Abstract
RationaleGlobally there are approximately 9 million new active tuberculosis cases and 1.4 million deaths annually. Effective antituberculosis treatment monitoring is difficult as there are no existing biomarkers of poor adherence or inadequate treatment earlier than 2 months after treatment initiation. Inadequate treatment leads to worsening disease, disease transmission and drug resistance.ObjectivesTo determine if blood transcriptional signatures change in response to antituberculosis treatment and could act as early biomarkers of a successful response.MethodsBlood transcriptional profiles of untreated active tuberculosis patients in South Africa were analysed before, during (2 weeks and 2 months), at the end of (6 months) and after (12 months) antituberculosis treatment, and compared to individuals with latent tuberculosis. An active-tuberculosis transcriptional signature and a specific treatment-response transcriptional signature were derived. The specific treatment response transcriptional signature was tested in two independent cohorts. Two quantitative scoring algorithms were applied to measure the changes in the transcriptional response. The most significantly represented pathways were determined using Ingenuity Pathway Analysis.ResultsAn active tuberculosis 664-transcript signature and a treatment specific 320-transcript signature significantly diminished after 2 weeks of treatment in all cohorts, and continued to diminish until 6 months. The transcriptional response to treatment could be individually measured in each patient.ConclusionsSignificant changes in the transcriptional signatures measured by blood tests were readily detectable just 2 weeks after treatment initiation. These findings suggest that blood transcriptional signatures could be used as early surrogate biomarkers of successful treatment response.
Highlights
One third of the world’s population is infected with the pathogen Mycobacterium tuberculosis (Mtb), the cause of tuberculosis (TB)
These findings suggest that blood transcriptional signatures could be used as early surrogate biomarkers of successful treatment response
Due to the population’s high Mtb exposure, controls were considered as asymptomatic individuals with previous exposure to Mtb; exposure was evidenced by a positive QuantiFERON-TB Gold In-Tube (QFT) (Cellestis)
Summary
One third of the world’s population is infected with the pathogen Mycobacterium tuberculosis (Mtb), the cause of tuberculosis (TB). Active pulmonary TB diagnosis requires culture of Mtb, which may take up to 6 weeks [3]. After diagnosis there are no available early biomarkers correlating with treatment success, resulting in significant delay in assessing treatment response. Chest X-rays are commonly used to assess response but are not universally available and assessment is difficult to standardise [8]. This lack of effective treatment monitoring can lead to the development and spread of multidrug resistant (MDR) and extensively drug resistant (XDR) TB, which are mainly caused by non-adherence or inappropriate drug regimens, with a detrimental impact on global TB control
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