Final treatment outcomes of multidrug- and extensively drug-resistant tuberculosis patients in Latvia receiving delamanid-containing regimens

QT prolongation and cardiac toxicity of new tuberculosis drugs in Europe: a Tuberculosis Network European Trialsgroup (TBnet) study

“…These findings support published results [8][9][10] and recent data from a Phase III clinical trial testing Dlm versus a placebo [11]. In addition, a relevant proportion of physicians used the new drugs for treatment for more than 6 months [12,13] and in combination with QT-interval prolonging agents [14,15]. Limitations of this study include retrospective data collection, the analysis of aggregate data, incomplete coverage of the WHO Europe region with over-representation of Western Europe, bias linked to surveys which may lead to underestimating the number of events and the absence of sudden death in the questionnaire.…”

New drugs and regimens for tuberculosis

“…(2) Case reports have demonstrated the safety of delamanid in the treatment of complicated MDR‐TB, including one showing prolonged use for 24 months in a child with XDR‐TB…”

“…A regimen containing linezolid, bedaquiline and delamanid may be adequate for the most difficult-totreat MDR-TB, but sequential acquisition of drug resistance to bedaquiline and delamanid, 19 and to linezolid and delamanid, 112 has been reported. This may be anticipated, as delamanid is prone to bacillary drug resistance, 117,118 and the 120-week culture conversion rates in patients with pre-XDR-and XDR-TB given an 108 Its open-label extension suggested that delamanid used for more than 6 months, in comparison with its use for less than 2 months, significantly increased favourable outcomes (cure or treatment completion) from 55% to 74.5%, and significantly reduced mortality from 8.3% to 1.0% 109 (4) Otsuka Trial 213, involving use of delamanid at 100 mg bd for the first 2 months and 200 mg once daily for the next 4 months, showed small benefit from adding delamanid to an optimized background regimen, although delamanid may help prevent amplification of drug resistance 110 (1) Although delamanid is associated with QT prolongation, the effect predictably maximizes within 8 weeks of treatment, without associated cardiac clinical manifestations, and is not materially affected by concomitant use of levofloxacin and clofazimine 111 (2) Case reports have demonstrated the safety of delamanid in the treatment of complicated MDR-TB, [112][113][114][115] including one showing prolonged use for 24 months in a child with XDR-TB 116 (3) Trial 213 found no significant difference regarding treatment-emergent adverse events, drug-drug interactions between delamanid and antiretroviral drugs, and prolongation of the corrected QT interval 110 (4) With a relatively high propensity to develop bacillary drug resistance, 117,118 delamanid may be better used with potent companion agents that are less prone to develop bacillary drug resistance, for example, linezolid or bedaquiline 8,112 Pretomanid (PA-824) (1) Being a nitroimidazole that shares the same mechanism of action with delamanid, pretomanid is bactericidal against actively replicating mycobacteria (inhibiting mycolic acid biosynthesis) and non-replicating mycobacteria (generating nitric oxide inside the tubercle bacilli) 117,119,120 (1) Owing to similar structure, pretomanid expectedly shares cross-resistance with delamanid as well as a relatively high propensity to acquiring bacillary drug resistance (2) Not yet approved for use in clinical practice optimized background regimen plus bedaquiline in a clinical trial setting were only 70.5% and 62.2%, respectively. 121 At least three case studies have reported combined use of bedaquiline with delamanid among patients with XDR-TB, [122]…”

Management of Multidrug-Resistant Tuberculosis

“…Early results with delamanid in the programmatic setting have shown high culture conversion rates and low frequency of QTc intervals over 500 millisecond. [80][81][82] Results from compassionate use in resource-limited settings demonstrated culture conversion at 6 months in 80% of patients, with QTc prolongation in only 3.8%. 83 As with bedaquiline, programmatic uptake of delamanid has been slow.…”