Performance of Tuberculosis Biomarker for Targeted Preventative Therapy

Tuberculosis bacillus in the lungs.
Tuberculosis bacillus in the lungs.
This randomized controlled trial prospectively measured diagnostic and prognostic performance of RISK11 for the triage of prevalent and prediction of incident tuberculosis in South African adults.

An RNA signature of tuberculosis, RISK11, was used to discriminate between individuals with prevalent tuberculosis or progression to incident tuberculosis and individuals who remained healthy, according to a study in The Lancet Infectious Diseases. However, the use of 3 months of once-weekly high-dose isoniazid and rifapentine (3HP) to treat signature-positive individuals did not reduce progression to tuberculosis over 15 months.

Targeted preventive therapy of high-risk individuals is a proposed strategy to reduce tuberculosis transmission. In this study, the diagnostic performance of RISK11 and signature-guided therapy was tested in parallel among adult volunteers without HIV aged 18 to 59 years from 5 geographically distinct South African communities ( identifier NCT02735590).

Of the 20,207 screened participants, 2923 were enrolled. This included 1784 RISK11-negative participants randomly assigned to no treatment, 375 RISK11-positive individuals randomly assigned to treatment with 3HP, and another 764 RISK11-positive participants randomly assigned to receive no 3HP.

Among RISK11-positive participants, there was a higher proportion of previous tuberculosis (9.8%) compared to RISK11-negative participants (6.7%; P =.003). In RISK11-positive (3HP-negative) participants, the cumulative probability of observing prevalent or incident tuberculosis over 15 months was 0.066 (95% CI, 0.049-0.084) and 0.018 (95% CI, 0.011-0) for the RISK11 negative group.

The risk of prevalent disease at baseline in RISK11-positive participants was increased 5.13 times (95% CI, 3.01-10.69) compared with RISK11-negative participants. Sensitivity was 35% (95% CI, 24% to 52%) and specificity, 91% (95% CI, 91% to 91%).

For incident tuberculosis, in the RISK11-positive group, annualized incidence was 2.1 per 100 person years and 0.8 per 100 person years in RISK11-negative participants. This was equivalent to cumulative incident probabilities of developing tuberculosis over 15 months of 0.26 (95% CI, 0.01-0.04) versus 0.010 (95% CI, 0.004-0.02) for the 2 groups, respectively.

For RISK11-positive participants, tuberculosis incidence through 15 months was 2.61 (95% CI, 1.15-5.94) times higher than RISK11-negative participants. RISK11 also discriminated between incident cases and control group participants with an area under the curve of 0.63 (95% CI, 0.47-0.80).

The incidence per 100 person years for the RISK11-positive 3HP treatment group versus RISK11-positive no treatment group was 1.94 (95% CI, 0.35-3.50) versus 2.09 (95% CI, 0.97-3.19), respectively, leading to an efficacy of 7.0% (95% CI, -145%-64.7%).

This hybrid study design was limited because it required an open-label treatment group with no placebo for RISK11-positive participants. Lower than expected prevalence of RISK11 meant enrollment times needed to be extended and fewer than expected incident tuberculosis outcomes were observed. Therefore, the power of analyses of treatment efficacy and RISK11 performance might have been reduced. Not all participants completed 3HP per protocol.

Investigators concluded that while biomarker-guided tuberculosis prevention strategies are possible, the optimal treatment regimen is not yet clear. Head-to-head analysis of other transcriptomic signatures are currently underway because it is also unclear how these signatures, which were developed in case-control studies, will perform in the field.

Disclosure: Several authors have patents of the RISK11 signature pending. Please refer to the original article for a full list of disclosures.


Scriba TJ, Fiore-Gartland A, Penn-Nicholson A, et al; CORTIS-01 Study Team. Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial. Lancet Infect Dis. 2021; 21(3): 354-365. doi:10.1016/S1473-3099(20)30914-2