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      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

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          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 MTBDR plus) 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 (B loadPaZ) or oral bedaquiline 200 mg daily (B 200PaZ). Patients with rifampicin-resistant tuberculosis received 56 days of the B 200PaZ 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 log 10 (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 B loadPaZ, 60 to B 200PaZ, and 61 to HRZE) and 60 patients with rifampicin-resistant tuberculosis. 57 patients in the B loadPaZ group, 56 in the B 200PaZ group, and 59 in the HRZE group were included in the primary analysis. B 200PaZ produced the highest daily percentage change in TTP (5·17% [95% Bayesian credibility interval 4·61–5·77]), followed by B loadPaZ (4·87% [4·31–5·47]) and HRZE group (4·04% [3·67–4·42]). The bactericidal activity in B 200PaZ and B loadPaZ groups versus that in the HRZE group was significantly different. Higher proportions of patients in the B loadPaZ (six [10%] of 59) and B 200PaZ (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 B loadPaZ group, three [5%] in the B 200PaZ group, and two [3%] in the HRZE group). Serious treatment-related adverse events affected two (3%) patients in the B loadPaZ 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

          B 200PaZ 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 B 200PaZ 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.

          Related collections

          Most cited references 29

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          HIV infection: epidemiology, pathogenesis, treatment, and prevention.

          HIV prevalence is increasing worldwide because people on antiretroviral therapy are living longer, although new infections decreased from 3.3 million in 2002, to 2.3 million in 2012. Global AIDS-related deaths peaked at 2.3 million in 2005, and decreased to 1.6 million by 2012. An estimated 9.7 million people in low-income and middle-income countries had started antiretroviral therapy by 2012. New insights into the mechanisms of latent infection and the importance of reservoirs of infection might eventually lead to a cure. The role of immune activation in the pathogenesis of non-AIDS clinical events (major causes of morbidity and mortality in people on antiretroviral therapy) is receiving increased recognition. Breakthroughs in the prevention of HIV important to public health include male medical circumcision, antiretrovirals to prevent mother-to-child transmission, antiretroviral therapy in people with HIV to prevent transmission, and antiretrovirals for pre-exposure prophylaxis. Research into other prevention interventions, notably vaccines and vaginal microbicides, is in progress. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946-1986, with relevant subsequent publications.

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                Author and article information

                Contributors
                Journal
                Lancet Respir Med
                Lancet Respir Med
                The Lancet. Respiratory Medicine
                Elsevier
                2213-2600
                2213-2619
                1 December 2019
                December 2019
                : 7
                : 12
                : 1048-1058
                Affiliations
                [a ]MRC Clinical Trials Unit at UCL, London, UK
                [b ]University of Cape Town Lung Institute, Cape Town, South Africa
                [c ]Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa
                [d ]Department of Statistics, University of Pretoria, Pretoria, South Africa
                [e ]TB Alliance, Pretoria, South Africa
                [f ]Global Alliance for TB Drug Development, New York, NY, USA
                [g ]Clinical HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa
                [h ]TASK Applied Science, Bellville, South Africa
                [i ]Division of Physiology, Department of Medical Biochemistry, Stellenbosch University, Tygerberg, South Africa
                [j ]NIMR-Mbeya Medical Research Centre, Mbeya, Tanzania
                [k ]Ifakara Health Institute Bagamoyo Research and Training Center, Bagamoyo, Tanzania
                [l ]Uganda Case Western Reserve University Research Collaboration, Kampala, Uganda
                [m ]Clinical HIV Research Unit, Helen Joseph Hospital, Johannesburg, South Africa
                [n ]Swiss Tropical and Public Health Institute, Basel, Switzerland
                [o ]The Aurum Institute, Tembisa Hospital, Tembisa, South Africa
                [p ]THINK, Durban, South Africa
                [q ]MDR Unit, Klerksdorp Tshepong Hospital, Klerksdorp, South Africa
                Author notes
                [* ]Correspondence to: Dr Conor D Tweed, MRC Clinical Trials Unit at UCL, London WC1V 6LJ, UK c.tweed@ 123456ucl.ac.uk
                Article
                S2213-2600(19)30366-2
                10.1016/S2213-2600(19)30366-2
                7641992
                31732485
                © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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