Estimating the Potential Public Health Value of BCG Revaccination.

An upcoming trial may provide further evidence that adolescent/adult-targeted BCG revaccination prevents sustained Mycobacterium tuberculosis infection, but its public health value depends on its impact on overall tuberculosis morbidity and mortality, which will remain unknown. Using previously calibrated models for India and South Africa, we simulated BCG revaccination assuming 45% prevention-of-infection efficacy, and we evaluated scenarios varying additional prevention-of-disease efficacy between +50% (reducing risk) and -50% (increasing risk). Given the assumed prevention-of-infection efficacy and range in prevention-of-disease efficacy, BCG revaccination may have a positive health impact and be cost-effective. This may be useful when considering future evaluations and implementation of adolescent/adult BCG revaccination.

The impact of blood transcriptomic biomarker targeted tuberculosis preventive therapy in people living with HIV: a mathematical modelling study.

BACKGROUND: Tuberculosis (TB) preventive therapy is recommended for all people living with HIV (PLHIV). Despite the elevated risk of TB amongst PLHIV, most of those eligible for preventive therapy would never develop TB. Tests which can identify individuals at greatest risk of disease would allow more efficient targeting of preventive therapy. METHODS: We used mathematical modelling to estimate the potential impact of using a blood transcriptomic biomarker (RISK11) to target preventive therapy amongst PLHIV. We compared universal treatment to RISK11 targeted treatment and explored the effect of repeat screening of the population with RISK11. RESULTS: Annual RISK11 screening, with preventive therapy provided to those testing positive, could avert 26% (95% CI 13-34) more cases over 10 years compared to one round of universal treatment. For the cost per case averted to be lower than universal treatment, the maximum cost of the RISK11 test was approximately 10% of the cost of preventive therapy. The benefit of RISK11 screening may be greatest amongst PLHIV on ART (compared to ART naïve individuals) due to the increased specificity of the test in this group. CONCLUSIONS: Biomarker targeted preventive therapy may be more effective than universal treatment amongst PLHIV in high incidence settings but would require repeat screening.

Informing Balanced Investment in Services and Health Systems: A Case Study of Priority Setting for Tuberculosis Interventions in South Africa.

OBJECTIVES: Health systems face nonfinancial constraints that can influence the opportunity cost of interventions. Empirical methods to explore their impact, however, are underdeveloped. We develop a conceptual framework for defining health system constraints and empirical estimation methods that rely on routine data. We then present an empirical approach for incorporating nonfinancial constraints in cost-effectiveness models of health benefit packages for the health sector. METHODS: We illustrate the application of this approach through a case study of defining a package of services for tuberculosis case-finding in South Africa. An economic model combining transmission model outputs with unit costs was developed to examine the cost-effectiveness of alternative screening and diagnostic algorithms. Constraints were operationalized as restrictions on achievable coverage based on: (1) financial resources; (2) human resources; and (3) policy constraints around diagnostics purchasing. Cost-effectiveness of the interventions was assessed under one "unconstrained" and several "constrained" scenarios. For the unconstrained scenario, incremental cost-effectiveness ratios were estimated with and without the costs of "relaxing" constraints. RESULTS: We find substantial differences in incremental cost-effectiveness ratios across scenarios, leading to variations in the decision rules for prioritizing interventions. In constrained scenarios, the limiting factor for most interventions was not financial, but rather the availability of human resources. CONCLUSIONS: We find that optimal prioritization among different tuberculosis control strategies in South Africa is influenced by whether and how constraints are taken into consideration. We thus demonstrate both the importance and feasibility of considering nonfinancial constraints in health sector resource allocation models.

The predicted impact of tuberculosis preventive therapy: the importance of disease progression assumptions.

BACKGROUND: Following infection with Mycobacterium tuberculosis (M.tb), individuals may rapidly develop tuberculosis (TB) disease or enter a "latent" infection state with a low risk of progression to disease. Mathematical models use a variety of structures and parameterisations to represent this process. The effect of these different assumptions on the predicted impact of TB interventions has not been assessed. METHODS: We explored how the assumptions made about progression from infection to disease affect the predicted impact of TB preventive therapy. We compared the predictions using three commonly used model structures, and parameters derived from two different data sources. RESULTS: The predicted impact of preventive therapy depended on both the model structure and parameterisation. At a baseline annual TB incidence of 500/100,000, there was a greater than 2.5-fold difference in the predicted reduction in incidence due to preventive therapy (ranging from 6 to 16%), and the number needed to treat to avert one TB case varied between 67 and 157. The relative importance of structure and parameters depended on baseline TB incidence and assumptions about the efficacy of preventive therapy, with the choice of structure becoming more important at higher incidence. CONCLUSIONS: The assumptions use to represent progression to disease in models are likely to influence the predicted impact of preventive therapy and other TB interventions. Modelling estimates of TB preventive therapy should consider routinely incorporating structural uncertainty, particularly in higher burden settings. Not doing so may lead to inaccurate and over confident conclusions, and sub-optimal evidence for decision making.

Should NICE reconsider the 2016 UK guidelines on TB contact tracing? A cost-effectiveness analysis of contact investigations in London.

BACKGROUND: In January 2016, clinical TB guidance in the UK changed to no longer recommend screening contacts of non-pulmonary, non-laryngeal (ETB) index cases. However, no new evidence was cited for this change, and there is evidence that screening these contacts may be worthwhile. The objective of this study was to estimate the cost-effectiveness of screening contacts of adult ETB cases and adult pulmonary or laryngeal TB (PTB) cases in London, UK. METHODS: We carried out a cross-sectional analysis of data collected on TB index cases and contacts in the London TB register and an economic evaluation using a static model describing contact tracing outcomes. Incremental cost-effectiveness ratios (ICERs) were calculated using no screening as the baseline comparator. All adult TB cases (≥15 years old) in London from 2012 to 2015, and their contacts, were eligible (2465/5084 PTB and 2559/6090 ETB index cases were included). RESULTS: Assuming each contact with PTB infects one person/month, the ICER of screening contacts of ETB cases was £78 000/quality-adjusted life-years (QALY) (95% CI 39 000 to 140 000), and screening contacts of PTB cases was £30 000/QALY (95% CI 18 000 to 50 000). The ICER of screening contacts of ETB cases was £30 000/QALY if each contact with PTB infects 3.4 people/month. Limitations of this study include the use of self-reported symptomatic periods and lack of knowledge about onward transmission from PTB contacts. CONCLUSIONS: Screening contacts of ETB cases in London was almost certainly not cost-effective at any conventional willingness-to-pay threshold in England, supporting recent changes to National Institute for Health and Care Excellence national guidelines.

A Bayesian Approach to Understanding Sex Differences in Tuberculosis Disease Burden.

Globally, men have a higher epidemiologic burden of tuberculosis (incidence, prevalence, mortality) than women do, possibly due to differences in disease incidence, treatment initiation, self-cure, and/or untreated-tuberculosis mortality rates. Using a simple, sex-stratified compartmental model, we employed a Bayesian approach to explore which factors most likely explain men's higher burden. We applied the model to smear-positive pulmonary tuberculosis in Vietnam (2006-2007) and Malawi (2013-2014). Posterior estimates were consistent with sex-specific prevalence and notifications in both countries. Results supported higher incidence in men and showed that both sexes faced longer durations of untreated disease than estimated by self-reports. Prior untreated disease durations were revised upward 8- to 24-fold, to 2.2 (95% credible interval: 1.7, 2.9) years for men in Vietnam and 2.8 (1.8, 4.1) years for men in Malawi, approximately a year longer than for women in each country. Results imply that substantial sex differences in tuberculosis burden are almost solely attributable to men's disadvantages in disease incidence and untreated disease duration. The latter, for which self-reports provide a poor proxy, implies inadequate coverage of case-finding strategies. These results highlight an urgent need for better understanding of gender-related barriers faced by men and support the systematic targeting of men for screening.

Quantifying the roles of host movement and vector dispersal in the transmission of vector-borne diseases of livestock.

The role of host movement in the spread of vector-borne diseases of livestock has been little studied. Here we develop a mathematical framework that allows us to disentangle and quantify the roles of vector dispersal and livestock movement in transmission between farms. We apply this framework to outbreaks of bluetongue virus (BTV) and Schmallenberg virus (SBV) in Great Britain, both of which are spread by Culicoides biting midges and have recently emerged in northern Europe. For BTV we estimate parameters by fitting the model to outbreak data using approximate Bayesian computation, while for SBV we use previously derived estimates. We find that around 90% of transmission of BTV between farms is a result of vector dispersal, while for SBV this proportion is 98%. This difference is a consequence of higher vector competence and shorter duration of viraemia for SBV compared with BTV. For both viruses we estimate that the mean number of secondary infections per infected farm is greater than one for vector dispersal, but below one for livestock movements. Although livestock movements account for a small proportion of transmission and cannot sustain an outbreak on their own, they play an important role in establishing new foci of infection. However, the impact of restricting livestock movements on the spread of both viruses depends critically on assumptions made about the distances over which vector dispersal occurs. If vector dispersal occurs primarily at a local scale (99% of transmission occurs <25 km), movement restrictions are predicted to be effective at reducing spread, but if dispersal occurs frequently over longer distances (99% of transmission occurs <50 km) they are not.

Empirical estimation of resource constraints for use in model-based economic evaluation: an example of TB services in South Africa.

BACKGROUND: Evidence on the relative costs and effects of interventions that do not consider 'real-world' constraints on implementation may be misleading. However, in many low- and middle-income countries, time and data scarcity mean that incorporating health system constraints in priority setting can be challenging. METHODS: We developed a 'proof of concept' method to empirically estimate health system constraints for inclusion in model-based economic evaluations, using intensified case-finding strategies (ICF) for tuberculosis (TB) in South Africa as an example. As part of a strategic planning process, we quantified the resources (fiscal and human) needed to scale up different ICF strategies (cough triage and WHO symptom screening). We identified and characterised three constraints through discussions with local stakeholders: (1) financial constraint: potential maximum increase in public TB financing available for new TB interventions; (2) human resource constraint: maximum current and future capacity among public sector nurses that could be dedicated to TB services; and (3) diagnostic supplies constraint: maximum ratio of Xpert MTB/RIF tests to TB notifications. We assessed the impact of these constraints on the costs of different ICF strategies. RESULTS: It would not be possible to reach the target coverage of ICF (as defined by policy makers) without addressing financial, human resource and diagnostic supplies constraints. The costs of addressing human resource constraints is substantial, increasing total TB programme costs during the period 2016-2035 by between 7% and 37% compared to assuming the expansion of ICF is unconstrained, depending on the ICF strategy chosen. CONCLUSIONS: Failure to include the costs of relaxing constraints may provide misleading estimates of costs, and therefore cost-effectiveness. In turn, these could impact the local relevance and credibility of analyses, thereby increasing the risk of sub-optimal investments.

An evaluation of tuberculosis contact investigations against national standards.

BACKGROUND: Contact tracing is a key element in England's 2015 collaborative TB strategy, although proposed indicators of successful contact tracing remain undescribed. METHODS: We conducted descriptive and multivariable analyses of contact tracing of TB cases in London between 1 July 2012 and 31 December 2015 using cohort review data from London's TB Register, identifying characteristics associated with improved indicators and yield. RESULTS: Of the pulmonary TB cases notified, 60% (2716/4561) had sufficient information for inclusion. Of these, 91% (2481/2716) had at least 1 contact (median: 4/case (IQR: 2-6)) identified, with 86% (10 251/11 981) of these contacts evaluated. 4.1% (177/4328), 1.3% (45/3421) and 0.70% (51/7264) of evaluated contacts of pulmonary smear-positive, pulmonary smear-negative and non-pulmonary cases, respectively, had active disease. Cases who were former prisoners or male were less likely to have at least one contact identified than those never imprisoned or female, respectively. Cases diagnosed at clinics with more directly observed therapy or social workers were more likely to have one or more contacts identified. Contacts screened at a different clinic to their index case or of male index cases were less likely to be evaluated than those screened at the same clinic or of women, respectively; yield of active disease was similar by sex. 10% (490/4850) of evaluated child contacts had latent TB infection. CONCLUSIONS: These are the first London-wide estimates of TB contact tracing indicators which are important for monitoring the strategy's success and informing risk assessment of index cases. Understanding why differences in indicators occur between groups could improve contact tracing outcomes.

Ability of preventive therapy to cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-burden settings.

Trials of isoniazid preventive therapy (IPT) for people living with HIV in southern Africa have shown high rates of tuberculosis disease immediately after cessation of therapy. This could be due to the lack of cure following preventive therapy or reinfection with rapid progression to disease. Using a model fitted to trial data, we estimate the degree to which preventive therapies cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-tuberculosis-burden settings. We identified randomized controlled trials that compared IPT to placebo or alternative regimen in HIV-positive, tuberculin skin test positive individuals. A mathematical model describing tuberculosis transmission in a closed cohort of HIV-positive, M. tuberculosis infected, antiretroviral therapy naive individuals following completion of preventive therapy (or placebo) was fitted to posttherapy tuberculosis rates to estimate the annual risk of M. tuberculosis reinfection and the proportion of individuals whose latent infection was cured after therapy. Three trials met our inclusion criteria. Estimated annual risks of reinfection ranged between 3.7 and 4.9%. Our results suggest 6 mo of isoniazid cured in a small proportion [estimated proportion cured = 0% (interquartile range 0-30.9%)]. The proportion cured for 3-mo regimens containing rifampicin or rifapentine was 19-100%. IPT alone does not cure existing infections in the majority of HIV-infected individuals. In high-incidence settings, continuous IPT should be integrated with HIV care. Where the risk of reinfection is lower, preventive therapy with more curative drugs should be preferred for HIV-positive individuals to achieve durable patient benefit.

Impact and cost-effectiveness of new tuberculosis vaccines in low- and middle-income countries.

To help reach the target of tuberculosis (TB) disease elimination by 2050, vaccine development needs to occur now. We estimated the impact and cost-effectiveness of potential TB vaccines in low- and middle-income countries using an age-structured transmission model. New vaccines were assumed to be available in 2024, to prevent active TB in all individuals, to have a 5-y to lifetime duration of protection, to have 40-80% efficacy, and to be targeted at "infants" or "adolescents/adults." Vaccine prices were tiered by income group (US $1.50-$10 per dose), and cost-effectiveness was assessed using incremental cost per disability adjusted life year (DALY) averted compared against gross national income per capita. Our results suggest that over 2024-2050, a vaccine targeted to adolescents/adults could have a greater impact than one targeted at infants. In low-income countries, a vaccine with a 10-y duration and 60% efficacy targeted at adolescents/adults could prevent 17 (95% range: 11-24) million TB cases by 2050 and could be considered cost-effective at $149 (cost saving to $387) per DALY averted. If targeted at infants, 0.89 (0.42-1.58) million TB cases could be prevented at $1,692 ($634-$4,603) per DALY averted. This profile targeted at adolescents/adults could be cost-effective at $4, $9, and $20 per dose in low-, lower-middle-, and upper-middle-income countries, respectively. Increased investments in adult-targeted TB vaccines may be warranted, even if only short duration and low efficacy vaccines are likely to be feasible, and trials among adults should be powered to detect low efficacies.

Tuberculosis control in South African gold mines: mathematical modeling of a trial of community-wide isoniazid preventive therapy.

A recent major cluster randomized trial of screening, active disease treatment, and mass isoniazid preventive therapy for 9 months during 2006-2011 among South African gold miners showed reduced individual-level tuberculosis incidence but no detectable population-level impact. We fitted a dynamic mathematical model to trial data and explored 1) factors contributing to the lack of population-level impact, 2) the best-achievable impact if all implementation characteristics were increased to the highest level achieved during the trial ("optimized intervention"), and 3) how tuberculosis might be better controlled with additional interventions (improving diagnostics, reducing treatment delay, providing isoniazid preventive therapy continuously to human immunodeficiency virus-positive people, or scaling up antiretroviral treatment coverage) individually and in combination. We found the following: 1) The model suggests that a small proportion of latent infections among human immunodeficiency virus-positive people were cured, which could have been a key factor explaining the lack of detectable population-level impact. 2) The optimized implementation increased impact by only 10%. 3) Implementing additional interventions individually and in combination led to up to 30% and 75% reductions, respectively, in tuberculosis incidence after 10 years. Tuberculosis control requires a combination prevention approach, including health systems strengthening to minimize treatment delay, improving diagnostics, increased antiretroviral treatment coverage, and effective preventive treatment regimens.

Modelling the health and economic impacts ofM72/AS01E vaccination and BCG-revaccination: Estimates for South Africa.

BACKGROUND: Tuberculosis remains a major public health problem in South Africa, with an estimated 300,000 cases and 55,000 deaths in 2021. New tuberculosis vaccines could play an important role in reducing this burden. Phase IIb trials have suggested efficacy of the M72/AS01E vaccine candidate and BCG-revaccination. The potential population impact of these vaccines is unknown. METHODS: We used an age-stratified transmission model of tuberculosis, calibrated to epidemiological data from South Africa, to estimate the potential health and economic impact of M72/AS01E vaccination and BCG-revaccination. We simulated M72/AS01E vaccination scenarios over the period 2030-2050 and BCG-revaccination scenarios over the period 2025-2050. We explored a range of product characteristics and delivery strategies. We calculated reductions in tuberculosis cases and deaths and costs and cost-effectiveness from health-system and societal perspectives. FINDINGS: M72/AS01E vaccination may have a larger impact than BCG-revaccination, averting approximately 80% more cases and deaths by 2050. Both vaccines were found to be cost-effective or cost saving (compared to no new vaccine) across a range of vaccine characteristics and delivery strategies from both the health system and societal perspective. The impact of M72/AS01E is dependent on the assumed efficacy of the vaccine in uninfected individuals. Extending BCG-revaccination to HIV-infected individuals on ART increased health impact by approximately 15%, but increased health system costs by approximately 70%. INTERPRETATION: Our results show that M72/AS01E vaccination or BCG-revaccination could be cost-effective in South Africa. However, there is considerable uncertainty in the estimated impact and costs due to uncertainty in vaccine characteristics and the choice of delivery strategy. FUNDING: This work was funded by the Bill & Melinda Gates Foundation (INV-001754). This work used the Cirrus UK National Tier-2 HPC Service at EPCC (https://www.cirrus.ac.uk) funded by the University of Edinburgh and EPSRC (EP/P020267/1).

The potential health and economic impacts of new tuberculosis vaccines under varying delivery strategies in Delhi and Gujarat, India: a modelling study.

Background: India has the largest tuberculosis burden globally, but this burden varies nationwide. All-age tuberculosis prevalence in 2021 ranged from 747/100,000 in Delhi to 137/100,000 in Gujarat. Previous modelling has demonstrated the benefits and costs of introducing novel tuberculosis vaccines in India overall. However, no studies have compared the potential impact of tuberculosis vaccines in regions within India with differing tuberculosis disease and infection prevalence. We used mathematical modelling to investigate how the health and economic impact of two potential tuberculosis vaccines, M72/AS01E and BCG-revaccination, could differ in Delhi and Gujarat under varying delivery strategies. Methods: We applied a compartmental tuberculosis model separately for Delhi (higher disease and infection prevalence) and Gujarat (lower disease and infection prevalence), and projected epidemiological trends to 2050 assuming no new vaccine introduction. We simulated M72/AS01E and BCG-revaccination scenarios varying target ages and vaccine characteristics. We estimated cumulative cases, deaths, and disability-adjusted life years averted between 2025-2050 compared to the no-new-vaccine scenario and compared incremental cost-effectiveness ratios to three cost-effectiveness thresholds. Results: M72/AS01E averted a higher proportion of tuberculosis cases than BCG-revaccination in both regions (Delhi: 16.0% vs 8.3%, Gujarat: 8.5% vs 5.1%) and had higher vaccination costs (Delhi: USD$118 million vs USD$27 million, Gujarat: US$366 million vs US$97 million). M72/AS01E in Delhi could be cost-effective, or even cost-saving, for all modelled vaccine characteristics. M72/AS01E could be cost-effective in Gujarat, unless efficacy was assumed only for those with current infection at vaccination. BCG-revaccination could be cost-effective, or cost-saving, in both regions for all modelled vaccine scenarios. Discussion: M72/AS01E and BCG-revaccination could be impactful and cost-effective in Delhi and Gujarat. Differences in impact, costs, and cost-effectiveness between vaccines and regions, were determined partly by differences in disease and infection prevalence, and demography. Age-specific regional estimates of infection prevalence could help to inform delivery strategies for vaccines that may only be effective in people with a particular infection status. Evidence on the mechanism of effect of M72/AS01E and its effectiveness in uninfected individuals, which were important drivers of impact and cost-effectiveness, particularly in Gujarat, are also key to improve estimates of population-level impact.

Variance-based sensitivity analysis of tuberculosis transmission models.

Mathematical models are widely used to provide evidence to inform policies for tuberculosis (TB) control. These models contain many sources of input uncertainty including the choice of model structure, parameter values and input data. Quantifying the role of these different sources of input uncertainty on the model outputs is important for understanding model dynamics and improving evidence for policy making. In this paper, we applied the Sobol sensitivity analysis method to a TB transmission model used to simulate the effects of a hypothetical population-wide screening strategy. We demonstrated how the method can be used to quantify the importance of both model parameters and model structure and how the analysis can be conducted on groups of inputs. Uncertainty in the model outputs was dominated by uncertainty in the intervention parameters. The important inputs were context dependent, depending on the setting, time horizon and outcome measure considered. In particular, the choice of model structure had an increasing effect on output uncertainty in high TB incidence settings. Grouping inputs identified the same influential inputs. Wider use of the Sobol method could inform ongoing development of infectious disease models and improve the use of modelling evidence in decision making.

Cost-effectiveness of routine adolescent vaccination with an M72/AS01E-like tuberculosis vaccine in South Africa and India.

The M72/AS01E tuberculosis vaccine showed 50% (95%CI: 2-74%) efficacy in a phase 2B trial in preventing active pulmonary tuberculosis disease, but potential cost-effectiveness of adolescent immunisation is unknown. We estimated the impact and cost-effectiveness of six scenarios of routine adolescent M72/AS01E-like vaccination in South Africa and India. All scenarios suggested an M72/AS01E-like vaccine would be highly (94-100%) cost-effective in South Africa compared to a cost-effectiveness threshold of $2480/disability-adjusted life-year (DALY) averted. For India, a prevention of disease vaccine, effective irrespective of recipient's M. tuberculosis infection status at time of administration, was also highly likely (92-100%) cost-effective at a threshold of $264/DALY averted; however, a prevention of disease vaccine, effective only if the recipient was already infected, had 0-6% probability of cost-effectiveness. In both settings, vaccinating 50% of 18 year-olds was similarly cost-effective to vaccinating 80% of 15 year-olds, and more cost-effective than vaccinating 80% of 10 year-olds. Vaccine trials should include adolescents to ensure vaccines can be delivered to this efficient-to-target population.

Population benefits of addressing programmatic and social determinants of gender disparities in tuberculosis in Viet Nam: A modelling study.

High prevalence of infectious tuberculosis among men suggests potential population-wide benefits from addressing programmatic and social determinants of gender disparities. Utilising a sex-stratified compartmental transmission model calibrated to tuberculosis burden estimates for Viet Nam, we modelled interventions to increase active case finding, to reduce tobacco smoking, and to reduce alcohol consumption by 2025 in line with national and global targets. For each intervention, we examined scenarios differentially targeting men and women and evaluated impact on tuberculosis morbidity and mortality in men, women, and children in 2035. Active case finding interventions targeting men projected greater reductions in tuberculosis incidence in men, women, and children (16.2%, uncertainty interval, UI, 11.4-23.0%, 11.8%, UI 8.0-18.6%, and 21.5%, UI 16.9-28.5%, respectively) than those targeting women (5.2%, UI 3.8-7.1%, 5.4%, UI 3.9-7.3%, and 8.6%, UI 6.9-10.7%, respectively). Projected reductions in tuberculosis incidence for interventions to reduce male tobacco smoking and alcohol consumption were greatest for men (17.4%, UI 11.8-24.7%, and 11.0%, UI 5.4-19.4%, respectively), but still substantial for women (6.9%, UI 3.8-12.5%, and 4.4%, UI 1.9-10.6%, respectively) and children (12.7%, UI 8.4-19.0%, and 8.0%, UI 3.9-15.0%, respectively). Comparable interventions targeting women projected limited impact, with declines of 0.3% (UI 0.2%-0.3%) and 0.1% (UI 0.0%-0.1%), respectively. Addressing programmatic and social determinants of men's tuberculosis burden has population-wide benefits. Future interventions to increase active case finding, to reduce tobacco smoking, and to reduce harmful alcohol consumption, whilst not ignoring women, should focus on men to most effectively reduce tuberculosis morbidity and mortality in men, women, and children.

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.

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.