title: Geographic differences in time to culture conversion in liquid media: Tuberculosis Trials Consortium study 28. Culture conversion is delayed in Africa.
abstract: BACKGROUND
  Tuberculosis Trials Consortium Study 28, was a double blind, randomized, placebo-controlled, phase 2 clinical trial examining smear positive pulmonary Mycobacterium tuberculosis. Over the course of intensive phase therapy, patients from African sites had substantially delayed and lower rates of culture conversion to negative in liquid media compared to non-African patients. We explored potential explanations of this finding.
  
  
  METHODS
  In TBTC Study 28, protocol-correct patients (n = 328) provided spot sputum specimens for M. tuberculosis culture in liquid media, at baseline and weeks 2, 4, 6 and 8 of study therapy. We compared sputum culture conversion for African and non-African patients stratified by four baseline measures of disease severity: AFB smear quantification, extent of disease on chest radiograph, cavity size and the number of days to detection of M. tuberculosis in liquid media using the Kaplan-Meier product-limit method. We evaluated specimen processing and culture procedures used at 29 study laboratories serving 27 sites.
  
  
  RESULTS
  African TB patients had more extensive disease at enrollment than non-African patients. However, African patients with the least disease by the 4 measures of disease severity had conversion rates on liquid media that were substantially lower than conversion rates in non-African patients with the greatest extent of disease. HIV infection, smoking and diabetes did not explain delayed conversion in Africa. Some inter-site variation in laboratory processing and culture procedures within accepted practice for clinical diagnostic laboratories was found.
  
  
  CONCLUSIONS
  Compared with patients from non-African sites, African patients being treated for TB had delayed sputum culture conversion and lower sputum conversion rates in liquid media that were not explained by baseline severity of disease, HIV status, age, smoking, diabetes or race. Further investigation is warranted into whether modest variation in laboratory processes substantially influences the efficacy outcomes of phase 2 TB treatment trials or if other factors (e.g., nutrition, host response) are involved.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00144417.
authors.affiliation: Tuberculosis Trials Consortium, Division of Tuberculosis Elimination, Centers for Disease Control, Atlanta, Georgia, United States of America. wrm0@cdc.gov
authors.forename: William R
authors.initials: WR
authors.lastname: Mac Kenzie
authors.forename: Charles M
authors.initials: CM
authors.lastname: Heilig
authors.forename: Lorna
authors.initials: L
authors.lastname: Bozeman
authors.forename: John L
authors.initials: JL
authors.lastname: Johnson
authors.forename: Grace
authors.initials: G
authors.lastname: Muzanye
authors.forename: Denise
authors.initials: D
authors.lastname: Dunbar
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Jost
authors.forename: Lois
authors.initials: L
authors.lastname: Diem
authors.forename: Beverly
authors.initials: B
authors.lastname: Metchock
authors.forename: Kathleen
authors.initials: K
authors.lastname: Eisenach
authors.forename: Susan
authors.initials: S
authors.lastname: Dorman
authors.forename: Stefan
authors.initials: S
authors.lastname: Goldberg
mesh_terms: D000349:Africa; D018929:Cell Culture Techniques / Q000379:methods*; D003470:Culture Media / Q000494:pharmacology*; D005843:Geography; D015658:HIV Infections / Q000150:complications; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development; D011336:Probability; D044469:Racial Groups; D011859:Radiography; D013048:Specimen Handling; D013183:Sputum / Q000187:drug effects / Q000382:microbiology; D013997:Time Factors; D014376:Tuberculosis / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000382:microbiology
chemical_list: D003470:Culture Media