Modeling of Novel Diagnostic Strategies for Active Tuberculosis – A Systematic Review: Current Practices and Recommendations

Introduction: The field of diagnostics for active tuberculosis (TB) is rapidly developing. TB diagnostic modeling can help to inform policy makers and support complicated decisions on diagnostic strategy, with important budgetary implications. Demand for TB diagnostic modeling is likely to increase, and an evaluation of current practice is important. We aimed to systematically review all studies employing mathematical modeling to evaluate cost-effectiveness or epidemiological impact of novel diagnostic strategies for active TB. Methods: Pubmed, personal libraries and reference lists were searched to identify eligible papers. We extracted data on a wide variety of model structure, parameter choices, sensitivity analyses and study conclusions, which were discussed during a meeting of content experts. Results & Discussion From 5619 records a total of 36 papers were included in the analysis. Sixteen papers included population impact/transmission modeling, 5 were health systems models, and 24 included estimates of cost-effectiveness. Transmission and health systems models included specific structure to explore the importance of the diagnostic pathway (n = 4), key determinants of diagnostic delay (n = 5), operational context (n = 5), and the pre-diagnostic infectious period (n = 1). The majority of models implemented sensitivity analysis, although only 18 studies described multi-way sensitivity analysis of more than 2 parameters simultaneously. Among the models used to make cost-effectiveness estimates, most frequent diagnostic assays studied included Xpert MTB/RIF (n = 7), and alternative nucleic acid amplification tests (NAATs) (n = 4). Most (n = 16) of the cost-effectiveness models compared new assays to an existing baseline and generated an incremental cost-effectiveness ratio (ICER). Conclusion: Although models have addressed a small number of important issues, many decisions regarding implementation of TB diagnostics are being made without the full benefits of insight from mathematical models. Further models are needed that address a wider array of diagnostic and epidemiological settings, that explore the inherent uncertainty of models and that include additional epidemiological data on transmission implications of false-negative diagnosis and the pre-diagnostic period

The Impact of Antiretroviral Therapy on Mortality in HIV Positive People during Tuberculosis Treatment: A Systematic Review and Meta-Analysis

Objective: To quantify the impact of antiretroviral therapy (ART) on mortality in HIV-positive people during tuberculosis (TB) treatment. Design: We conducted a systematic literature review and meta-analysis. Studies published from 1996 through February 15, 2013, were identified by searching electronic resources (Pubmed and Embase) and conference books, manual searches of references, and expert consultation. Pooled estimates for the outcome of interest were acquired using random effects meta-analysis. Subjects The study population included individuals receiving ART before or during TB treatment. Main Outcome Measures: Main outcome measures were: (i) TB-case fatality ratio (CFR), defined as the proportion of individuals dying during TB treatment and, if mortality in HIV-positive people not on ART was also reported, (ii) the relative risk of death during TB treatment by ART status. Results: Twenty-one studies were included in the systematic review. Random effects pooled meta-analysis estimated the CFR between 8% and 14% (pooled estimate 11%). Among HIV-positive TB cases, those receiving ART had a reduction in mortality during TB treatment of between 44% and 71% (RR = 0.42, 95%CI: 0.29–0.56). Conclusion: Starting ART before or during TB therapy reduces the risk of death during TB treatment by around three-fifths in clinical settings. National programmes should continue to expand coverage of ART for HIV positive in order to control the dual epidemic

Small contribution of gold mines to the ongoing tuberculosis epidemic in South Africa: a modeling-based study.

BACKGROUND: Gold mines represent a potential hotspot for Mycobacterium tuberculosis (Mtb) transmission and may be exacerbating the tuberculosis (TB) epidemic in South Africa. However, the presence of multiple factors complicates estimation of the mining contribution to the TB burden in South Africa. METHODS: We developed two models of TB in South Africa, a static risk model and an individual-based model that accounts for longer-term trends. Both models account for four populations - mine workers, peri-mining residents, labor-sending residents, and other residents of South Africa - including the size and prevalence of latent TB infection, active TB, and HIV of each population and mixing between populations. We calibrated to mine- and country-level data and used the static model to estimate force of infection (FOI) and new infections attributable to local residents in each community compared to other residents. Using the individual-based model, we simulated a counterfactual scenario to estimate the fraction of overall TB incidence in South Africa attributable to recent transmission in mines. RESULTS: We estimated that the majority of FOI in each community is attributable to local residents: 93.9% (95% confidence interval 92.4-95.1%), 91.5% (91.4-91.5%), and 94.7% (94.7-94.7%) in gold mining, peri-mining, and labor-sending communities, respectively. Assuming a higher rate of Mtb transmission in mines, 4.1% (2.6-5.8%), 5.0% (4.5-5.5%), and 9.0% (8.8-9.1%) of new infections in South Africa are attributable to gold mine workers, peri-mining residents, and labor-sending residents, respectively. Therefore, mine workers with TB disease, who constitute ~ 2.5% of the prevalent TB cases in South Africa, contribute 1.62 (1.04-2.30) times as many new infections as TB cases in South Africa on average. By modeling TB on a longer time scale, we estimate 63.0% (58.5-67.7%) of incident TB disease in gold mining communities to be attributable to recent transmission, of which 92.5% (92.1-92.9%) is attributable to local transmission. CONCLUSIONS: Gold mine workers are estimated to contribute a disproportionately large number of Mtb infections in South Africa on a per-capita basis. However, mine workers contribute only a small fraction of overall Mtb infections in South Africa. Our results suggest that curtailing transmission in mines may have limited impact at the country level, despite potentially significant impact at the mining level

Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India: a combined analysis of 11 mathematical models

Background The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements. Methods 11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specifi c intervention scenarios, which included screening for symptoms, active case fi nding, and preventive therapy. Findings Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31–62%) and a 72% reduction in mortality (range 64–82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis. Interpretation Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specifi c tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level

Contribution of remote M. tuberculosis infection to tuberculosis disease: A 30-year population study

Background: The importance of remote infection with M.tuberculosis as a cause of tuberculosis disease (TB) is unclear, with limited evidence of impact on TB rates beyond 10 years. Our objective was to assess rates of tuberculosis over 30 years by M.tuberculosis infection status at baseline in Karonga District, Northern Malawi. Materials and methods: Population-based surveys of tuberculin skin testing (TST) from the 1980s were linked with follow-up and TB surveillance in Karonga district. We compared rates of microbiologically-confirmed TB by baseline TST induration <5mm (no evidence of M.tuberculosis infection) and those with baseline TST >17mm (evidence of M.tuberculosis infection), using hazard ratios by time since baseline and attributable risk percent. The attributable risk percent was calculated to estimate the proportion of TB in those infected that can be attributed to that prior infection. We analysed whole genome sequences of M.tuberculosis strains to identify recent transmission. Results: Over 412,959 person-years, 208 incident TB episodes were recorded. Compared to the small induration group, rates of TB were much higher in the first two years in the large induration group, and remained higher to 20 years: age, sex and area-adjusted hazard ratios (HR) 2–9 years post-TST 4.27 (95%CI 2.56–7.11); 10–19 years after TST 2.15 (1.10–4.21); ≥20 years post-TST 1.88 (0.76–4.65). The attributable risk percent of remote infection was 76.6% (60.9–85.9) 2–9 years post-TST, and 53.5% (9.1–76.2) 10–19 years post-TST. Individuals with large TST indurations had higher rates of unique-strain TB (HR adjusted for age, sex and area = HR 6.56 (95% CI 1.96–22.99)), suggesting disease following remote infection, but not of linked-strain TB (recent transmission). Conclusions: M.tuberculosis infection can increase the risk of TB far beyond 10 years, accounting for a substantial proportion of TB occurring among those remotely infected

Correction to: Small contribution of gold mines to the ongoing tuberculosis epidemic in South Africa: a modeling-based study.

The original article [1] did not contain comprehensive information regarding two authors' affiliations that may be considered a potential competing interest

Estimating the contribution of transmission in primary healthcare clinics to community-wide TB disease incidence, and the impact of infection prevention and control interventions, in KwaZulu-Natal, South Africa

From BMJ via Jisc Publications RouterHistory: received 2021-08-07, accepted 2022-03-20, ppub 2022-04, epub 2022-04-08Publication status: PublishedAaron S. Karat - ORCID: 0000-0001-9643-664X http://orcid.org/0000-0001-9643-664XKarin Diaconu - ORCID: 0000-0002-5810-9725 http://orcid.org/0000-0002-5810-9725Karina Kielmann - ORCID: 0000-0001-5519-1658 http://orcid.org/0000-0001-5519-1658Background: There is a high risk of Mycobacterium tuberculosis (Mtb) transmission in healthcare facilities in high burden settings. WHO guidelines on tuberculosis (TB) infection prevention and control (IPC) recommend a range of measures to reduce transmission in healthcare settings. These were evaluated primarily based on evidence for their effects on transmission to healthcare workers in hospitals. To estimate the overall impact of IPC interventions, it is necessary to also consider their impact on community-wide TB incidence and mortality. Methods: We developed an individual-based model of Mtb transmission in households, primary healthcare (PHC) clinics, and all other congregate settings. The model was parameterised using data from a high HIV prevalence community in South Africa, including data on social contact by setting, by sex, age, and HIV/antiretroviral therapy status; and data on TB prevalence in clinic attendees and the general population. We estimated the proportion of disease in adults that resulted from transmission in PHC clinics, and the impact of a range of IPC interventions in clinics on community-wide TB. Results: We estimate that 7.6% (plausible range 3.9%–13.9%) of non-multidrug resistant and multidrug resistant TB in adults resulted directly from transmission in PHC clinics in the community in 2019. The proportion is higher in HIV-positive people, at 9.3% (4.8%–16.8%), compared with 5.3% (2.7%–10.1%) in HIV-negative people. We estimate that IPC interventions could reduce incident TB cases in the community in 2021–2030 by 3.4%–8.0%, and deaths by 3.0%–7.2%. Conclusions: A non-trivial proportion of TB results from transmission in clinics in the study community, particularly in HIV-positive people. Implementing IPC interventions could lead to moderate reductions in disease burden. We recommend that IPC measures in clinics should be implemented for their benefits to staff and patients, but also for their likely effects on TB incidence and mortality in the surrounding community.The support of the Economic and Social Research Council (UK) is gratefully acknowledged. The project is partly funded by the Antimicrobial Resistance Cross Council Initiative supported by the seven research councils in partnership with other funders including support from the GCRF. Grant reference: ES/P008011/1. NM is additionally funded the Wellcome Trust (218261/Z/19/Z). RGW is funded by the Wellcome Trust (218261/Z/19/Z), NIH (1R01AI147321-01), EDTCP (RIA208D-2505B), UK MRC (CCF17-7779 via SET Bloomsbury), ESRC (ES/P008011/1), BMGF (OPP1084276, OPP1135288 & INV-001754), and the WHO (2020/985800-0). RMGJH is funded by ERC (action number 757699). TAY receives an NIHR Academic Clinical Fellowship.7pubpub

Treatment for radiographically active, sputum culture-negative pulmonary tuberculosis: a systematic review and meta-analysis

Background: People with radiographic evidence for pulmonary tuberculosis (TB), but negative sputum cultures, have increased risk of developing culture-positive TB. Recent expansion of X-ray screening is leading to increased identification of this group. We set out to synthesise the evidence for treatment to prevent progression to culture-positive disease. Methods: We conducted a systematic review and meta-analysis. We searched for prospective trials evaluating the efficacy of TB regimens against placebo, observation, or alternative regimens, for the treatment of adults and children with radiographic evidence of TB but culture-negative respiratory samples. Databases were searched up to 18 Oct 2022. Study quality was assessed using ROB 2·0 and ROBINS-I. The primary outcome was progression to culture-positive TB. Meta-analysis with a random effects model was conducted to estimate pooled efficacy. This study was registered with PROSPERO (CRD42021248486). Findings: We included 13 trials (32,568 individuals) conducted between 1955 and 2018. Radiographic and bacteriological criteria for inclusion varied. 19·1% to 57·9% of participants with active x-ray changes and no treatment progressed to culture-positive disease. Progression was reduced with any treatment (6 studies, risk ratio [RR] 0·27, 95%CI 0·13–0·56), although multi-drug TB treatment (RR 0·11, 95%CI 0·05–0·23) was significantly more effective than isoniazid treatment (RR 0·63, 95%CI 0·35–1·13) (p = 0·0002). Interpretation: Multi-drug regimens were associated with significantly reduced risk of progression to TB disease for individuals with radiographically apparent, but culture-negative TB. However, most studies were old, conducted prior to the HIV epidemic and with outdated regimens. New clinical trials are required to identify the optimal treatment approach

Modelling the effect of infection prevention and control measures on rate of Mycobacterium tuberculosis transmission to clinic attendees in primary health clinics in South Africa

Aaron S Karat - ORCID: 0000-0001-9643-664X https://orcid.org/0000-0001-9643-664XKarin Diaconu - ORCID: 0000-0002-5810-9725 https://orcid.org/0000-0002-5810-9725Karina Kielmann - ORCID: 0000-0001-5519-1658 https://orcid.org/0000-0001-5519-1658Background Elevated rates of tuberculosis in health care workers demonstrate the high rate of Mycobacterium tuberculosis (Mtb) transmission in health facilities in high burden settings. In the context of a project taking a whole systems approach to tuberculosis infection prevention and control (IPC), we aimed to evaluate the potential impact of conventional and novel IPC measures on Mtb transmission to patients and other clinic attendees.Methods An individual-based model of patient movements through clinics, ventilation in waiting areas, and Mtb transmission was developed, and parameterised using empirical data from eight clinics in two provinces in South Africa. Seven interventions – co-developed with health professionals and policymakers - were simulated: 1. queue management systems with outdoor waiting areas, 2. ultraviolet germicidal irradiation systems (UVGI), 3. appointment systems, 4. opening windows and doors, 5. surgical mask wearing by clinic attendees, 6. simple clinic retrofits, and 7. increased coverage of long antiretroviral therapy prescriptions and community medicine collection points through the CCMDD service.Results In the model, 1. outdoor waiting areas reduced the transmission to clinic attendees by 83% (interquartile range [IQR] 76-88%), 2. UVGI by 77% (IQR 64-85%), 3. appointment systems by 62% (IQR 45-75%), 4. opening windows and doors by 55% (IQR 25-72%), 5. masks by 47% (IQR 42-50%), 6. clinic retrofits by 45% (IQR 16-64%), and 7. increasing the coverage of CCMDD by 22% (IQR 12-32%).Conclusions The majority of the interventions achieved median reductions in the rate of transmission to clinic attendees of at least 45%, meaning that a range of highly effective intervention options are available, that can be tailored to the local context. Measures that are not traditionally considered to be IPC interventions, such as appointment systems, may be as effective as more traditional IPC measures, such as mask wearing.The support of the Economic and Social Research Council (IK) is gratefully acknowledged. The project is partly funded by the Antimicrobial Resistance Cross Council Initiative supported by the seven research councils in partnership with other funders including support from the GCRF. Grant reference: ES/P008011/1. NM is additionally funded the Wellcome Trust (218261/Z/19/Z). RGW is funded by the Wellcome Trust (218261/Z/19/Z), NIH (1R01AI147321-01), EDTCP (RIA208D-2505B), UK MRC (CCF17-7779 via SET Bloomsbury), ESRC (ES/P008011/1), BMGF (OPP1084276, OPP1135288 & INV-001754), and the WHO (2020/985800-0). TAY is funded via an NIHR Academic Clinical Fellowship. RMGHJ is funded by ERC (action number 757699)https://doi.org/10.1136/bmjgh-2021-0071246pubpub1

The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling.

BACKGROUND: The existing estimate of the global burden of latent TB infection (LTBI) as "one-third" of the world population is nearly 20 y old. Given the importance of controlling LTBI as part of the End TB Strategy for eliminating TB by 2050, changes in demography and scientific understanding, and progress in TB control, it is important to re-assess the global burden of LTBI. METHODS AND FINDINGS: We constructed trends in annual risk in infection (ARI) for countries between 1934 and 2014 using a combination of direct estimates of ARI from LTBI surveys (131 surveys from 1950 to 2011) and indirect estimates of ARI calculated from World Health Organisation (WHO) estimates of smear positive TB prevalence from 1990 to 2014. Gaussian process regression was used to generate ARIs for country-years without data and to represent uncertainty. Estimated ARI time-series were applied to the demography in each country to calculate the number and proportions of individuals infected, recently infected (infected within 2 y), and recently infected with isoniazid (INH)-resistant strains. Resulting estimates were aggregated by WHO region. We estimated the contribution of existing infections to TB incidence in 2035 and 2050. In 2014, the global burden of LTBI was 23.0% (95% uncertainty interval [UI]: 20.4%-26.4%), amounting to approximately 1.7 billion people. WHO South-East Asia, Western-Pacific, and Africa regions had the highest prevalence and accounted for around 80% of those with LTBI. Prevalence of recent infection was 0.8% (95% UI: 0.7%-0.9%) of the global population, amounting to 55.5 (95% UI: 48.2-63.8) million individuals currently at high risk of TB disease, of which 10.9% (95% UI:10.2%-11.8%) was isoniazid-resistant. Current LTBI alone, assuming no additional infections from 2015 onwards, would be expected to generate TB incidences in the region of 16.5 per 100,000 per year in 2035 and 8.3 per 100,000 per year in 2050. Limitations included the quantity and methodological heterogeneity of direct ARI data, and limited evidence to inform on potential clearance of LTBI. CONCLUSIONS: We estimate that approximately 1.7 billion individuals were latently infected with Mycobacterium tuberculosis (M.tb) globally in 2014, just under a quarter of the global population. Investment in new tools to improve diagnosis and treatment of those with LTBI at risk of progressing to disease is urgently needed to address this latent reservoir if the 2050 target of eliminating TB is to be reached