Outcomes of Bedaquiline Treatment in Patients With Multidrug-Resistant Tuberculosis

Lawrence Mbuagbaw; Lorenzo Guglielmetti; Catherine Hewison; Nyasha Bakare; Mathieu Bastard; Eric Caumes; Mathilde Fréchet-Jachym; Jérôme Robert; Nicolas Veziris; Naira Khachatryan; Tinatin Kotrikadze; Armen Hayrapetyan; Zaza Avaliani; Holger J. Schünemann; Christian Lienhardt

Disclosures

Emerging Infectious Diseases. 2019;25(5):936-943. 

In This Article

Abstract and Introduction

Abstract

Bedaquiline is recommended by the World Health Organization for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). We pooled data from 5 cohorts of patients treated with bedaquiline in France, Georgia, Armenia, and South Africa and in a multicountry study. The rate of culture conversion to negative at 6 months (by the end of 6 months of treatment) was 78% (95% CI 73.5%–81.9%), and the treatment success rate was 65.8% (95% CI 59.9%–71.3%). Death rate was 11.7% (95% CI 7.0%–19.1%). Up to 91.1% (95% CI 82.2%–95.8%) of the patients experienced ≥1 adverse event, and 11.2% (95% CI 5.0%–23.2%) experienced a serious adverse event. Lung cavitations were consistently associated with unfavorable outcomes. The use of bedaquiline in MDR and XDR TB treatment regimens appears to be effective and safe across different settings, although the certainty of evidence was assessed as very low.

Introduction

In 2017, there were ≈10 million (range, 9.0–11.1 million) new cases of tuberculosis (TB) worldwide, of which ≈558,000 were rifampin-resistant TB (RR TB) or multidrug-resistant TB (MDR TB).[1] MDR TB refers to resistance to isoniazid and rifampin, 2 of the most powerful TB drugs, with or without resistance to other first-line drugs. Extensively drug-resistant tuberculosis (XDR TB), a more severe form of drug-resistant TB, is defined as MDR TB with additional resistance to any fluoroquinolone and to any of the 3 second-line injectables (amikacin, capreomycin, or kanamycin).[2] Treatment outcomes in patients with MDR TB are generally poor, with treatment success in about half of those who receive treatment (56.4%), and much worse in patients with XDR TB.[3] In 2017, MDR TB and RR TB caused ≈230,000 deaths.[1] The treatment of MDR and XDR TB is complex and expensive, requiring the use of ≥4 medications considered to be active in longer regimens (18–20 months),[4–6] and is fraught with many adverse events that can be debilitating or life threatening.[7,8]

Bedaquiline is a new compound belonging to the diarylquinoline class used to treat MDR TB; cure and culture conversion rates using bedaquiline are promising.[9,10] A recent cost-effectiveness analysis showed that bedaquiline added to a background MDR TB regimen would improve health outcomes and reduce costs in high TB burden countries.[11] Bedaquiline received accelerated approval in the United States in 2012 for the treatment of pulmonary MDR TB as part of an appropriate combination therapy in adult patients with resistance or intolerability to other treatment regimens. However, in 2013, limited data and concerns about higher death rates among patients who received bedaquiline in the phase II randomized controlled trial[10] led the World Health Organization (WHO) to issue an interim conditional recommendation on its use under specific conditions: proper patient inclusion, signed informed consent, adherence to the WHO-recommended principles of designing an MDR TB regimen, close monitoring, and active pharmacovigilance.[12] Since 2013, many countries have introduced bedaquiline as part of their management strategy for MDR TB, and in 2018, WHO updated its guidance for the use of bedaquiline in MDR TB, including children ≥6 years of age.[6]

In 2016, to update the interim guidance, the WHO Guideline Development Group (GDG) conducted a review of newly available data on the use of bedaquiline in the treatment of MDR TB.[13] After the publication of the GDG report, further outcome data were retrieved from cohorts in Armenia and Georgia. We report the results of the updated analysis from 5 cohorts of patients with MDR TB treated with bedaquiline, taking into account both study-level and patient-level characteristics on outcomes, including deaths. We also report on the use of bedaquiline in research and nonresearch settings and on adverse events.

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