Delamanid for rifampicin-resistant tuberculosis: a retrospective study from South Africa

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Abstract

Experience with delamanid (Dlm) is limited, particularly among HIV-positive individuals. We describe early efficacy and safety data from a programmatic setting in South Africa.

This was a retrospective cohort study of patients receiving Dlm-containing treatment regimens between November 2015 and August 2017. We report 12-month interim outcomes, sputum culture conversion (SCC) by months 2 and 6, serious adverse events (SAEs) and QT intervals corrected using the Frederica formula (QTcF).

Overall, 103 patients were initiated on Dlm; 79 (77%) were HIV positive. The main indication for Dlm was intolerance to second-line anti-tuberculosis (TB) drugs (n=58, 56%). There were 12 months of follow-up for 46 patients; 28 (61%) had a favourable outcome (cure, treatment completion or culture negativity). Positive cultures were found for 57 patients at Dlm initiation; 16 out of 31 (52%) had SCC within 2 months and 25 out of 31 (81%) within 6 months. There were 67 SAEs reported in 29 patients (28%). There were four instances of QTcF prolongation >500 ms in two patients (2%), leading to permanent discontinuation in one case; however, no cardiac arrhythmias occurred.

This large cohort of difficult-to-treat patients receiving Dlm for rifampicin-resistant TB treatment in a programmatic setting with high HIV prevalence had favourable early treatment response and tolerated treatment well. Dlm should remain available, particularly for those who cannot be treated with conventional regimens or with limited treatment options.

Abstract

Patients with rifampicin-resistant TB treated with delamanid had good treatment response and cardiotoxicity was rare http://ow.ly/bVQu30jGPVJ

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Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis.

Neel Gandhi, Paul Nunn, Keertan Dheda … (2010)

Although progress has been made to reduce global incidence of drug-susceptible tuberculosis, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis during the past decade threatens to undermine these advances. However, countries are responding far too slowly. Of the estimated 440,000 cases of MDR tuberculosis that occurred in 2008, only 7% were identified and reported to WHO. Of these cases, only a fifth were treated according to WHO standards. Although treatment of MDR and XDR tuberculosis is possible with currently available diagnostic techniques and drugs, the treatment course is substantially more costly and laborious than for drug-susceptible tuberculosis, with higher rates of treatment failure and mortality. Nonetheless, a few countries provide examples of how existing technologies can be used to reverse the epidemic of MDR tuberculosis within a decade. Major improvements in laboratory capacity, infection control, performance of tuberculosis control programmes, and treatment regimens for both drug-susceptible and drug-resistant disease will be needed, together with a massive scale-up in diagnosis and treatment of MDR and XDR tuberculosis to prevent drug-resistant strains from becoming the dominant form of tuberculosis. New diagnostic tests and drugs are likely to become available during the next few years and should accelerate control of MDR and XDR tuberculosis. Equally important, especially in the highest-burden countries of India, China, and Russia, will be a commitment to tuberculosis control including improvements in national policies and health systems that remove financial barriers to treatment, encourage rational drug use, and create the infrastructure necessary to manage MDR tuberculosis on a national scale. Copyright 2010 Elsevier Ltd. All rights reserved.

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Which QT Correction Formulae to Use for QT Monitoring?

Bert Vandenberk, Eline Vandael, Tomas Robyns … (2016)

Background Drug safety precautions recommend monitoring of the corrected QT interval. To determine which QT correction formula to use in an automated QT‐monitoring algorithm in our electronic medical record, we studied rate correction performance of different QT correction formulae and their impact on risk assessment for mortality. Methods and Results All electrocardiograms (ECGs) in patients >18 years with sinus rhythm, normal QRS duration and rate <90 beats per minute (bpm) in the University Hospitals of Leuven (Leuven, Belgium) during a 2‐month period were included. QT correction was performed with Bazett, Fridericia, Framingham, Hodges, and Rautaharju formulae. In total, 6609 patients were included (age, 59.8±16.2 years; 53.6% male and heart rate 68.8±10.6 bpm). Optimal rate correction was observed using Fridericia and Framingham; Bazett performed worst. A healthy subset showed 99% upper limits of normal for Bazett above current clinical standards: men 472 ms (95% CI, 464–478 ms) and women 482 ms (95% CI 474–490 ms). Multivariate Cox regression, including age, heart rate, and prolonged QTc, identified Framingham (hazard ratio [HR], 7.31; 95% CI, 4.10–13.05) and Fridericia (HR, 5.95; 95% CI, 3.34–10.60) as significantly better predictors of 30‐day all‐cause mortality than Bazett (HR, 4.49; 95% CI, 2.31–8.74). In a point‐prevalence study with haloperidol, the number of patients classified to be at risk for possibly harmful QT prolongation could be reduced by 50% using optimal QT rate correction. Conclusions Fridericia and Framingham correction formulae showed the best rate correction and significantly improved prediction of 30‐day and 1‐year mortality. With current clinical standards, Bazett overestimated the number of patients with potential dangerous QTc prolongation, which could lead to unnecessary safety measurements as withholding the patient of first‐choice medication.

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Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study.

Sergey E Borisov, Keertan Dheda, Martin Enwerem … (2017)

Large studies on bedaquiline used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) are lacking. This study aimed to evaluate the safety and effectiveness of bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents.428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92-280) days and exposed to bedaquiline for 168 (86-180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively).Sputum smear and culture conversion rates in MDR-TB cases were 63.6% and 30.1%, respectively at 30 days, 81.1% and 56.7%, respectively at 60 days; 85.5% and 80.5%, respectively at 90 days and 88.7% and 91.2%, respectively at the end of treatment. The median (IQR) time to smear and culture conversion was 34 (30-60) days and 60 (33-90) days. Out of 247 culture-confirmed MDR-TB cases completing treatment, 71.3% achieved success (62.4% cured; 8.9% completed treatment), 13.4% died, 7.3% defaulted and 7.7% failed. Bedaquiline was interrupted due to adverse events in 5.8% of cases. A single case died, having electrocardiographic abnormalities that were probably non-bedaquiline related.Bedaquiline-containing regimens achieved high conversion and success rates under different nonexperimental conditions.

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Journal

Journal ID (nlm-ta): Eur Respir J

Journal ID (iso-abbrev): Eur. Respir. J

Journal ID (publisher-id): ERJ

Journal ID (hwp): erj

Title: The European Respiratory Journal

Publisher: European Respiratory Society

ISSN (Print): 0903-1936

ISSN (Electronic): 1399-3003

Publication date Collection: June 2018

Publication date (Electronic): 14 June 2018

Volume: 51

Issue: 6

Electronic Location Identifier: 1800017

Affiliations

[1 ]Médecins Sans Frontières, Operational Centre Brussels (OCB), Khayelitsha Project, Cape Town, South Africa

[2 ]Médecins Sans Frontières, South African Medical Unit (SAMU), Cape Town, South Africa

[3 ]City of Cape Town Health Dept, Cape Town, South Africa

[4 ]Provincial Government of the Western Cape Dept of Health, Cape Town, South Africa

[5 ]Médecins Sans Frontières, Operational Centre Brussels (OCB), Cape Town Coordination, Cape Town, South Africa

[6 ]Faculty of Medicine, University of Parakou, Parakou, Benin

[7 ]Main Medical Dept, Ministry of Justice, Baku, Azerbaijan

[8 ]Médecins Sans Frontières, Medical Dept (Operational Research), Operational Centre Brussels (OCB), Luxembourg City, Luxembourg

[9 ]Dept of Global Health, University of Washington, Seattle, WA, USA

[10 ]Division of Medical Microbiology and the Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa

[11 ]Dept of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA

Author notes

Erika Mohr, Médecins Sans Frontières, The Isisivana Center, 1 Tsolo Road, Khayelitsha 7784, South Africa. E-mail: msfocb-khayelitsha-drtb-epi@ 123456brussels.msf.org

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Erika Mohr http://orcid.org/0000-0001-5269-6503

Jennifer Hughes http://orcid.org/0000-0002-5349-9509

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Publisher ID: ERJ-00017-2018

DOI: 10.1183/13993003.00017-2018

PMC ID: 6485275

PubMed ID: 29724920

SO-VID: a6d96e90-ce11-4b58-a375-f7d6b7ab5d40

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This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

History

Date received : 10 January 2018

Date accepted : 23 April 2018

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Delamanid for rifampicin-resistant tuberculosis: a retrospective study from South Africa

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Most cited references 22

Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis.

Which QT Correction Formulae to Use for QT Monitoring?

Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study.

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