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

Abstract

Background: Targeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design.

Methods: Adult volunteers aged 18-59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie, <3 years before screening), or comorbidities at screening. RISK11-positive participants were block randomised (1:2; block size 15) to once-weekly, directly-observed, open-label isoniazid and rifapentine for 12 weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11 positive and 3HP negative). A subset of eligible RISK11-negative volunteers were randomly assigned to no treatment (ie, RISK11 negative and 3HP negative). Diagnostic discrimination of prevalent tuberculosis was tested in all participants at baseline. Thereafter, prognostic discrimination of incident tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative groups, and treatment efficacy in the 3HP-treated versus untreated RISK11-positive groups, during active surveillance through 15 months. The primary endpoint was microbiologically confirmed pulmonary tuberculosis. The primary outcome measures were risk ratio [RR] for tuberculosis of RISK11-positive to RISK11-negative participants, and treatment efficacy. This trial is registered with ClinicalTrials.gov, NCT02735590.

Findings: 20 207 volunteers were screened, and 2923 participants were enrolled, including RISK11-positive participants randomly assigned to 3HP (n=375) or no 3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in RISK11-negative participants (RR 3·69, 95% CI 2·25-6·05) over 15 months. Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in RISK11-positive compared with RISK11-negative participants, respectively (diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in RISK11-positive (3HP-negative) participants compared with RISK11-negative participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious adverse events related to 3HP included one hospitalisation for seizures (unintentional isoniazid overdose) and one death of unknown cause (possibly temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35 to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3HP-treated RISK11-positive participants compared with untreated RISK11-positive participants (efficacy 7·0%, 95% CI -145 to 65).

Interpretation: The RISK11 signature discriminated between individuals with prevalent tuberculosis, or progression to incident tuberculosis, and individuals who remained healthy, but provision of 3HP to signature-positive individuals after exclusion of baseline disease did not reduce progression to tuberculosis over 15 months.

Funding: Bill and Melinda Gates Foundation, South African Medical Research Council.

Figure 1

Study design The prevalence of RISK11 positivity was not precisely known in the study population; therefore, the number of individuals to be screened and the randomisation of RISK11-negative participants to enrolment was monitored and adjusted adaptively to ensure concurrent enrolment of the target number of RISK11-positive and RISK11-negative participants, per protocol specifications. The study used a three-group design to evaluate efficacy of the intervention and, in parallel, performance of the biomarker used to allocate that intervention. Diagnostic performance for differentiation of prevalent tuberculosis was tested in all three groups at baseline; prognostic performance for differentiation of incident tuberculosis over 15 months was tested in the two untreated groups (untreated RISK11 positive and untreated RISK11 negative); and treatment efficacy of 3HP over 15 months was tested in the two RISK11-positive groups (treated and untreated RISK11 positive). *Participants evaluated for eligibility at screening and enrolment. †Groups randomly assigned in blocks to ensure concurrent enrolment.

Figure 2

Trial profile ITT=intention to treat. mITT=modified intention to treat. LTFU=lost to follow-up. PP=per protocol analysis. *585 participants did not complete the trial for reasons including: 53 (9%) pregnancies, 22 (4%) investigator withdrawals, 46 (8%) consent withdrawals, 26 (4%) HIV infections, 422 (72%) LTFU, and 16 (3%) deaths.

Figure 3

RISK11 detection of combined prevalent and incident tuberculosis and diagnostic performance (A) Prevalence of tuberculosis in RISK11-positive (47 cases,) and RISK11-negative (14 cases, red bar) participants at trial enrolment. Error bars depict 95% CI. Cumulative incidence probability of tuberculosis in RISK11-positive (14 cases, blue line) or RISK11-negative (10 cases, red line) mITT participants during follow-up. Shaded areas represent 95% CI. (B) Ratio of RISK11-positive versus RISK11 negative cumulative incidence probability of observing prevalent or incident tuberculosis disease, in the ITT population of the observation group. (C) RISK11 signature scores (each dot represents a participant) measured at screening in trial participants, stratified on tuberculosis diagnosis. Boxes depict IQR, midline represents the median, and whiskers indicate range among enrolled participants. (D) RISK11 signature scores measured at screening in prevalent tuberculosis cases with or without any tuberculosis symptoms, in incident tuberculosis cases or those who did not have a tuberculosis diagnosis. The enrolled population, not the screened population, is represented in (C) and (D), because a large fraction of RISK11-negative participants were not enrolled by design. (E) ROC curves depicting RISK11 diagnostic performance for prevalent tuberculosis in the ITT population, for prevalent tuberculosis among individuals with no symptoms of tuberculosis (asymptomatic) and among individuals with at least one symptom consistent with tuberculosis disease (symptomatic). Shaded areas represent the 95% CI. The grey and black dots indicate the minimum and optimal criteria, respectively, set out in the WHO target product profile for a triage test. The empty dot indicates the criteria set out in the WHO target product profile for a confirmatory diagnostic test. TRP=true positive rate. ITT=intention to treat. FPR=false positive rate. AUC=area under the receiver operating characteristic curve.

Figure 4

Prognostic performance of RISK11 and treatment efficacy of 3HP (A) ROC curve depicting RISK11 prognostic performance for incident tuberculosis through 15 months of follow-up. The shaded area represents 95% CI. The grey and black dots depict the minimum and optimal criteria, respectively, set out in the WHO target product profile for an incipient tuberculosis test. (B) RISK11 performance (area under the ROC curve) for endpoints within a 6-month sliding window from month 0 through 15. The shaded area represents 95% CI. (C) ROC curves depicting RISK11 prognostic performance for incident tuberculosis through expanding follow-up periods. The grey and black dots depict the minimum and optimal criteria, respectively, set out in the WHO target product profile for an incipient tuberculosis test. (D) Cumulative incidence of tuberculosis in RISK11-positive participants who were randomly assigned to 3HP (six cases, red line) and RISK11-positive participants who were randomly assigned to observation (14 cases, blue line) during follow-up. The shaded areas represent 95% CI. (E) Cumulative incidence of tuberculosis in participants who met criteria for treatment adherence per protocol, stratified into RISK11-positive participants who were randomly assigned to 3HP (four cases, red line) and RISK11-positive participants who were randomly assigned to observation (14 cases, blue line) during follow-up. (F) TE estimated through follow-up in participants who met criteria for treatment adherence per protocol. The shaded areas represent 95% CI. TRP=true positive rate. FPR=false positive rate. AUC=area under the receiver operating characteristic curve. TPP=target product profile. TE=treatment efficacy.