDR/RR-TB patients (mean age 37.9 ± 17.6 years), mostly male (53.0 %), underweight (68.0 %), with TB treatment history (66.1 %), MDR-TB (84.9 %), lung cavitation (71.0 %), and no comorbidities (86.4 %). Fluoroquinolone resistance was found in 41.9 %, 16 % had used second-line drugs, and 9.8 % had previous MDR-TB treatment. A total of 400 (62.1 %) patients were declared cured, 53 (8.2 %) treatment completed, 117 (18.2 %) died, 37 (5.7 %) lost to follow-up (LTFU), and 37 (5.7 %) treatment failures. Overall treatment success rate was 70.3 % (n = 453). In multivariate analysis, history of TB treatment (OR:1.63, 95 %CI:1.09-2.64, p = 0.023), previous SLD use (OR:2.09, 95 %CI: 1.20-3.37, p = 0.012), resistance to Z (OR:0.43, 95 %CI: 0.20-0.81, p = 0.023), and resistance to > 5 drugs (OR:3.12, 95 %CI:1.36-11.64, p = 0.013) were significantly associated with death and treatment failure. Whereas, lung cavitation had statistically significant association with LTFU (OR:2.66, 95 %CI:1.10-7.32, p = 0.045). CONCLUSION: Treatment success rate (70.3 %) in this study fell below the WHO recommended target success rate (>90 %). Enhanced clinical management, coupled with special attention to patients exhibiting identified risk factors could improve treatment outcomes.

Intranasal Administration of Bedaquiline-Loaded Fucosylated Liposomes Provides Anti-Tubercular Activity while Reducing the Potential for Systemic Side Effects.

Liposomal formulations of antibiotics for inhalation offer the potential for the delivery of high drug doses, controlled drug release kinetics in the lung, and an excellent safety profile. In this study, we evaluated the in vivo performance of a liposomal formulation for the poorly soluble, antituberculosis agent, bedaquiline. Bedaquiline was encapsulated within monodisperse liposomes of ∼70 nm at a relatively high drug concentration (∼3.6 mg/mL). Formulations with or without fucose residues, which bind to C-type lectin receptors and mediate a preferential binding to macrophage mannose receptor, were prepared, and efficacy was assessed in an in vivo C3HeB/FeJ mouse model of tuberculosis infection (H37Rv strain). Seven intranasal instillations of 5 mg/kg bedaquiline formulations administered every second day resulted in a significant reduction in lung burden (∼0.4-0.6 Δlog10 CFU), although no differences between fucosylated and nonfucosylated formulations were observed. A pharmacokinetic study in healthy, noninfected Balb/c mice demonstrated that intranasal administration of a single dose of 2.5 mg/kg bedaquiline liposomal formulation (fucosylated) improved the lung bioavailability 6-fold compared to intravenous administration of the same formulation at the same dose. Importantly, intranasal administration reduced systemic concentrations of the primary metabolite, N-desmethyl-bedaquiline (M2), compared with both intravenous and oral administration. This is a clinically relevant finding as the M2 metabolite is associated with a higher risk of QT-prolongation in predisposed patients. The results clearly demonstrate that a bedaquiline liposomal inhalation suspension may show enhanced antitubercular activity in the lung while reducing systemic side effects, thus meriting further nonclinical investigation.

Treatment outcomes of multidrug resistant tuberculosis (MDR TB) treated with bedaquiline under programmatic management of drug resistant tuberculosis at a tertiary care hospital in Punjab, India.

INTRODUCTION: MDR TB is a serious global concern which is hampering TB elimination goals badly. Standardized MDR TB regimen had high default rates, more side effects and poor treatment outcomes. Bedaquiline is a newer anti-tubercular drug which has made oral regimens possible for MDR TB. We aimed to study the outcomes of MDR TB patients treated with Bdq containing regimens. METHODS: 155 patients of MDR TB on Bdq containing regimen enrolled at GMC, Patiala under NTEP from 2017 to 2020 were enrolled retrospectively. RESULTS: Out of 155 patients enrolled, 82 (52.9 %) were cured, 31 (20 %) completed treatment, 18 (11.6 %) defaulted, 22 (14.2 %) died and 2 (0.12 %) failed treatment. CONCLUSION: Bdq is well tolerated with very less side effects and has better outcomes as compared to standard MDR regimens which were followed earlier.

Clinical outcomes of multidrug-resistant tracheobronchial tuberculosis receiving anti-tuberculosis regimens containing bedaquiline or delamanid.

The treatment of multidrug-resistant tracheobronchial tuberculosis poses challenges, and research investigating the efficacy of bedaquiline or delamanid as treatment for this condition is limited. This retrospective cohort study was conducted from 2017 to 2021. The study extracted data of patients with multidrug-resistant tracheobronchial tuberculosis from medical records and followed up on prognoses. Participants were divided into three groups: the bedaquiline, delamanid, and control group. Clinical outcomes and the risk factors associated with early culture conversion were analyzed. This study included 101 patients, with 32, 25, and 44 patients in the bedaquiline, delamanid, and control groups respectively. The differences in the treatment success rates among the three groups did not show statistical significance. Both the bedaquiline and delamanid groups had significantly higher culture conversion rates compared to the control after 2 or 6 months of treatment, with significantly shorter median times to culture conversion (bedaquiline group: 2 weeks, delamanid group: 2 weeks, control group: 12 weeks, P < 0.001). Treatment with bedaquiline or delamanid were identified as independent predictors of culture conversion at 2 months (bedaquiline group: aOR = 13.417, 95% CI 4.067-44.260, delamanid group: aOR = 9.333, 95% CI 2.498-34.878) or 6 months (bedaquiline group: aOR = 13.333, 95% CI 3.379-52.610, delamanid group: aOR = 5.000, 95% CI 1.357-18.426) of treatment through multivariable logistic regression analyses. The delamanid group showed better improvement in lumen stenosis compared to bedaquiline. Regimens containing bedaquiline or delamanid may accelerate the culture conversion during the early treatment phase in multidrug-resistant tracheobronchial tuberculosis, and delamanid appears to have the potential to effectively improve airway stenosis.

Impact of bedaquiline regimen on the treatment success rates of multidrug-resistant tuberculosis patients in Egypt.

Bedaquiline (BDQ), an innovative anti-tuberculous (TB) agent, has attracted attention for its potential effectiveness against drug-resistant TB. This study investigated the impact of BDQ-containing regimens on treatment success rates among multi-drug resistant tuberculosis (MDR-TB) patients in Egypt. We conducted a prospective cohort study that included all adult non-pregnant patients treated in MDR-TB centers in Egypt from April 1, 2020, to June 30, 2021, with follow-up extended until December 31, 2022. The study compared patients prescribed BDQ according to national protocols with those receiving conventional treatments for MDR-TB. Treatment success rates, mortality rates, and adverse events were analyzed using descriptive statistics, chi-square tests, logistic regression, and Kaplan-Meier survival curves. Adjustment for potential confounders was conducted using propensity score matching and Cox-hazard regressions. A total of 84 patients were included in this study. The median age of the study participants was 39 years; 22.6% were women, 57.1% were unemployed or housewives, and 1.2% had human immunodeficiency virus (HIV). Regarding the treatment regimen, 67.8% were exposed to BDQ-based treatment. Among the 55 patients (65.5%) with treatment success, a significantly higher success rate was observed in the BDQ group (73.7%) compared to the conventional group (48.1%), P = 0.042. Additionally, the incidence of skin discoloration was significantly higher in the BDQ group compared to the conventional group (38.6% versus 0.0%, P < 0.001). Despite the lower mortality incidence in the BDQ-group (14.0% versus 22.2% in the conventional group), the Kaplan-Meier survival analysis revealed no excess mortality associated with the BDQ-group, with a hazard ratio (HR) of 0.62 (95% CI 0.21-1.78, P = 0.372). Propensity score matching, while considering factors such as lesion site, diabetes mellitus, hepatitis C virus, and smoking, revealed a significant increase in the success rate associated with BDQ inclusion, with an HR of 6.79 (95% CI 1.8-25.8). In conclusion, BDQ is an effective and tolerable medication for treating MDR-TB, associated with lower mortality rates compared to conventional treatment.

Cost and cost-effectiveness of BPaL regimen used in drug-resistant TB treatment in the Philippines.

BACKGROUND: In 2022, the WHO announced that the 6-month BPaL/M regimen should be used for drug-resistant TB (DR-TB). We estimate the patient and provider costs of BPaL compared to current standard-of-care treatment in the Philippines. METHODS: Patients on BPaL under operational research, or 9-11-month standard short oral regimen (SSOR) and 18-21-month standard long oral regimen (SLOR) under programmatic conditions were interviewed using the WHO cross-sectional TB patient cost tool. Provider costs were assessed through a bottom-up and top-down costing analysis. RESULTS: Total patient costs per treatment episode were lowest with BPaL (USD518.0) and increased with use of SSOR (USD825.8) and SLOR (USD1,023.0). Total provider costs per successful treatment were lowest with BPaL (USD1,994.5) and increased with SSOR (USD3,121.5) and SLOR (USD10,032.4). Compared to SSOR, BPaL treatment was cost-effective at even the lowest willingness to pay threshold. As expected, SLOR was the costliest and least effective regimen. CONCLUSIONS: Costs incurred by patients on BPaL were 37% (95% CI 22-56) less than SSOR and 50% (95% CI 32-68) less than SLOR, while providers could save 36% (95% CI 21-56) to 80% (95% CI 64-93) per successful treatment, respectively. The study shows that treatment of DR-TB with BPaL was cost-saving for patients and cost-effective for the health system.

CONTEXTE: En 2022, l'OMS a annoncé que le traitement BPaL/M de 6 mois devrait être utilisé pour la TB pharmacorésistante (DR-TB). Nous estimons les coûts du BPaL pour les patients et les prestataires par rapport au traitement standard actuel aux Philippines. MÉTHODES: Des patients sous BPaL dans le cadre d'une recherche opérationnelle, ou un régime oral court standard de 9 à 11 mois (SSOR, pour l'anglais « standard short oral regimen ¼) et un régime oral long standard de 18 à 21 mois (SLOR, pour l'anglais « standard long oral regimen ¼) dans des conditions programmatiques ont été interrogés à l'aide de l'outil transversal de l'OMS sur le coût pour les patients atteints de TB. Les coûts des fournisseurs ont été évalués par une analyse ascendante et descendante des coûts. RÉSULTATS: Les coûts totaux pour les patients par épisode de traitement étaient les plus bas avec BPaL (518,0 USD) et augmentaient avec l'utilisation de SSOR (825,8 USD) et SLOR (1 023,0 USD). Les coûts totaux des prestataires par traitement réussi étaient les plus bas avec BPaL (1 994,5 USD) et ont augmenté avec SSOR (3 121,5 USD) et SLOR (10 032,4 USD). Comparé à SSOR, le traitement BPaL était rentable même au seuil de volonté de payer le plus bas. Comme prévu, le SLOR était le régime le plus coûteux et le moins efficace. CONCLUSIONS: Les coûts encourus par les patients sous BPaL étaient inférieurs de 37% (IC à 95% 22­56) à ceux du SSOR et de 50% (IC à 95% 32­68) à ceux du SLOR, tandis que les prestataires pouvaient économiser respectivement 36 % (IC à 95% 21­56) à 80% (IC à 95% 64­93) par traitement réussi. L'étude montre que le traitement de la DR-TB par BPaL a permis de réaliser des économies pour les patients et pour le système de santé.

Savings from the introduction of BPaL and BPaLM regimens at the country level.

BACKGROUND: In 2022, the WHO recommended the 6-month regimens BPaL (bedaquiline + pretomanid + linezolid) and BPaLM (BPaL + moxifloxacin) as treatment options for most forms of drug-resistant TB. SLASH-TB estimates the cost-saving and cost-effectiveness for the healthcare system and patients when a country switches from current standard-of-care treatment regimens to BPaL/BPaLM. METHODOLOGY: Country data from national TB programmes (NTP) are used to calculate the costs for all regimens and treatment outcomes. Where BPaL/BPaLM is not currently used, clinical trial outcomes data are used to estimate cost-effectiveness. DALYs are calculated using the Global Burden of Disease (GBD) database. RESULTS: We present the results of four countries that have used the tool and shared their data. When shorter and longer regimens are replaced with BPaL/BPaLM, the savings per patient treated in Pakistan, the Philippines, South Africa, and Ukraine are $746, $478, $757, and $2,636, respectively. An increased number of patients would be successfully treated with BPaL/BPaLM regimens, with 411, 1,025, 1,371 and 829 lives saved and 20,179, 27,443, 33,384 and 21,924 DALYs averted annually in the four countries, respectively. CONCLUSION: Through BPaL/BPaLM regimens, drug-resistant TB treatment has become more effective, shorter, less burdensome for patients, cheaper for both health systems and patients, and saves more lives.

CONTEXTE: En 2022, l'OMS a préconisé l'utilisation des schémas thérapeutiques (bedaquiline + pretomanid + linezolid) et BPaLM (BPaL + moxifloxacin), d'une durée de 6 mois, comme alternatives pour traiter la plupart des formes de TB résistante aux médicaments. SLASH-TB a réalisé une estimation des économies et de la rentabilité pour le système de santé et les patients lorsqu'un pays décide de passer des schémas thérapeutiques standards actuels au BPaL/BPaLM. MÉTHODOLOGIE: Les programmes nationaux de lutte contre la TB (NTP) utilisent les données nationales pour évaluer les coûts des différents schémas thérapeutiques et des résultats des traitements. Si le BPaL/BPaLM n'est pas utilisé actuellement, les données des essais cliniques sont utilisées pour estimer le rapport coût-efficacité. Les années de vie ajustées sur l'incapacité (DALYs, pour l'anglais « disability-adjusted life-years ¼) sont calculées à l'aide de la base de données Global Burden of Disease (GBD). RÉSULTATS: Nous présentons les résultats de quatre pays qui ont utilisé l'outil et partagé leurs données. Lorsque les schémas plus courts et plus longs sont remplacés par BPaL/BPaLM, les économies par patient traité au Pakistan, aux Philippines, en Afrique du Sud et en Ukraine sont respectivement de 746, 478, 757 et 2 636 dollars. L'utilisation des schémas BPaL/BPaLM permettrait de traiter un plus grand nombre de patients avec succès, ce qui sauverait respectivement 411, 1 025, 1 371 et 829 vies et éviterait 20 179, 27 443, 33 384 et 21 924 DALYs par an dans les quatre pays. CONCLUSION: Les schémas BPaL/BPaLM ont révolutionné le traitement de la tuberculose pharmacorésistante en le rendant plus efficace, plus rapide, moins contraignant pour les patients, plus économique pour les systèmes de santé et les patients, et en sauvant un plus grand nombre de vies.

Safety and effectiveness of three novel all-oral shortened regimens for rifampicin- or multidrug-resistant tuberculosis in Kazakhstan.

BACKGROUND: In 2019, WHO called for operational research on all-oral shortened regimens for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). We report safety and effectiveness of three nine-month all-oral regimens containing bedaquiline (Bdq), linezolid (Lzd), and levofloxacin (Lfx) and reinforced with cycloserine (Cs) and clofazimine (Cfz), delamanid (Dlm) and pyrazinamide (Z), or Dlm and Cfz. METHODS: We conducted a prospective cohort study of patients initiating treatment for pulmonary MDR/RR-TB under operational research conditions at public health facilities in Kazakhstan. Participants were screened monthly for adverse events. Participants with baseline resistance were excluded from the study and treated with a longer regimen. We analyzed clinically relevant adverse events of special interest in all participants and sputum culture conversion and end-of-treatment outcomes among individuals who were not excluded. RESULTS: Of 510 participants, 41% were women, median age was 37 years (interquartile range: 28-49), 18% had a body mass index <18·5 kg/m2, and 51% had cavitary disease. Three hundred and ninety-nine (78%) initiated Bdq-Lzd-Lfx-Cs-Cfz, 83 (16%) started Bdq-Lzd-Lfx-Dlm-Z, and 28 (5%) initiated Bdq-Lzd-Lfx-Dlm-Cfz. Fifty-eight individuals (11%) were excluded from the study, most commonly due to identification of baseline drug resistance (n = 52; 90%). Among the remaining 452 participants, treatment success frequencies were 92% (95% confidence interval [CI]: 89 to 95), 89% (95%CI: 80 to 94), and 100% (95%CI: 86 to 100) for regimens with Cs/Cfz, Dlm/Z, and Dlm/Cfz respectively. Clinically-relevant adverse events of special interest were uncommon. CONCLUSION: All regimens demonstrated excellent safety and effectiveness, expanding the potential treatment options for patients, providers, and programs.

How much should we still worry about QTc prolongation in rifampicin-resistant tuberculosis? ECG findings from TB-PRACTECAL clinical trial.

Regimens for the treatment of rifampicin-resistant tuberculosis currently rely on the use of QT-prolonging agents. Using data from the randomized controlled trial, TB-PRACTECAL, we investigated differences in QTcF among participants in the three interventional arms: BPaL (bedaquiline, pretomanid, and linezolid), BPaLC (BPaL with clofazimine), and BPaLM (BPaL with moxifloxacin). Additionally, we assessed whether age, body mass index, and country were causally associated with QTcF prolongation. The trial included participants from South Africa, Uzbekistan, and Belarus. A post hoc analysis of electrocardiogram data was undertaken. Random effects regression was used to model QTcF longitudinally over 24 weeks and causal frameworks guided the analysis of non-randomized independent variables. 328 participants were included in BPaL-based arms. The longitudinal analysis of investigational arms showed an initial QTcF steep increase in the first week. QTcF trajectories between weeks 2 and 24 differed slightly by regimen, with highest mean peak for BPaLC (QTcF 446.5 ms). Overall, there were 397 QTcF >450 ms (of 3,744) and only one QTcF >500 ms. The odds of QTcF >450 ms among participants in any investigational arm, was 8.33 times higher in Uzbekistan compared to Belarus (95% confidence interval: 3.25-21.33). No effect on QTcF prolongation was found for baseline age or body mass index (BMI). Clinically significant QTc prolongation was rare in this cohort of closely monitored participants. Across BPaL-based regimens, BPaLC showed a slightly longer and sustained effect on QTcF prolongation, but the differences (both in magnitude of change and trajectory over time) were clinically unimportant. The disparity in the risk of QTc prolongation across countries would be an important factor to further investigate when evaluating monitoring strategies. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT02589782.

Study of Culture Conversion in Drug-Resistant Pulmonary Tuberculosis on All-Oral Longer Regimen at IGIMS, Patna.

Background: Multidrug-resistant tuberculosis (MDR-TB) refers to tuberculosis that resists at least two primary drugs, namely isoniazid and rifampicin. To assess the management of MDR-TB, sputum culture conversion is performed. This study aimed to determine the culture conversion status of MDR-TB patients undergoing an all-oral longer regimen. Methods: This research constitutes an observational and prospective study conducted within a hospital setting. The study was done at the Department of Microbiology, IGIMS, Patna, from October 2020 to March 2022. Culture conversion in multidrug resistance pulmonary tuberculosis on all-oral longer regimens took one spot and one morning sample of sputum as per standard protocol after completing two months of all-oral longer regimens and culturing it in liquid broth using Mycobacterium Growth Indicator Tube (MGIT) 960 System at two, four then six months till we got a negative result. Results: Maximum number of the cases, 77 (74.8%), belonged to 19-35 years of age group. Males were 68 (66.1%) and females were 35 (33.9%), respectively, with male to female ratio of 1.9:1. After 2 months of oral longer regimen treatment, out of 103 cases, we found 98 (95.1%) patients had sputum for culture positive and only five (4.2%) patients had sputum for culture negative. After 6 months of oral longer regimen treatment, out of 101 cases, we found 16 (15.8%) patients had sputum for culture positive and 85 (85.2%) patients had sputum for culture negative. Conclusion: In patients with multidrug-resistant pulmonary tuberculosis (MDR-TB) who received an all-oral longer regimen, the introduction of bedaquiline led to positive outcomes as evidenced by a greater number of negative sputum cultures, a decrease in culture reversions, and a reduced risk of developing a more resistant form of MDR-TB.

Delamanid and bedaquiline resistance patterns in Mycobacterium tuberculosis in Iran: A cross-sectional analysis.

Introduction: The surge of multidrug-resistant TB (MDR-TB) in Iran poses a significant challenge to global healthcare. The introduction of delamanid (DLM) and bedaquiline (BDQ), two potent antimycobacterial drugs, marks a crucial advance. Nevertheless, as resistance in Mycobacterium tuberculosis is on the rise in Iran and resistance to these newer medications is emerging, investigations in this field are of utmost importance. Methods: In this cross-sectional study, 38 MDR-TB strains were collected from five distinct regional TB laboratories in Iran. The clinical isolates were confirmed as M. tuberculosis using the phenotypic tests and IS6110-based PCR assay. Drug susceptibility testing (DST) for isoniazid, rifampicin, ethambutol, DLM, and BDQ was performed using WHO-approved methods. Sequencing was used to investigate genetic mutations in DLM (ddn, fgd1) and BDQ (Rv0678, atpE, pepQ) genes associated with resistance. Results: Among the 38 collected MDR-TB isolates, 7 (18.5 %) exhibited resistance to DLM, while all remained susceptible to BDQ. Analysis of the sequencing data revealed that the ddn gene exhibited the highest number of mutations in DLM-resistant isolates, including 18 nonsynonymous mutations and 1 indel leading to frameshift mutations. A common mutation, Gly81Ser, was present in 4 of the DLM-resistant isolates (4/7; 57.1 %). A synonymous mutation, T960C, in the fgd1 gene was uniformly found in DLM-resistant samples. Notably, no significant mutations were observed in the atpE, Rv0678, or pepQ genes in any of the BDQ-susceptible isolates. Conclusions: Our study underscores the emergence of DLM resistance in a subset of MDR-TB isolates in Iran, primarily associated with mutations in the ddn gene. This emphasizes the ongoing necessity for TB drug resistance surveillance and research. While BDQ remains efficacious, the emergence of DLM resistance is a concerning development, warranting further exploration into resistance mechanisms and the formulation of effective TB control strategies.

Identification of urine biomarkers predictive of prolonged QTc interval in multidrug-resistant tuberculosis patients treated with bedaquiline.

The most frequent adverse event associated with bedaquiline (BDQ) is the QTc interval prolongation; however, there was no biomarkers that could be used to predict the occurrence of QTc prolongation in BDQ-treated patients. In this study, we employed the ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS) to generate metabolic profiling for the discovery of potential predictive urine biomarkers of QTc prolongation in these patients. Untargeted metabolomic technique was used to concentrate the differential metabolic pathway, and targeted metabolomic technique was subsequently performed to identify predictive biomarkers for QTc prolongation. A total of 45 rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB) patients were enrolled in our study, including 15 RR/MDR-TB patients with QTc interval prolongation (QIP) and 30 RR/MDR-TB patients with QTc interval un-prolongations (QIU). Untargeted technique revealed that the lipid metabolism was the most differential metabolic pathway between two groups. Further targeted technique identified four differential metabolites, including betaine, LPE (18:2), LPE (20:3), and LPE (20:4). The combined analysis of metabolisms revealed that the combined use of LPE (20:3) and LPE (20:4) had the best performance for predicting the occurrence of QTc prolongation in TB patients, yielding a sensitivity of 87.4% and a specificity of 78.5%. In addition, with the progression of BDQ treatment, the LPEs exhibited persistent difference in the BDQ-treated TB patients experiencing QTc interval prolongation. In conclusion, our data demonstrate that the combined use of LPE (20:3) and LPE (20:4) yields promising performance for predicting the occurrence of QTc interval prolongation in BDQ-treated patients.

Mitigating treatment failure of pulmonary pre-extensively drug-resistant tuberculosis: The role of new and repurposed drugs.

BACKGROUND: Pre-extensively drug-resistant tuberculosis (pre-XDR-TB), defined as multidrug-resistant TB (MDR-TB) with additional resistance to any fluoroquinolone (FQ) is difficult to treat. We assessed whether the use of new or repurposed drugs (bedaquiline, delamanid, linezolid, carbapenem, clofazimine, pretomanid) mitigated treatment failure of pre-XDR-TB. METHODS: MDR-TB patients managed in the Taiwan MDR-TB consortium between July 2009-December 2019 were eligible. Treatment outcomes at 30 months were assessed. Logistic regression models were constructed to investigate factors associated with treatment outcomes. RESULTS: 109 patients with FQ-resistant MDR-TB and 218 patients with FQ-susceptible MDR-TB were included. 60 (55.1%) patients with FQ-resistant MDR-TB and 63 (28.9%) patients with FQ-susceptible MDR-TB have been treated with new or repurposed drugs (p < 0.01). Of the 218 patients with FQ-susceptible MDR-TB, 187 (85.8%) had treatment success, 30 (13.8%) died, no treatment failure, and 1 (0.5%) was loss-to-follow-up; of the 109 patients with FQ-resistant MDR-TB, 78 (71.6%) had treatment success, 21 (19.3%) died, 9 (8.3%) had treatment failure, and 1 (0.9%) was loss-to-follow-up (p < 0.01). The use of new or repurposed drugs was not associated with treatment outcomes among patients with FQ-susceptible MDR-TB. No patients with FQ-resistant MDR-TB treated with ≥2 new or repurposed drugs within 6 months of treatment initiation had treatment failure (p = 0.03). Patients with FQ-resistant MDR-TB treated with 1 new or repurposed drugs was more likely to have treatment failure as compared with patients not treated with new or repurposed drugs (adjOR 7.06, 95% CI 1.72-29.06). CONCLUSIONS: Proper use of new or repurposed anti-TB drugs can mitigate treatment failure in FQ-resistant MDR-TB.