#Bedaquiline, #moxifloxacin, #pretomanid, and #pyrazinamide during the first 8 weeks of #treatment of patients with drug-susceptible or drug-resistant #pulmonary #TB:… (Lancet Resp Med., abstract)

[Source: The Lancet Respiratory Medicine, full page: (LINK). Abstract, edited.]

Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial

Conor D Tweed, MD, Rodney Dawson, MD, Divan A Burger, PhD, Almari Conradie, MPharm, Angela M Crook, PhD, Carl M Mendel, MD, Francesca Conradie, MBBCh, Andreas H Diacon, MD, Nyanda E Ntinginya, PhD, Daniel E Everitt, MD, Frederick Haraka, MD, Mengchun Li, MD, Christo H van Niekerk, MD, Alphonse Okwera, PhD, Mohammed S Rassool, MBChB, Klaus Reither, PhD, Modulakgotla A Sebe, MBChB, Suzanne Staples, MPhil, Ebrahim Variava, MD, Melvin Spigelman, MD

Open Access / Published: November 12, 2019 / DOI: https://doi.org/10.1016/S2213-2600(19)30366-2

 

Summary

Background

New anti-tuberculosis regimens that are shorter, simpler, and less toxic than those that are currently available are needed as part of the global effort to address the tuberculosis epidemic. We aimed to investigate the bactericidal activity and safety profile of combinations of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in the first 8 weeks of treatment of pulmonary tuberculosis.

Methods

In this multicentre, open-label, partially randomised, phase 2b trial, we prospectively recruited patients with drug-susceptible or rifampicin-resistant pulmonary tuberculosis from seven sites in South Africa, two in Tanzania, and one in Uganda. Patients aged 18 years or older with sputum smear grade 1+ or higher were eligible for enrolment, and a molecular assay (GeneXpert or MTBDRplus) was used to confirm the diagnosis of tuberculosis and to distinguish between drug-susceptible and rifampicin-resistant tuberculosis. Patients who were HIV positive with a baseline CD4 cell count of less than 100 cells per uL were excluded. Patients with drug-susceptible tuberculosis were randomly assigned (1:1:1) using numbered treatment packs with sequential allocation by the pharmacist to receive 56 days of treatment with standard tuberculosis therapy (oral isoniazid, rifampicin, pyrazinamide, and ethambutol; HRZE), or pretomanid (oral 200 mg daily) and pyrazinamide (oral 1500 mg daily) with either oral bedaquiline 400 mg daily on days 1–14 then 200 mg three times per week (BloadPaZ) or oral bedaquiline 200 mg daily (B200PaZ). Patients with rifampicin-resistant tuberculosis received 56 days of the B200PaZ regimen plus moxifloxacin 400 mg daily (BPaMZ). All treatment groups were open label, and randomisation was not stratified. Patients, trial investigators and staff, pharmacists or dispensers, laboratory staff (with the exception of the mycobacteriology laboratory staff), sponsor staff, and applicable contract research organisations were not masked. The primary efficacy outcome was daily percentage change in time to sputum culture positivity (TTP) in liquid medium over days 0–56 in the drug-susceptible tuberculosis population, based on non-linear mixed-effects regression modelling of log10 (TTP) over time. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, NCT02193776, and all patients have completed follow-up.

Findings

Between Oct 24, 2014, and Dec 15, 2015, we enrolled 180 patients with drug-susceptible tuberculosis (59 were randomly assigned to BloadPaZ, 60 to B200PaZ, and 61 to HRZE) and 60 patients with rifampicin-resistant tuberculosis. 57 patients in the BloadPaZ group, 56 in the B200PaZ group, and 59 in the HRZE group were included in the primary analysis. B200PaZ produced the highest daily percentage change in TTP (5·17% [95% Bayesian credibility interval 4·61–5·77]), followed by BloadPaZ (4·87% [4·31–5·47]) and HRZE group (4·04% [3·67–4·42]). The bactericidal activity in B200PaZ and BloadPaZ groups versus that in the HRZE group was significantly different. Higher proportions of patients in the BloadPaZ (six [10%] of 59) and B200PaZ (five [8%] of 60) groups discontinued the study drug than in the HRZE group (two [3%] of 61) because of adverse events. Liver enzyme elevations were the most common grade 3 or 4 adverse events and resulted in the withdrawal of ten patients (five [8%] in the BloadPaZ group, three [5%] in the B200PaZ group, and two [3%] in the HRZE group). Serious treatment-related adverse events affected two (3%) patients in the BloadPaZ group and one (2%) patient in the HRZE group. Seven (4%) patients with drug-susceptible tuberculosis died and four (7%) patients with rifampicin-resistant tuberculosis died. None of the deaths were considered to be related to treatment.

Interpretation

B200PaZ is a promising regimen to treat patients with drug-susceptible tuberculosis. The bactericidal activity of both these regimens suggests that they have the potential to shorten treatment, and the simplified dosing schedule of B200PaZ could improve treatment adherence in the field. However, these findings must be investigated further in a phase 3 trial assessing treatment outcomes.

Funding

TB Alliance, UK Department for International Development, Bill & Melinda Gates Foundation, US Agency for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, and the Federal Ministry for Education and Research of Germany.

Keywords: Tuberculosis; Antibiotics; Drugs Resistance; Bedaquiline; Moxifloxacin; Pretomanid; Pyrazinamide.

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Acquisition of cross- #resistance to #Bedaquiline and #Clofazimine following #treatment for #Tuberculosis in #Pakistan (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Acquisition of cross-resistance to Bedaquiline and Clofazimine following treatment for Tuberculosis in Pakistan

Arash Ghodousi, Alamdar Hussain Rizvi, Aurangzaib Quadir Baloch, Abdul Ghafoor, Faisal Masood Khanzada, Mehmood Qadir, Emanuele Borroni, Alberto Trovato, Sabira Tahseen,Daniela Maria Cirillo

DOI: 10.1128/AAC.00915-19

 

ABSTRACT

We report on the first six cases of acquired-resistance to bedaquiline in Pakistan. Seventy sequential isolates from 30 drug-resistant tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC test and by detection of mutations in relevant genes. We documented cases failing therapy developed specific mutations in Rv0678 and increased MICs associated with cross-resistance to clofazimine during treatment. This study underlines the relevance of surveillance programs following the introduction of new drugs.

Copyright © 2019 Ghodousi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; Pakistan; Bedaquiline; Clofazimine.

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#Outcomes of #Bedaquiline #Treatment in Patients with #MDR #Tuberculosis (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 5—May 2019 / Research

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, and Christian Lienhardt

Author affiliations: St. Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada (L. Mbuagbaw); Centre for the Development of Best Practices in Health, Yaoundé, Cameroon (L. Mbuagbaw); McMaster University, Hamilton (L. Mbuagbaw, H.J. Schünnemann); Centre d’Immunologie et des Maladies Infectieuses, INSERM, Paris (L. Guglielmetti, E. Caumes, J. Robert, N. Veziris); Centre Hospitalier de Bligny, Bris-sous-Forges, France (L. Guglielmetti, M. Frechet-Jachym); Sorbonne Université, Paris, France (L. Guglielmetti, J. Robert, N. Veziris); Médecins Sans Frontières, Paris (C. Hewison); Janssen Research & Development, LLC, Titusville, New Jersey, USA (N. Bakere); Epicentre, Paris (M. Bastard); Hôpitaux Universitaires de l’Est Parisien, Paris (N. Veziris); Médecins Sans Frontières, Yerevan, Armenia (N. Khachatryan); Médecins Sans Frontières, Tbilisi, Georgia (T. Kotrikadze); National Tuberculosis Control Centre, Yerevan (A. Hayrapetyan); National Centre for Tuberculosis and Lung Disease, Tbilisi (Z. Avaliani); World Health Organization, Geneva, Switzerland (C. Lienhardt); Université de Montpellier, Montpellier, France (C. Lienhardt)

 

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.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; MDR-TB; XDR-TB; Bedaquiline.

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