Background Bedaquiline and delamanid offer the possibility of more effective and less toxic multidrug-resistant tuberculosis (MDR-TB) treatment. With this treatment, however, some patients, remain at high risk for an unfavorable treatment outcome. The endTB observational study is the largest multicountry cohort of patients with rifampin-resistant/MDR-TB treated in routine care, according to WHO guidance, with delamanid-and/or bedaquiline-containing regimens. We report frequency of sputum culture conversion within six-months of treatment initiation and risk factors for non-conversion. Methods We included patients with a positive baseline culture who initiated a first endTB regimen prior to April 2018. Two consecutive negative cultures collected > 15 days apart constituted culture conversion. We used generalized mixed models to derive marginal predictions for the probability of culture conversion in key subgroups. Findings 1,109 patients initiated a multidrug treatment containing bedaquiline (63%), delamanid (27%) or both (10%). Of these, 939 (85%) experienced culture conversion within six months. In adjusted analyses, patients with HIV had a lower probability of conversion (0•73 [95% CI: 0•62, 0•84]) than patients without HIV (0•84 [95% CI: 0•79, 0•90]; p=0•03). Patients with both cavitary disease and highly positive sputum smear had a lower probability of conversion (0•68 [95% CI: 0•57, 0•79]) relative to patients without either (0•89; 95% CI: 0•84, 0•95; p=0•0004). Hepatitis C infection, diabetes mellitus/glucose intolerance, and baseline resistance were not associated with conversion.

SUMMARY Setting Bangladesh – National Institute of Diseases of the Chest and Hospital, Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders and Chittagong Chest Disease Hospital. Objective To present operational data and discuss the challenges of implementing FAST (Find cases Actively, Separate safely and Treat effectively) as a TB transmission control strategy. Design FAST was implemented sequentially at three hospitals. Results Using Xpert MTB/RIF, 733/6028 (12.2%, 95%CI [11.4,13.0]) patients were diagnosed with unsuspected TB. Patients admitted with other lung diseases with a prior TB history had more than twice the odds of being diagnosed with unsuspected TB as those without a TB history (OR 2.6, 95%CI 2.2–3.0, p<0.001). Unsuspected MDR-TB was diagnosed in 89/1415 (6.3%, 95%CI [5.1,7.7]) patients. Patients with unsuspected TB had nearly five times the odds of being diagnosed with MDR-TB than those admitted with a known TB diagnosis (OR 4.9, 95%CI 3.1–7.6, p<0.001). Implementation challenges include staff shortages, diagnostic failure, supply-chain issues and reliance on external funding. Conclusion FAST implementation revealed a high frequency of unsuspected TB in hospitalized patients in Bangladesh. Patients with a prior TB history have increased risk. Ensuring financial resources, stakeholder engagement and laboratory capacity are important for sustainability and scalability.

Rationale Safety of treatment for multidrug-resistant tuberculosis (MDR/RR-TB) can be an obstacle to treatment completion Objectives Evaluate safety of longer MDR/RR-TB regimens containing bedaquiline and/or delamanid. Methods Multicentre (16 countries), prospective, observational study, reporting incidence and frequency of clinically relevant adverse events of special interest (AESI) amongst patients who received MDR/RR-TB treatment containing bedaquiline and/or delamanid. The AESIs were defined a priori as important events caused by bedaquiline, delamanid, linezolid, injectables, and other commonly used drugs. Occurrence of these events was also reported by exposure to the likely causative agent. Results Among 2296 patients, the most common clinically relevant AESIs were: peripheral neuropathy in 26.4%, electrolyte depletion in 26.0%, and hearing loss in 13.2% of patients. Per 1000 person-months of treatment, the incidence of these events was 21.5 (95% confidence interval [CI]: 19.8-23.2), 20.7 (95% CI: 19.1-22.4), and 9.7 (95% CI: 8.6-10.8), respectively. QT interval was prolonged in 2.7% or 1.8 (95% CI: 1.4-2.3)/1000 person-months of treatment. Patients who received injectables (N=925) and linezolid (N=1826) were most likely to experience events during exposure: Hearing loss, acute renal failure, or electrolyte depletion occurred in 36.8% or 72.8 (95%CI: 66.0-80.0) times/1000 person-months of injectable drug exposure. Peripheral neuropathy, optic neuritis and/or myelosuppression occurred in 27.8% or 22.8 (95% CI: 20.9-24.8) times/1000 patient-months of linezolid exposure. Conclusions Adverse events often related to linezolid and injectable drugs were more common than those frequently attributed to bedaquiline and delamanid. MDR-TB treatment monitoring schedules and individual drug durations should reflect expected safety profiles of drug combinations.

No abstract

Abstract Delamanid should be effective against highly resistant strains of Mycobacteriumtuberculosis, but uptake has been slow globally. In the endTB (expand new drug markets for TB) Observational Study, which enrolled a large, heterogeneous cohorts of patients receiving delamanid as part of a multidrug regimen, 80% of participants experienced sputum culture conversion within 6 months. Clinical Trials Registration. NCT02754765.