Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial.

BACKGROUND: The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB. METHODS: SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid. Participants with DR-TB had M tuberculosis with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov (NCT03338621) and is completed. FINDINGS: Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2·93 (95% CI 2·17-3·96; p<0·0001). Median time to negative culture (TTN) was 6 weeks (IQR 4-8) on 4 months of BPaMZ and 11 weeks (6-12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3-7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]). INTERPRETATION: For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments. FUNDING: TB Alliance.

Adjunctive pascolizumab in rifampicin-susceptible pulmonary tuberculosis: proof-of-concept, partially-randomised, double-blind, placebo-controlled, dose-escalation trial.

BACKGROUND: Interleukin-4 (IL-4), increased in tuberculosis infection, may impair bacterial killing. Blocking IL-4 confers benefit in animal models. We evaluated safety and efficacy of pascolizumab (humanised anti-IL-4 monoclonal antibody) as adjunctive tuberculosis treatment. METHODS: Participants with rifampicin-susceptible pulmonary tuberculosis received a single intravenous infusion of pascolizumab or placebo; and standard 6-month tuberculosis treatment. Pascolizumab dose increased in successive cohorts: [1] non-randomised 0.05 mg/kg (n = 4); [2] non-randomised 0.5 mg/kg (n = 4); [3] randomised 2.5 mg/kg (n = 9) or placebo (n = 3); [4] randomised 10 mg/kg (n = 9) or placebo (n = 3). Co-primary safety outcome was study-drug-related grade 4 or serious adverse event (G4/SAE); in all cohorts (1-4). Co-primary efficacy outcome was week-8 sputum culture time-to-positivity (TTP); in randomised cohorts (3-4) combined. RESULTS: Pascolizumab levels exceeded IL-4 50% neutralising dose for 8 weeks in 78-100% of participants in cohorts 3-4. There were no study-drug-related G4/SAEs. Median week-8 TTP was 42 days in pascolizumab and placebo groups (p = 0.185). Rate of TTP increase was greater with pascolizumab (difference from placebo 0.011 [95% Bayesian credible interval 0.006 to 0.015] log10TTP/day. CONCLUSIONS: There was no evidence to suggest blocking IL-4 was unsafe. Preliminary efficacy findings are consistent with animal models. This supports further investigation of adjunctive anti-IL-4 interventions for tuberculosis in larger phase 2 trials.

Evaluation of 2 Artificial Intelligence Software for Chest X-Ray Screening and Pulmonary Tuberculosis Diagnosis: Protocol for a Retrospective Case-Control Study.

BACKGROUND: According to the World Bank, Malaysia reported an estimated 97 tuberculosis cases per 100,000 people in 2021. Chest x-ray (CXR) remains the best conventional method for the early detection of pulmonary tuberculosis (PTB) infection. The intervention of artificial intelligence (AI) in PTB diagnosis could efficiently aid human interpreters and reduce health professionals' work burden. To date, no AI studies have been evaluated in Malaysia. OBJECTIVE: This study aims to evaluate the performance of Putralytica and Qure.ai software for CXR screening and PTB diagnosis among the Malaysian population. METHODS: We will conduct a retrospective case-control study at the Respiratory Medicine Institute, National Cancer Institute, and Sungai Buloh Health Clinic. A total of 1500 CXR images of patients who completed treatments or check-ups will be selected and categorized into three groups: (1) abnormal PTB cases, (2) abnormal non-PTB cases, and (3) normal cases. These CXR images, along with their clinical findings, will be the reference standard in this study. All patient data, including sociodemographic characteristics and clinical history, will be collected prior to screening via Putralytica and Qure.ai software and readers' interpretation, which are the index tests for this study. Interpretation from all 3 index tests will be compared with the reference standard, and significant statistical analysis will be computed. RESULTS: Data collection is expected to commence in August 2023. It is anticipated that 1 year will be needed to conduct the study. CONCLUSIONS: This study will measure the accuracy of Putralytica and Qure.ai software and whether their findings will concur with readers' interpretation and the reference standard, thus providing evidence toward the effectiveness of implementing AI in the medical setting. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/36121.

Tuberculous pleural effusion in a patient with sympathetic ophthalmia on immunosuppression: a case report.

BACKGROUND: Tuberculous pleural effusion (TPE) is paucibacillary, making its diagnosis difficult based on laboratory investigations alone. We present a case of a patient with a TPE who was initially misdiagnosed to have azathioprine-induced lung injury. The diagnosis of TPE was arrived at with the help of clinical assessment, laboratory and radiological investigations. CASE PRESENTATION: A 25-year-old chronic smoker with sympathetic ophthalmia on long-term immunosuppression, latent tuberculosis infection and a significant family history of tuberculosis presented with a three-week history of productive cough, low-grade fever, night sweats and weight loss. Examination of the lungs showed reduced breath sounds at the right lower zone. Chest x-ray showed minimal right pleural effusion with a small area of right upper lobe consolidation. The pleural fluid was exudative with predominant mononuclear leukocytes. Direct smears of sputum and pleural fluid; polymerase chain reaction of pleural fluid; and sputum, pleural fluid and blood cultures were negative for M. tuberculosis (MTB) and other organisms. As he did not respond to a course of broad-spectrum antibiotics, he was then treated as a case of azathioprine-induced lung injury. However, his condition did not improve despite the cessation of azathioprine. A contrast-enhanced computed tomography of the thorax showed right upper lobe consolidation with tree-in-bud changes, bilateral lung atelectasis, subpleural nodule, mild right pleural effusion and mediastinal lymphadenopathy. Bronchoalveolar lavage was negative for malignant cells and microorganisms including, MTB. However, no pleural biopsy was done. He was empirically treated with anti-tubercular therapy for 9 months duration and showed complete recovery. CONCLUSION: A high index of suspicion for TPE is required in individuals with immunosuppression living in regions endemic to tuberculosis. Targeted investigations and sound clinical judgement allow early diagnosis and prompt treatment initiation to prevent morbidity and mortality.

Draft Genome Sequences of Local Clinical Isolates of Drug-Resistant and Drug-Sensitive Mycobacterium tuberculosis.

In the battle against tuberculosis (TB), plasticity of the Mycobacterium tuberculosis genome is believed to contribute to the pathogen's virulence and drug resistance. Here, we report 10 draft genome sequences of clinical M. tuberculosis isolated in Malaysia as the basis for understanding the genome plasticity of the M. tuberculosis isolates.