Concurrent use of bedaquiline and delamanid for the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis: a nationwide cohort study in South Korea

To the Editor:

Multidrug-resistant tuberculosis (MDR-TB), a major global health concern, requires long-term treatment with multiple drugs, which can cause many side-effects [1]. Therefore, an effective regimen with a minimum number of drugs is essential to control this disease. Bedaquiline (Bdq) and delamanid (Dlm) are new drugs that exhibit good efficacy and safety for MDR-TB treatment [1]. However, adding only one of the new drugs to a regimen may be insufficient to cure this disease when the infecting strain has a high level of drug resistance, such as fluoroquinolone-resistant MDR-TB or extensively drug-resistant TB (XDR-TB) [1–3]. Therefore, the concurrent use of Bdq and Dlm can effectively strengthen the treatment regimen if the best practices in “off-label” use are followed [4–10]. This study analysed the efficacy and safety of concurrent use of Bdq and Dlm in patients with MDR-TB and XDR-TB treated under a programmatic condition.

This retrospective cohort study included patients with pulmonary MDR-TB treated between September 2016 and December 2019 at tertiary referral and TB-specific hospitals in South Korea. The National TB Expert Review Committee (NTBERC) of the Korean Centers for Disease Control and Prevention was responsible for reviewing Bdq and Dlm approval from September 2016. In this study, we used the NTBERC database [8]. The process of submitting cases and obtaining permission to report cases has been described in a previous report [8]. Accompanying drugs were used according to NTBERC recommendation, which was based on the World Health Organization (WHO) guidelines [11].

MDR-TB was defined as TB resistant to both isoniazid and rifampin, while XDR-TB was defined as TB with additional resistance to any of the fluoroquinolones and to at least one of the three injectable second-line drugs (amikacin, capreomycin or kanamycin).

Although the decision to initiate treatment with both new TB drugs was made by the attending physicians, these new TB drugs were prescribed only when an effective treatment regimen could not be provided because of drug resistance, adverse drug reactions, poor tolerance or contraindication to any component of the combination regimen. All enrolled patients were monitored for drug compliance and adverse drug reactions during treatment by specially trained nurses who participated in the Public-Private Mix project for TB control in South Korea [5].

We analysed the patients’ baseline clinical characteristics, including treatment duration of new drugs, adverse drug reactions (including QT interval prolongation), sputum culture results at baseline and sputum culture conversion. The QT interval was corrected using Fridericia's formula (QTcF). Significant QTcF prolongation was defined as any absolute QTcF value ≤500 ms or any increase in QTcF value >60 ms from baseline. The interim treatment outcomes at 12 months, as of 1 August, 2020, were analysed. Interim treatment outcomes were deemed favourable or unfavourable. Favourable outcomes included cure, treatment completion, and culture conversion and maintenance of culture conversion on treatment. Unfavourable outcomes included death, loss to follow-up, and treatment failure, including failed culture conversion. Culture conversion was defined as two consecutive negative results obtained at least 30 days apart in a patient with positive sputum culture results at baseline. The day of sputum collection for the first of the two consecutive negative results was defined as the date of culture conversion.

28 patients with MDR-TB were treated concurrently with Bdq and Dlm. Their median age was 49.5 years and most were male (table 1). All the patients had fluoroquinolone-resistant MDR-TB and 18 (64.3%) patients had XDR-TB. None of the patients tested positive for HIV. The median (interquartile range (IQR)) duration of the concurrent treatment was 167 (146–168) days. The treatment duration in three patients was >24 weeks (197, 230 and 334 days), whereas that in 22 patients was 24 weeks. However, the remaining three patients were treated for <24 weeks. Of them, one patient died due to bacterial pneumonia after taking 3 days of concurrent treatment. In another patient, Dlm was discontinued after 3 days of concurrent treatment owing to severe gastrointestinal side-effects, including nausea and vomiting. In the last patient, although both drugs were administered for 24 weeks, concurrent treatment with both drugs was administered for only 3 weeks. During concurrent treatment, 25 (89.3%) patients received linezolid; however, three patients did not receive linezolid due to adverse drug reactions induced by previous linezolid therapy. Common accompanying drugs, other than linezolid, included clofazimine (n=20, 71.4%), meropenem–clavulanate (n=19, 67.8%), cycloserine (n=14, 50.0%), para-aminosalicylic acid (n=8, 28.6%) and amikacin (n=7, 25.0%).

Sputum culture conversion was achieved in 18 of 19 (94.7%) patients who had positive culture results at the time of concurrent treatment initiation. The median (IQR) time from the initiation of the concurrent treatment to culture conversion was 32.5 (17.0–51.3) days. Of the 28 patients who had 12-month interim outcomes of MDR-TB treatment available, 23 (82.1%) patients showed favourable outcomes (cure, n=15; complete, n=2; maintenance of culture conversion on treatment, n=6) and five (17.9%) patients showed unfavourable outcomes (failure, n=2; deaths, n=1; lost to follow-up, n=2). One death was not related to TB (bacterial pneumonia). Among the 22 (78.6%) patients who completed MDR-TB treatment, the median (IQR) duration of the treatment was 624 (508–741) days. 18 (64.3%) patients were treated successfully (cure, n=16; treatment completion, n=2); treatment failure (n=1), death (n=1) and lost to follow-up (n=2) were reported for the remaining four (14.3%) patients.

Significant QTcF prolongation and QTcF >500 ms were observed in 15 (53.6%) and two (7.1%) patients, respectively. However, there were no clinically significant cardiac events, and the new drugs were used without a permanent discontinuance. Of the two patients with QTcF >500 ms, one patient who had 504 ms of a maximum QTcF without symptoms recovered to 466 ms without discontinuing the new TB drugs. The other patient who had a maximum QTcF of 518 ms without symptoms was managed by discontinuing the two new TB drugs for 20 days, followed by successful reintroduction.

Regarding the other adverse drug reactions aside from QTcF prolongation, one patient experienced severe nausea and vomiting, resulting in discontinuation of Dlm.

This cohort study revealed that concurrent use of Bdq and Dlm in combination with the WHO-recommended regimens showed good efficacy and safety. Fluoroquinolone-resistant MDR-TB and XDR-TB have poor treatment outcomes [2, 3]. However, in this study, 95% patients achieved culture conversion during concurrent treatment with the two new TB drugs and 82% patients achieved favourable outcomes at the 12-month interim analysis, despite fluoroquinolone-resistant MDR-TB in all patients and XDR-TB in 64% of patients. Therefore, this study emphasises the effectiveness of treatment in patients with MDR-TB who have limited treatment options, including those with fluoroquinolone-resistant MDR-TB or XDR-TB. Drug-induced QTcF prolongation is an important safety issue associated with the new TB drugs, especially under conditions that require additional TB drugs to magnify QTcF prolongation [12, 13]. Additional information regarding the cardiac safety of this treatment in combination with various regimens that may potentiate the side-effects is required. In this study, although more than half of patients experienced significant QTcF prolongation, none of the drugs were discontinued. These results are consistent with those of previous studies, including a phase 2 randomised study (DELIBERATE trial) showing the efficacy and safety of sequential and concurrent therapy with the new anti-TB drugs [4–8, 14, 15].

The study limitations include the retrospective study design, and lack of a control arm, information on long-term treatment outcomes and data on drug resistance against Bdq and Dlm.

In conclusion, the concurrent use of Bdq and Dlm is effective and well-tolerated in MDR-TB patients with fluoroquinolone resistance. This treatment represents an attractive option for patients with fluoroquinolone-resistant MDR-TB or XDR-TB.

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