The Molecular Bacterial Load Assay Replaces Solid Culture for Measuring Early Bactericidal Response to Antituberculosis Treatment

Honeyborne, Isobella; Mtafya, Bariki; Phillips, Patrick P. J.; Höelscher, Michael; Ntinginya, Elias N.; Kohlenberg, Anke; Rachow, Andrea; Rojas-Ponce, Gabriel; McHugh, Timothy D.; Heinrich, Norbert

doi:10.1128/jcm.01128-14

Cited by 70 publications

(73 citation statements)

References 17 publications

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“…As a result, the multi-arm, multi-stage design resulted in a reduction in the final sample size of only 2%. A real-time biomarker such as the molecular bacterial load assay could overcome this problem by replacing culture allowing the endpoint results to be available rapidly 35 . Nevertheless, this was a crucial opportunity to assess the feasibility of this novel design in the context of an African multicentre infectious diseases clinical trial.…”

Section: Discussionmentioning

confidence: 99%

High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial

Boeree

Heinrich

Aarnoutse

et al. 2017

The Lancet Infectious Diseases

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SummaryBackgroundTuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis.MethodsWe did a randomised controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15–20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15–20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0·05 for non-proportionality. The trial is registered with ClinicalTrials.gov (NCT01785186).FindingsBetween May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1·78; 95% CI 1·22–2·58, p=0·003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3–5 adverse events, with similar proportions in each arm.Interpr...

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Section: Discussionmentioning

confidence: 99%

High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial

Boeree

Heinrich

Aarnoutse

et al. 2017

The Lancet Infectious Diseases

Self Cite

322

285

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“…An alternative approach includes quantification of abundant ribonucleic acid (RNA) species extracted from sputum as surrogate markers of bacterial clearance [32,33]. Honeyborne et al showed a high correlation between 16S ribosomal RNA (rRNA) with TTP in liquid media and CFUs on solid media over the first 14 days of treatment [34]. Although the half-life of messenger RNA (mRNA) and rRNA is significantly shorter than DNA in sputum, in the context of ongoing chemotherapy, it is unclear what proportion of m- and rRNA in expectorated sputum originates from dying bacteria.…”

Section: Pathogen Based Models and Biomarkersmentioning

confidence: 99%

Assessment of treatment response in tuberculosis

Rockwood

Bruyn

Morris

et al. 2016

Expert Review of Respiratory Medicine

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Antibiotic treatment of tuberculosis has a duration of several months. There is significant variability of the host immune response and the pharmacokineticpharmacodynamic properties of Mycobacterium tuberculosis sub-populations at the site of disease. A limitation of sputum-based measures of treatment response may be sub-optimal detection and monitoring of Mycobacterium tuberculosis sub-populations. Potential biomarkers and surrogate endpoints should be benchmarked against hard clinical outcomes (failure/relapse/death) and may need tailoring to specific patient populations. Here, we assess the evidence supporting currently utilized and future potential host and pathogen-based models and biomarkers for monitoring treatment response in active and latent tuberculosis. Biomarkers for monitoring treatment response in extrapulmonary, pediatric and drug resistant tuberculosis are research priorities.

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“…In this respect, the MBL assay seem to be a better measurement as it detects ribosomal RNA that its decrease correlates better with the reduction of mycobacterial populations due to effect of chemotherapy. In addition, the data of the MBL assay are in good agreement when compared to both liquid culture (MGIT) and solid CFU measurements during a two-week EBA study (Honeyborne et al, 2014) as well as during current clinical trials (unpublished data).…”

Section: Measurement Of Patient Outcomementioning

confidence: 50%

Improving the Tuberculosis Drug Development Pipeline

Evangelopoulos

McHugh

2015

Chem Biol Drug Des

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Mycobacterium tuberculosis is considered one of the most successful pathogens and drug resistant Tuberculosis (MDRTB) a disease that urgently requires new chemical entities to be developed for treatment. There are currently several new molecules under clinical investigation in the TB drug development pipeline. However the complex lifestyle of M. tuberculosis within the host presents a barrier to the development of new drugs. In this review, we highlight the reasons that make TB drug discovery and development challenging as well as providing solutions, future directions and alternative approaches to new therapeutics for TB.

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The Molecular Bacterial Load Assay Replaces Solid Culture for Measuring Early Bactericidal Response to Antituberculosis Treatment

Cited by 70 publications

References 17 publications

High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial

High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial

Assessment of treatment response in tuberculosis

Improving the Tuberculosis Drug Development Pipeline

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