Clean Blood, Religion, and Moral Triage in Tuberculosis Vaccine Trials.

During ethnographic research at a tuberculosis vaccine trial site in South Africa, trial participants often evoked the idiom of "clean blood." In this article, we illustrate how the trials enacted a form of moral triage in which "objective" bioscientific knowledge and moral subjectivity were coproduced. Participation created possibilities to demonstrate healthiness, respectability, and godliness in a context where positive self-imaginings were hard won, but could also lead to dejection and shame. We suggest that struggles to be recognized as virtuous are often overlooked in anthropological critiques of clinical trials and bioethics, but are important for understanding how trials meld with local moral worlds

Validation of a host blood transcriptomic biomarker for pulmonary tuberculosis in people living with HIV: a prospective diagnostic and prognostic accuracy study.

BACKGROUND: A rapid, blood-based triage test that allows targeted investigation for tuberculosis at the point of care could shorten the time to tuberculosis treatment and reduce mortality. We aimed to test the performance of a host blood transcriptomic signature (RISK11) in diagnosing tuberculosis and predicting progression to active pulmonary disease (prognosis) in people with HIV in a community setting. METHODS: In this prospective diagnostic and prognostic accuracy study, adults (aged 18-59 years) with HIV were recruited from five communities in South Africa. Individuals with a history of tuberculosis or household exposure to multidrug-resistant tuberculosis within the past 3 years, comorbid risk factors for tuberculosis, or any condition that would interfere with the study were excluded. RISK11 status was assessed at baseline by real-time PCR; participants and study staff were masked to the result. Participants underwent active surveillance for microbiologically confirmed tuberculosis by providing spontaneously expectorated sputum samples at baseline, if symptomatic during 15 months of follow-up, and at 15 months (the end of the study). The coprimary outcomes were the prevalence and cumulative incidence of tuberculosis disease confirmed by a positive Xpert MTB/RIF, Xpert Ultra, or Mycobacteria Growth Indicator Tube culture, or a combination of such, on at least two separate sputum samples collected within any 30-day period. FINDINGS: Between March 22, 2017, and May 15, 2018, 963 participants were assessed for eligibility and 861 were enrolled. Among 820 participants with valid RISK11 results, eight (1%) had prevalent tuberculosis at baseline: seven (2·5%; 95% CI 1·2-5·0) of 285 RISK11-positive participants and one (0·2%; 0·0-1·1) of 535 RISK11-negative participants. The relative risk (RR) of prevalent tuberculosis was 13·1 times (95% CI 2·1-81·6) greater in RISK11-positive participants than in RISK11-negative participants. RISK11 had a diagnostic area under the receiver operating characteristic curve (AUC) of 88·2% (95% CI 77·6-96·7), and a sensitivity of 87·5% (58·3-100·0) and specificity of 65·8% (62·5-69·0) at a predefined score threshold (60%). Of those with RISK11 results, eight had primary endpoint incident tuberculosis during 15 months of follow-up. Tuberculosis incidence was 2·5 per 100 person-years (95% CI 0·7-4·4) in the RISK11-positive group and 0·2 per 100 person-years (0·0-0·5) in the RISK11-negative group. The probability of primary endpoint incident tuberculosis was greater in the RISK11-positive group than in the RISK11-negative group (cumulative incidence ratio 16·0 [95% CI 2·0-129·5]). RISK11 had a prognostic AUC of 80·0% (95% CI 70·6-86·9), and a sensitivity of 88·6% (43·5-98·7) and a specificity of 68·9% (65·3-72·3) for incident tuberculosis at the 60% threshold. INTERPRETATION: RISK11 identified prevalent tuberculosis and predicted risk of progression to incident tuberculosis within 15 months in ambulant people living with HIV. RISK11's performance approached, but did not meet, WHO's target product profile benchmarks for screening and prognostic tests for tuberculosis. FUNDING: Bill & Melinda Gates Foundation and the South African Medical Research Council

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

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

A disease beyond reach: nurse perspectives on the past and present of tuberculosis control in South Africa

Although access to healthcare has improved since South Africa’s democratic transition, neoliberal reforms have had detrimental effects on clinic-community and nurse-patient relationships, undermining efforts to control tuberculosis (TB). This article focuses upon the work of nurses in three public health clinics in the Western Cape, South Africa. We explore how they experienced, made sense of and grappled with the challenges of TB control, especially patients “defaulting” on medication. Paying particular attention to confrontations between nurses and patients, we build upon previous qualitative studies that have contested popular constructions of nurses as “rude” and “uncaring.” We argue that patient blaming and scolding need to be understood in light of nurses having to tread a fine line between compassion and assertiveness, individual and public good against the backdrop of a dissonance between the theory and reality of TB control. Nurses’ confrontational approaches are responses to the messy reality of TB control on the ground, solutions to which require attention to the socioeconomic and historical context of nursing and primary healthcare. In the absence of such attention, animosities between clinics and communities could continue being cyclically reproduced

Validation of Correlates of Risk of TB Disease in High Risk Populations (CORTIS-HR) Study: Public, subject-level RISK11 signature scores and metadata

The Validation of Correlates of Risk of TB Disease in High Risk Populations (CORTIS-HR) Study, a companion study of the CORTIS-01 Trial (ClinicalTrials.gov: NCT02735590), was conducted to test the diagnostic and prognostic performance of the RISK11 biomarker for tuberculosis (TB) disease in people living with HIV (PLHIV) in an ambulant community setting. The “CORTIS-HR pubdata.csv” is a public, subject-level dataset for the CORTIS-HR study containing key variables necessary to reconstruct the study findings. A data dictionary is provided below. The “CORTIS-HR PCR data.csv” provides subject-level TaqMan qPCR probe raw CT (cycle threshold) gene expression data from the Fluidigm microfluidic 96.96 Gene Expression Integrated Fluidic Circuits (chips) with sample quality control (“SAMPLE_QC”) results. Analyses of the qPCR probe data are ongoing; the embargo on this data ends 1 July 2021 when the data will be available on ZivaHub. “CORTIS-HR Protocol Version 1.0.pdf” and “CORTIS-HR SAP Version 1.0.pdf” are the protocol and the statistical analysis plan for the study respectively and have been included for reference

RISK11 signature scores for the biomarker-guided tuberculosis preventive therapy (CORTIS) randomised controlled trial

RISK11 transcriptomic signature scores for 20,207 volunteers who were screened at five geographically diverse sites across South Africa. Signature scores were computed from QC'ed gene expression measurements performed by microfluidic RT-qPCR on mRNA derived from whole blood collected in PAXgene tubes. Participants were randomised into three groups and followed-up for 15 months to evaluate diagnostic and prognostic performance of RISK11 and to evaluate efficacy of high-dose isoniazid and rifapentine for prevention of incident TB