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Leprosy, results from infection with the unculturable pathogen Mycobacterium leprae, and ~200,000 new cases are reported annually1. Multidrug therapy (MDT) for multibacillary leprosy lasts 12 months and is compromised by antimicrobial resistance and side-effects1. A potent candidate to improve leprosy treatment is the anti-tuberculosis drug, bedaquiline (BDQ)2, which has shortened treatment duration for drug-resistant tuberculosis3. At doses as low as 1 mg/kg 4, BDQ is active against M. leprae in murine models thereby supporting its use in humans. In the open label clinical trial reported here, BDQ4LEP (PACTR202408643515316), we assessed the bactericidal activity of BDQ in 30 patients with untreated multibacillary leprosy at a single site in Bamako, Mali. The protocol was approved by the relevant ethics committees according to local regulations and all participants provided written informed consent. Patients were treated daily with 200 mg for two weeks, then 3 times per week with 100 mg for six weeks. Patients subsequently received standard MDT for one year and were followed for relapse for another year. All BDQ-treatment was supervised and skin biopsies taken at days 0, 56 and after MDT, to measure microbiologic and molecular biomarker levels that reflect treatment efficacy. All three biopsies were obtained from 17 patients and for days 0 and 56 from 25 BDQ-treated patients.

were followed for relapse for another year. All BDQ-treatment was supervised and skin biopsies taken at days 0, 56 and after MDT, to measure microbiologic and molecular biomarker levels that reflect treatment efficacy. All three biopsies were obtained from 17 patients and for days 0 and 56 from 25 BDQ-treated patients. The bacillary and morphological indices decreased over time (Fig. 1A, B and Table S2 and S7 in the Supplementary Appendix available at NEJM.org) in biopsies from the 17 patients who completed both BDQ and MDT treatment. We also monitored the decline in DNA and mRNA levels, surrogate molecular biomarkers for M. leprae viability, using the RLEP repetitive sequence, and esxA and hsp18 gene expression5. The RLEP signal decreased modestly between days 0 and 56 and DNA could still be detected after MDT, albeit at low levels (Fig. 1C, Tables S4 and S7). A decrease was detected in mRNA levels by the molecular viability assay (Fig. 1D, Tables S5 and S7) between days 0 and 56 and no mRNA was detectable after MDT. Bacilli from biopsies were inoculated into mice and bacterial growth enumerated after 12 months. All 30 day 0 biopsies were culture positive, whereas 24 of 25 (96%) biopsies were culture negative after 56 days of BDQ-treatment (Fig. 3E, Table S6). Likewise, all 17 biopsies tested from patients who completed MDT were culture negative (Table S4). No relapse was observed during the follow-up period (at least 12 months). The BDQ4LEP findings indicate that BDQ monotherapy clears M leprae by day 56. BDQ has potential as a leprosy treatment and merits further study.