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1.
EBioMedicine ; 25: 112-121, 2017 Nov.
Article in English | MEDLINE | ID: mdl-29100778

ABSTRACT

More efficacious treatment regimens are needed for tuberculosis, however, drug development is impeded by a lack of reliable biomarkers of disease severity and of treatment effect. We conducted a directed screen of host biomarkers in participants enrolled in a tuberculosis clinical trial to address this need. Serum samples from 319 protocol-correct, culture-confirmed pulmonary tuberculosis patients treated under direct observation as part of an international, phase 2 trial were screened for 70 markers of infection, inflammation, and metabolism. Biomarker assays were specifically developed for this study and quantified using a novel, multiplexed electrochemiluminescence assay. We evaluated the association of biomarkers with baseline characteristics, as well as with detailed microbiologic data, using Bonferroni-adjusted, linear regression models. Across numerous analyses, seven proteins, SAA1, PCT, IL-1ß, IL-6, CRP, PTX-3 and MMP-8, showed recurring strong associations with markers of baseline disease severity, smear grade and cavitation; were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8weeks. With treatment, all proteins decreased, except for osteocalcin, MCP-1 and MCP-4, which significantly increased. Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response. In conclusion, across a geographically diverse and large population of tuberculosis patients enrolled in a clinical trial, several previously reported putative biomarkers were not significantly associated with treatment response, however, seven proteins had recurring strong associations with baseline radiographic and microbiologic measures of disease severity, as well as with early treatment response, deserving additional study.


Subject(s)
Biomarkers/blood , Severity of Illness Index , Tuberculosis, Pulmonary/blood , Tuberculosis, Pulmonary/drug therapy , Adult , Aged , Antitubercular Agents , Drug Combinations , Ethambutol/administration & dosage , Female , Humans , Isoniazid/administration & dosage , Male , Middle Aged , Pyrazinamide/administration & dosage , Rifampin/administration & dosage , Treatment Outcome , Tuberculosis, Pulmonary/pathology
2.
Clin Pharmacol Ther ; 102(2): 321-331, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28124478

ABSTRACT

Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses.


Subject(s)
Antibiotics, Antitubercular/administration & dosage , Antibiotics, Antitubercular/pharmacokinetics , Rifampin/analogs & derivatives , Tuberculosis, Pulmonary/drug therapy , Tuberculosis, Pulmonary/metabolism , Adult , Dose-Response Relationship, Drug , Female , Humans , Male , Rifampin/administration & dosage , Rifampin/pharmacokinetics , Tuberculosis, Pulmonary/epidemiology
3.
J Clin Microbiol ; 54(12): 3028-3033, 2016 12.
Article in English | MEDLINE | ID: mdl-27733634

ABSTRACT

The Xpert MTB/RIF assay is both sensitive and specific as a diagnostic test. Xpert also reports quantitative output in cycle threshold (CT) values, which may provide a dynamic measure of sputum bacillary burden when used longitudinally. We evaluated the relationship between Xpert CT trajectory and drug exposure during tuberculosis (TB) treatment to assess the potential utility of Xpert CT for treatment monitoring. We obtained serial sputum samples from patients with smear-positive pulmonary TB who were consecutively enrolled at 10 international clinical trial sites participating in study 29X, a CDC-sponsored Tuberculosis Trials Consortium study evaluating the tolerability, safety, and antimicrobial activity of rifapentine at daily doses of up to 20 mg/kg of body weight. Xpert was performed at weeks 0, 2, 4, 6, 8, and 12. Longitudinal CT data were modeled using a nonlinear mixed effects model in relation to rifapentine exposure (area under the concentration-time curve [AUC]). The rate of change of CT was higher in subjects receiving rifapentine than in subjects receiving standard-dose rifampin. Moreover, rifapentine exposure, but not assigned dose, was significantly associated with rate of change in CT (P = 0.02). The estimated increase in CT slope for every additional 100 µg · h/ml of rifapentine drug exposure (as measured by AUC) was 0.11 CT/week (95% confidence interval [CI], 0.05 to 0.17). Increasing rifapentine exposure is associated with a higher rate of change of Xpert CT, indicating faster clearance of Mycobacterium tuberculosis DNA. These data suggest that the quantitative outputs of the Xpert MTB/RIF assay may be useful as a dynamic measure of TB treatment response.


Subject(s)
DNA, Bacterial/genetics , Mycobacterium tuberculosis/drug effects , Rifampin/analogs & derivatives , Sputum/microbiology , Tuberculosis, Pulmonary/diagnosis , Tuberculosis, Pulmonary/drug therapy , Adolescent , Adult , Female , Humans , Male , Middle Aged , Mycobacterium tuberculosis/genetics , Rifampin/adverse effects , Rifampin/therapeutic use , Sensitivity and Specificity , Young Adult
4.
Int J Tuberc Lung Dis ; 20(5): 600-4, 2016 May.
Article in English | MEDLINE | ID: mdl-27084812

ABSTRACT

SETTING: Two-month solid medium culture conversion is a commonly used, if suboptimal, endpoint for phase 2 anti-tuberculosis treatment trials. OBJECTIVE AND DESIGN: To model the effect of the performance characteristics (sensitivity and contamination rate) of solid medium on required sample size for a two-arm clinical trial with 85% true (gold standard) culture conversion in the control and 95% in the experimental arm. RESULTS: Increasing sensitivity and decreasing contamination reduced the sample size from 239 subjects/arm (60% sensitivity, 30% contamination) to 138 subjects/arm (95% sensitivity, 1% contamination). CONCLUSION: Optimizing solid medium has significant potential to reduce sample size and increase the efficiency of tuberculosis clinical trials.


Subject(s)
Antitubercular Agents/therapeutic use , Bacteriological Techniques , Clinical Trials, Phase II as Topic/methods , Controlled Clinical Trials as Topic/methods , Culture Media , Mycobacterium tuberculosis/drug effects , Sample Size , Tuberculosis/drug therapy , Endpoint Determination , Humans , Mycobacterium tuberculosis/growth & development , Mycobacterium tuberculosis/isolation & purification , Predictive Value of Tests , Reproducibility of Results , Time Factors , Treatment Outcome , Tuberculosis/diagnosis , Tuberculosis/microbiology
5.
Tissue Antigens ; 59(5): 436-9, 2002 May.
Article in English | MEDLINE | ID: mdl-12144632

ABSTRACT

HLA-DRB1, DRB3, DRB4, DRB5 and DQB1 polymorphisms were studied using molecular methods in a population of 100 unrelated healthy individuals from an area in north-west Colombia (Medellin) inhabited by the "Paisa", a community with features of a genetically isolated group. The most frequently observed specificities at the DRB1 locus were *07 (16.4%) and *15 (12%), and at the DQB1 locus *02 (18.8%) and *03 (33.6%), of which *0302 was the most prevalent allele (14.3%). The most polymorphic specificities were DRB1*04, 13 and 11, and DQB1*06. Both the HLA-DRB1 and DQB1 loci were in linkage disequilibrium. Haplotypes were estimated using maximum likelihood methods. The most frequent two locus haplotype was DRB1*07-DQB1*02 (6.6%) and these specificities were in linkage disequilibrium. Several unusual possible haplotypes were observed. Both the HLA-DRB1 and DQB1 locus were in Hardy-Weinberg equilibrium.


Subject(s)
HLA-DQ Antigens/genetics , HLA-DR Antigens/genetics , Polymorphism, Genetic , Colombia , HLA-DQ beta-Chains , Haplotypes , Humans , Linkage Disequilibrium
6.
J Immunol ; 155(4): 1951-63, 1995 Aug 15.
Article in English | MEDLINE | ID: mdl-7636246

ABSTRACT

We identified functionally important regions of the DR(alpha, beta 1*0401) peptide binding site and present a model of bound peptide. DR(alpha, beta 1*0401)-restricted T cell recognition and peptide binding of Mycobacterium leprae (ML) peptide 38-50 and overlapping peptides from the 18-kDa heat-shock protein were analyzed. ML38-50 is unusual in its restricted binding pattern, binding to only one of five DR4 subtypes and no other DR molecules tested. Amino acid substitutions were introduced into ML38-50 and the DR(alpha, beta 1*0401) peptide binding site at positions likely to influence peptide-MHC or peptide- or MHC-TCR interactions. Peptide binding, T cell proliferation, and computer modeling studies suggest that residues 39F, 42E, and 44D of ML38-50 interact with pockets 1, 4, and 6, respectively, of the peptide binding site. Only DR(alpha, beta 1*0401) substitutions at residues in pockets 4 or 7 prevented binding of ML38-50, while multiple substitutions at other positions negatively affected its T cell recognition. In contrast, T cell recognition of some high affinity ML peptides that overlapped ML38-50, and contained N-terminal extensions, was only abolished with pocket 4 substitutions. An inverse correlation of peptide affinity for DR(alpha, beta 1*0401) with negative effects of MHC substitutions on T cell recognition of the overlapping ML peptides was observed. Thus, some regions, such as pocket 4, dominantly influence T cell recognition of multiple DR(alpha, beta 1*0401)-binding peptides. However, each DR(alpha, beta 1*0401)-binding peptide appears to have unique properties that determine the outcome of its MHC-peptide interactions and the relative importance of other polymorphic pockets.


Subject(s)
HLA-DR Antigens/chemistry , Peptide Fragments/metabolism , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes/immunology , Amino Acid Sequence , Autoimmune Diseases/immunology , Binding Sites , HLA-DR Antigens/metabolism , Humans , Molecular Sequence Data , Mycobacterium leprae/immunology , Protein Structure, Secondary , Structure-Activity Relationship , Vaccines/immunology
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