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Tuberculosis bacillary load, an early marker of disease severity: the utility of tuberculosis Molecular Bacterial Load Assay
  1. Wilber Sabiiti1,
  2. Khalide Azam2,
  3. Eoghan Charles William Farmer1,
  4. Davis Kuchaka3,
  5. Bariki Mtafya4,
  6. Ruth Bowness1,
  7. Katarina Oravcova5,
  8. Isobella Honeyborne6,
  9. Dimitrios Evangelopoulos7,
  10. Timothy Daniel McHugh6,
  11. Celso Khosa2,
  12. Andrea Rachow8,
  13. Norbert Heinrich8,
  14. Elizabeth Kampira9,
  15. Geraint Davies9,10,
  16. Nilesh Bhatt2,
  17. Elias N Ntinginya4,
  18. Sofia Viegas2,
  19. Ilesh Jani2,
  20. Mercy Kamdolozi9,
  21. Aaron Mdolo9,
  22. Margaret Khonga9,
  23. Martin J Boeree11,
  24. Patrick P J Phillips12,
  25. Derek Sloan1,
  26. Michael Hoelscher,
  27. Gibson Kibiki13,
  28. Stephen H Gillespie1
  1. 1School of Medicine, University of St Andrews, St Andrews, UK
  2. 2Instituto Nacional de Saúde, Ministério da Saúde, Maputo, Mozambique
  3. 3Biotechnology Laboratory, Kilimanjaro Clinical Research Institute, Moshi, Tanzania
  4. 4Mbeya Medical Research Centre, National Institute of Medical Research, Mbeya, Tanzania
  5. 5Institute of Biodiversity, Animal Health & Comparative Medicine, College of Medical, Veterinary & Life Sciences University of Glasgow, Glasgow, UK
  6. 6Centre for Clinical Microbiology, Division of Infection and Immunity, University College London, London, UK
  7. 7Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, London, UK
  8. 8Division of Infectious and Tropical Medicine, Medical Centre of the University of Munich, Munich, Germany
  9. 9College of Medicine, University of Malawi, Blantyre, Malawi
  10. 10Institutes of Global Health & Translational Medicine, University of Liverpool, Liverpool, UK
  11. 11Department of Lung Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
  12. 12UCSF Center for Tuberculosis, University of San Francisco, San Francisco, California, USA
  13. 13East African Health Research Commission, Bujumbura, Burundi
  1. Correspondence to Dr Wilber Sabiiti, School of Medicine, University of St Andrews, St Andrews KY16 9TF, UK; ws31{at}st-andrews.ac.uk

Abstract

In this comparative biomarker study, we analysed 1768 serial sputum samples from 178 patients at 4 sites in Southeast Africa. We show that tuberculosis Molecular Bacterial Load Assay (TB-MBLA) reduces time-to-TB-bacillary-load-result from days/weeks by culture to hours and detects early patient treatment response. By day 14 of treatment, 5% of patients had cleared bacillary load to zero, rising to 58% by 12th week of treatment. Fall in bacillary load correlated with mycobacterial growth indicator tube culture time-to-positivity (Spearmans r=−0.51, 95% CI (−0.56 to −0.46), p<0.0001). Patients with high pretreatment bacillary burdens (above the cohort bacillary load average of 5.5log10eCFU/ml) were less likely to convert-to-negative by 8th week of treatment than those with a low burden (below cohort bacillary load average), p=0.0005, HR 3.1, 95% CI (1.6 to 5.6) irrespective of treatment regimen. TB-MBLA distinguished the bactericidal effect of regimens revealing the moxifloxacin—20 mg rifampicin regimen produced a shorter time to bacillary clearance compared with standard-of-care regimen, p=0.008, HR 2.9, 95% CI (1.3 to 6.7). Our data show that the TB-MBLA could inform clinical decision making in real-time and expedite drug TB clinical trials.

  • tuberculosis
  • bacterial Infection
  • respiratory infection
http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • Twitter @CelsoKhosa

  • Correction notice This article has been corrected since it was published Online First. The funding statement has been amended.

  • Contributors Study design: SHG, TDMH, KO, WS, IH, AR, NH, MH, MJB, GSK, GM, MB. Literature search: SHG, IH, TDMH. Training: WS, SHG, KO, DE, IH, TDM. Data collection: KA, DK, BM, MK, AM, ECWF, GSK, MK, EK, NEN, NB, SV, IJ. Data analysis: PP, SHG, RB, WS, DS. Data interpretation: SHG, DE, WS, RB. Drafting the paper: WS, RB, DS, SHG. Figures and tables: WS, KA, ECWF, DE. Manuscript reviewing: All authors.

  • Funding This study was funded by European and Developing Countries Clinical Trials Partnership PanACEA 1 grants SP.2011.41304.008: PanAfrican Biomarker Expansion Programme, IP.2007.32011.011: Rapid Evaluation of Moxifloxacin in the treatment of sputum smear positive tuberculosis: REMoxTB (REMox I), IP.2007.32011.012: Rapid evaluation of high-dose rifampicin and other rifamycins in tuberculosis and IP.2007.32011.013: Evaluation of a novel TB drug (SQ109) to shorten and simplify TB treatment; supplemented by funding from Innovative Medicines Initiative (FP7/2007-2013).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Ethical approval for the study was obtained from relevant ethics committees in Tanzania (NIMR/HQ/R.8c/242), Mozambique (147/CNBS/14) and Malawi (P.08/13/1448) (detailed methods on line file 1).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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