Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial.

Area of Science:

• Infectious Disease Epidemiology
• Molecular Diagnostics
• Clinical Trial Design

Background:

• Targeted tuberculosis (TB) preventive therapy aims to reduce transmission by intervening in high-risk individuals.
• A transcriptomic signature, RISK11, was developed to identify individuals at high risk of developing active TB.
• Evaluating the efficacy of signature-guided preventive therapy is crucial for TB control strategies.

Purpose of the Study:

• To assess the performance of the RISK11 transcriptomic signature in identifying individuals at risk of prevalent and incident tuberculosis.
• To evaluate the efficacy of 12-week, once-weekly isoniazid and rifapentine (3HP) preventive therapy guided by the RISK11 signature.

Main Methods:

• A hybrid study enrolled 2923 adult volunteers in South Africa, assessing RISK11 status and TB disease.
• RISK11-positive participants were randomized to receive 3HP or no treatment; RISK11-negative participants received no treatment.
• Active surveillance for microbiologically confirmed pulmonary TB was conducted over 15 months, with primary outcomes being risk ratios and treatment efficacy.

Main Results:

• The RISK11 signature demonstrated significant diagnostic discrimination for prevalent TB (RR 5.13) and prognostic discrimination for incident TB (RR 3.69) over 15 months.
• Tuberculosis incidence was higher in RISK11-positive (2.09 per 100 person-years) compared to RISK11-negative participants (0.80 per 100 person-years).
• Treatment with 3HP in RISK11-positive individuals showed no significant reduction in TB incidence (efficacy 7.0%, 95% CI -145 to 65).

Conclusions:

• The RISK11 transcriptomic signature effectively identifies individuals at increased risk of developing tuberculosis.
• However, 12-week 3HP preventive therapy guided by the RISK11 signature did not demonstrate efficacy in reducing TB progression in this cohort.
• Further research is needed to optimize targeted preventive strategies for tuberculosis.