Early efficacy and safety of Bedaquiline and Delamanid given together in a "Salvage Regimen" for treatment of drug-resistant tuberculosis.

BACKGROUND: Drug-Resistant Tuberculosis (DR-TB) patients for whom a WHO recommended regimen along with Bedaquiline (BDQ) cannot be prescribed, Delamanid (DLM) was added along with other drugs to provide a "Salvage Regimen". The experience of the Institute in respect of early efficacy and safety of both drugs given together is presented. OBJECTIVE: To ascertain the early efficacy, safety and tolerability of Bedaquline and Delamanid given together as a part of salvage regimen. METHODS: BDQ and DLM were used together to make regimens along with other drugs where four effective anti TB drugs could not be prescribed as per WHO recommendations. Patients were followed up for sputum smear and culture conversion and adverse events during the treatment. RESULTS: In this cohort study, 53 DR-TB patients (Median age-24) were initiated on regimens containing both BDQ and DLM. Sputum smear conversion was seen in 35% and 94% patients at the end of 1st week and 3rd month respectively. 84% patients had culture conversion at the end of 4th month. 29 adverse events (AE) were reported among 17 patients and there were 11 deaths. QTc prolongation more than 500 MS was seen in only 1 patient. CONCLUSION: BDQ and DLM given together in a salvage regimen is efficacious with low rate of adverse events. The combination provides hope to DR-TB patients with limited treatment options and should be provided as a life saving option.

Initial experience of bedaquiline implementation under the National TB Programme at NITRD, Delhi, India.

BACKGROUND: Bedaquiline (BDQ) was approved for treatment of drug resistant TB (DR-TB) under Conditional Access Programme (CAP) of Revised National Tuberculosis Control Programme (RNTCP) and was also implemented in the National Institute of TB and Respiratory Diseases (NITRD). We present early efficacy and safety of BDQ containing regimens for DR-TB. OBJECTIVE: To ascertain the early efficacy and safety of Bedaquline containing regimens in treatment of DR-TB. METHODS: BDQ containing regimens along with other drugs were designed as per WHO recommendations for DR-TB patients. They were followed up for sputum smear and culture conversion, adverse events during the treatment. RESULTS: A cohort of 290 DR-TB patients (Median age-29.77) were initiated on BDQ containing regimens. Of the available Sputum results, smear conversion was seen in 51% and 91% patients at the end of 1st week and 3rd month respectively. Similarly, 93% and 98% patients had culture conversion at the end of 3rd and 6th month respectively. 201 adverse events (AE) including 47 deaths were reported among 109 patients. QTc prolongation was seen in 29% patients but only 4 required discontinuation of BDQ. Lost to follow up of treatment was about 6%. CONCLUSION: Bedaquiline along with an optimized background regimen has shown early sputum conversion in larger number of difficult to treat patients having additional resistance of second line drugs along with INH and Rifampicin. The regimen is feasible in programmatic conditions and is relatively safe.

Quantitative approach for cardiac risk assessment and interpretation in tuberculosis drug development.

Cardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which represented a range of clinical TdP risk. The algorithm correctly classified 89% of reference compounds with moderate sensitivity and high specificity (71 and 96%, respectively) as well as 10 out of 12 external validation compounds and the anti-TB drugs moxifloxacin and bedaquiline. The cardiac risk algorithm is suitable to help inform early drug development decisions in TB and will evolve with the addition of emerging data.