Biomarkers for tuberculosis disease activity, cure, and relapse

Wallis, Robert S.; Doherty, T. Mark; Onyebujoh, Phillip; Vahedi, Mahnaz; Laang, Hannu; Olesen, Ole F.; Parida, Shreemanta K.; Zumla, Alimuddin

doi:10.1016/s1473-3099(09)70042-8

Cited by 162 publications

(108 citation statements)

References 85 publications

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“…These include the PCR [12,42], antigen 85 induction [69,70], whole blood bactericidal assay [71,72], the Early bactericidal activity of antituberculosis drugs Review www.expert-reviews.com measurement of mRNA [73,74], molecular bacterial load assay [75] and most recently the use of GeneXpert MTB/RIF to quantitate mycobacteria in sputum [76,77]. Each of these techniques could potentially either add value to the current determination of the fall in sputum CFU counts or replace it.…”

Section: Alternative Means Of Determining Ebamentioning

confidence: 99%

The early bactericidal activity of antituberculosis drugs

Diacon

Donald

2014

Expert Review of Anti-infective Therapy

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Early bactericidal activity studies measure the ability of antituberculosis treatments to reduce the burden of Mycobacterium tuberculosis in sputum specimens collected overnight from smear-positive pulmonary tuberculosis patients during the first 14 days of therapy. This confirms the efficacy of novel agents or drug combinations in human patients, allows comparison of different drug dosages and a preliminary assessment of the drugs' pharmacokinetics and toxicity in closely observed patients. In the past few years several novel antituberculosis agents have demonstrated significant early bactericidal activity and progressed to studies of longer duration. Most recently the early bactericidal activity of drug combinations was found to be similar to results predicted by murine studies. This may contribute to expediting the future progress of drug evaluation.

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Section: Alternative Means Of Determining Ebamentioning

confidence: 99%

The early bactericidal activity of antituberculosis drugs

Diacon

Donald

2014

Expert Review of Anti-infective Therapy

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“…Eight week sputum culture status is the most frequently used surrogate marker of treatment outcome. However, its ability to distinguish efficacy of regimens has come under scrutiny recently [7–12]. The discovery of a robust, quantitative, non-culture based biomarker or “biomarker signature” of treatment effect that can be measured early in treatment could speed up clinical development of new regimens and could potentially also be helpful for individual monitoring of patients on treatment [13, 14].…”

Section: Introductionmentioning

confidence: 99%

Aptamer-based proteomic signature of intensive phase treatment response in pulmonary tuberculosis

et al. 2014

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Background New drug regimens of greater efficacy and shorter duration are needed for tuberculosis (TB) treatment. The identification of accurate, quantitative, non-culture based markers of treatment response would improve the efficiency of Phase 2 TB drug testing. Methods In an unbiased biomarker discovery approach, we applied a highly multiplexed, aptamer-based, proteomic technology to analyze serum samples collected at baseline and after 8 weeks of treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in a Centers for Disease Control and Prevention (CDC) TB Trials Consortium Phase 2B treatment trial. Results We identified protein expression differences associated with 8-week culture status, including Coagulation Factor V, SAA, XPNPEP1, PSME1, IL-11 Rα, HSP70, Galectin-8, α2-Antiplasmin, ECM1, YES, IGFBP-1, CATZ, BGN, LYNB, and IL-7. Markers noted to have differential changes between responders and slow-responders included nectin-like protein 2, EphA1 (Ephrin type-A receptor 1), gp130, CNDP1, TGF-b RIII, MRC2, ADAM9, and CDON. A logistic regression model combining markers associated with 8-week culture status revealed an ROC curve with AUC=0.96, sensitivity=0.95 and specificity=0.90. Additional markers showed differential changes between responders and slow-responders (nectin-like protein), or correlated with time-to-culture-conversion (KLRK1). Conclusions Serum proteins involved in the coagulation cascade, neutrophil activity, immunity, inflammation, and tissue remodeling were found to be associated with TB treatment response. A quantitative, non-culture based, five-marker signature predictive of 8-week culture status was identified in this pilot study.

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“…It should be borne in mind that the predictive value of culture conversion itself for a long-term favourable outcome (failure or relapse at 2 years) is suboptimal. 58 However, the lack of correlation of initial and serial IGRAs with bacterial load and the high proportion of HIV-TB cases remaining IGRA-positive at 6 and 12 months post treatment makes it unlikely that it would make a good marker of treatment response. Chiappini et al concluded that monitoring IGRA changes over time seems to have only speculative value in adults.…”

Section: Discussionmentioning

confidence: 99%