Recent publications

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The use of mathematical modelling to inform and support tuberculosis (TB) policy-making has been encouraged by major funders and adopted by several high-burden countries. These quantitative planning exercises are undertaken to provide evidence for proposed interventions, improve the impact of TB funding and support funding applications. In recent years, a number of technical assistance providers have developed mathematical models and technical assistance capacity to support in-country TB policy decisions, and it is expected that the demand for technical assistance to support TB modelling will increase. The WHO Global Task Force on TB Impact Measurement provides global oversight to ensure that assessments of progress towards ending TB at global, regional and country levels are as rigorous, robust and consensus based as possible. The Task Force supports countries to improve the analysis and use of TB data for policy, planning and programmatic action, and is committed to the ongoing improvement of model-based policy analysis as a tool for strategic planning and budgeting. This document aims to provide concrete, pragmatic guidance for how TB modelling and related technical assistance is undertaken to support country decision-making. The target audience for this document are the participants and stakeholders in country-level TB modelling efforts, including the individuals who build and apply models; policy-makers, technical experts and other members of the TB community; international funding and technical partners; and individuals and organizations engaged in supporting TB policy-making.
Author: World Health Organization
Posted: May 16, 2019, 10:58 am
Tuberculosis caused 20% of all human deaths in the Western world between the seventeenth and nineteenth centuries and remains a cause of high mortality in developing countries. In analogy to other crowd diseases, the origin of human tuberculosis has been associated with the Neolithic Demographic Transition, but recent studies point to a much earlier origin. We analyzed the whole genomes of 259 M. tuberculosis complex (MTBC) strains and used this data set to characterize global diversity and to reconstruct the evolutionary history of this pathogen. Coalescent analyses indicate that MTBC emerged about 70,000 years ago, accompanied migrations of anatomically modern humans out of Africa and expanded as a consequence of increases in human population density during the Neolithic period. This long coevolutionary history is consistent with MTBC displaying characteristics indicative of adaptation to both low and high host densities.
Author: Inaki Comas
Posted: March 7, 2019, 4:18 pm
Mathematical models are increasingly used to compare strategies for tuberculosis control and inform policy decisions. Models often do not consider financial and other constraints on implementation and may overestimate the impact that can be achieved. We developed a pragmatic approach for incorporating resource constraints into mathematical models of tuberculosis. Using a transmission model calibrated for South Africa, we estimated the epidemiologic impact and resource requirements (financial, human resource (HR) and diagnostic) of nine case finding interventions. We compared the model-estimated resources to scenarios of future resource availability and estimated the impact of interventions under these constraints. Without constraints, symptom screening in public health clinics or in those attending HIV care was predicted to lead to larger reductions in tuberculosis incidence (9.5% (95% range (8.6%–12.2%)) and 14.5 (12.2–16.3)) than improved adherence to diagnostic guidelines (2.7% (1.6%–4.1%)). However, symptom screening required large increases in resources, exceeding future HR capacity. Even under our most optimistic HR scenario, the reduction in tuberculosis incidence from clinic symptom screening was 0.2%–0.9%, less than that of improved adherence to diagnostic guidelines. Ignoring resource constraints may result in incorrect conclusions about intervention impact, and to suboptimal policy decisions. Models used for decision making should consider resource constraints.
Author: Thomas Sumner
Posted: March 5, 2019, 3:49 pm
BACKGROUND: A sizeable fraction of tuberculosis (TB) cases go undiagnosed. By analysing data from enhanced demographic, microbiological and geospatial surveillance of TB registrations, we aimed to identify modifiable predictors of inequitable access to diagnosis and care.
METHODS: Governmental community health workers (CHW) enumerated all households in 315 catchment areas during October-December 2015. From January 2015, government TB Officers routinely implemented enhanced TB surveillance at all public and private TB treatment registration centres within Blantyre (18 clinics in total). This included collection from registering TB patients of demographic and clinical characteristics, a single sputum sample for TB microscopy and culture, and geolocation of place of residence using an electronic satellite map application. We estimated catchment area annual TB case notification rates (CNRs), stratified by microbiological status. To identify population and area-level factors predictive of CHW catchment area TB case notification rates, we constructed Bayesian spatially autocorrelated regression models with Poisson response distributions. Worldpop data were used to estimate poverty.
RESULTS: In total, the 315 CHW catchment areas comprised 753,489 people (range 162 to 13,066 people/catchment area). Between 2015 and 2017, 6077 TB cases (61% male; 99% HIV tested; 67% HIV positive; 55% culture confirmed) were geolocated, with 3723 (61%) resident within a CHW catchment area. In adjusted models, greater distance to the nearest TB registration clinic was negatively correlated with TB CNRs, which halved for every 3.2-fold (95% CI 2.24-5.21) increase in distance. Poverty, which increased with distance from clinics, was negatively correlated with TB CNRs; a 23% increase (95% CI 17-34%) in the mean percentage of the population living on less than US$2 per day corresponded to a halving of the TB case notification rates.
CONCLUSIONS: Using enhanced surveillance of TB cases in Blantyre, we show an ecological relationship consistent with an ‘inverse care law’ whereby poorer neighbourhoods and those furthest from TB clinics have lower relative CNRs. If confirmed as low case detection, then pro-poor strategies to facilitate equitable access to TB diagnosis and treatment are required.
Author: Peter MacPherson
Posted: February 21, 2019, 4:29 pm
South Africa has the highest tuberculosis (TB) disease incidence rate in the world, and TB is the leading infectious cause of death. Decisions on, and funding for, TB prevention and care policies are decentralised to the provincial governments and therefore, tools to inform policy need to operate at this level. We describe the use of a mathematical model planning tool at provincial level in a high HIV and TB burden country, to estimate the impact on TB burden of achieving the 90-(90)-90 targets of the Stop TB Partnership Global Plan to End TB. “TIME Impact” is a freely available, user-friendly TB modelling tool. In collaboration with provincial TB programme staff, and the South African National TB Programme, models for three (of nine) provinces were calibrated to TB notifications, incidence, and screening data. Reported levels of TB programme activities were used as baseline inputs into the models, which were used to estimate the impact of scale-up of interventions focusing on screening, linkage to care and treatment success. All baseline models predicted a trend of decreasing TB incidence and mortality, consistent with recent data from South Africa. The projected impacts of the interventions differed by province and were greatly influenced by assumed current coverage levels. The absence of provincial TB burden estimates and uncertainty in current activity coverage levels were key data gaps. A user-friendly modelling tool allows TB burden and intervention impact projection at the sub-national level. Key sub-national data gaps should be addressed to improve the quality of sub-national model predictions.
Author: Piotr Hippner
Posted: February 1, 2019, 2:27 pm
Disease case definitions are important instruments for clinical care, interventional research, and surveillance. Therefore, it is concerning that the current case definitions for tuberculosis remain underscored by the classic paradigm of binary states of latent infection and active disease, with a stepwise, linear transition under which symptoms, bacteriological positivity, and disease pathology are assumed to emerge broadly together (figure, A).1
This assumption has resulted in a reliance on symptom screening to distinguish these two states. However, in recent prevalence surveys, 40–79% of bacteriologically positive tuberculosis occurs in the absence of patient-recognised tuberculosis symptoms.2
Rather than explicitly addressing this discordance, tuberculosis case definitions are often ambiguous regarding tuberculosis symptoms, or internally inconsistent.
Author: Rein Houben
Posted: February 1, 2019, 10:04 am
BACKGROUND:Transmission patterns in high tuberculosis incidence areas in England are poorly understood but need elucidating to focus contact tracing. We study transmission within and between age, ethnic and immigrant groups using molecular data from the high incidence West Midlands region. METHODS:Isolates from culture-confirmed tuberculosis cases during 2007-2011 were typed using 24-locus Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeats (MIRU-VNTR). We estimated the proportion of disease attributable to recent transmission, calculated the proportion of isolates matching those from the two preceding years (“retrospectively clustered”), and identified risk factors for retrospective clustering using multivariate analyses. We calculated the ratio (RCR) between the observed and expected proportion clustered retrospectively within or between age, ethnic and immigrant groups. RESULTS:Of the 2159 available genotypes (79% of culture-confirmed cases), 34% were attributed to recent transmission. The percentage retrospectively clustered decreased from 50 to 24% for 0-14 and ≥ 65 year olds respectively (p = 0.01) and was significantly lower for immigrants than the UK-born. Higher than expected clustering occurred within 15-24 year olds (RCR: 1.4 (95% CI: 1.1-1.8)), several ethnic groups, and between UK-born or long-term immigrants with the UK-born (RCR: 1.8 (95% CI: 1.1-2.4) and 1.6 (95% CI: 1.2-1.9) respectively). CONCLUSIONS:This study is the first to consider “who clusters with whom” in a high incidence area in England, laying the foundation for future whole-genome sequencing work. The higher than expected clustering seen here suggests that preferential mixing between some age, ethnic and immigrant groups occurs; prioritising contact tracing to groups with which cases are most likely to cluster retrospectively could improve TB control.
Author: Emilia Vynnycky
Posted: January 12, 2019, 12:05 pm
This thesis investigates the epidemiology of tuberculosis (TB) disease in populations. It applies molecular epidemiological methods to elucidate the relative effects of HIV on TB disease following recent first infection, reactivation and recent reinfection with Mycobacterium tuberculosis (Mtb). Finally it aims to explore the impact of Antiretroviral Therapy (ART) on the incidence of TB in a population in rural Sub Saharan Africa. The data in chapters 2 and 3 is taken from a systematic literature review I performed of population based studies that reported TB molecular epidemiological data. In the subsequent chapters I analyse existing and newly collected data from the Karonga Prevention Study, set in Northern Malawi, to address the research questions. The results strongly suggest that HIV-infection increases an individual’s risk of TB disease due to recent Mtb (re)infection more than through reactivation in populations with generalised HIV epidemics. The last chapter suggests that patients on ART experience a high risk of TB compared to HIV positive/ART naive patients, especially in the first months after initiating ART. Also, it appears that after the introduction of ART in 2005 TB incidence in Karonga District plateaued after declining in the previous 10 years. These findings strongly suggest that TB programmes in areas with generalised HIV epidemics should focus more of their efforts on reducing Mtb transmission. Improved collaboration between TB and ART programmes may help to reduce TB rates in the highly vulnerable ART receiving population and subsequently in the general population.
Author: RM Houben
Posted: January 11, 2019, 12:31 pm
<ns4:p>Tuberculosis kills more people worldwide than any other single infectious disease agent, a threat made more dire by the spread of drug-resistant strains of <ns4:italic>Mycobacterium tuberculosis (Mtb)</ns4:italic>. Development of new vaccines capable of preventing TB disease and new <ns4:italic>Mtb</ns4:italic> infection are an essential component of the strategy to combat the TB epidemic. Accordingly, the WHO considers the development of new TB vaccines a major public health priority. In October 2017, the WHO convened a consultation with global leaders in the TB vaccine development field to emphasize the WHO commitment to this effort and to facilitate creative approaches to the discovery and development of TB vaccine candidates. This review summarizes the presentations at this consultation, updated with scientific literature references, and includes discussions of the public health need for a TB vaccine; the status of efforts to develop vaccines to replace or potentiate BCG in infants and develop new TB vaccines for adolescents and adults; strategies being employed to diversify vaccine platforms; and new animal models being developed to facilitate TB vaccine development. A perspective on the status of these efforts from the major funders and organizational contributors also is included. This presentation highlights the extraordinary progress being made to develop new TB vaccines and provided a clear picture of the exciting development pathways that are being explored.</ns4:p>
Author: Lewis K Schrager
Posted: December 17, 2018, 1:52 pm
Background
Tuberculosis is the leading single-pathogen cause of death worldwide, and China has the third largest number of cases worldwide. New tools, such as new vaccines, are needed to meet WHO tuberculosis goals. Tuberculosis vaccine development strategies mostly target infants or adolescents, but given China’s ageing epidemic, vaccinating older people might be important. We modelled the potential impact of new tuberculosis vaccines in China targeting adolescents (15–19 years) or older adults (60–64 years) with varying vaccine characteristics to inform strategic vaccine development.
Methods
A Mycobacterium tuberculosis transmission model was calibrated to age-stratified demographic and epidemiological data from China. Varying scenarios of vaccine implementation (age targeting [adolescents or older adults] and coverage [30% or 70%]) and characteristics (efficacy [40%, 60%, or 80%], duration of protection [10 years or 20 years], and host infection status required for efficacy [pre-infection, post-infection in latency, post-infection in latency or recovered, or pre-infection and post-infection]) were assessed. Primary outcomes were tuberculosis incidence and mortality rate reduction in 2050 in each vaccine scenario compared with the baseline (no new vaccine) scenario and cumulative number needed to vaccinate (NNV) per case or death averted, 2025–50.
Findings
By 2050, results suggest that 74·5% (uncertainty interval [UI] 70·2–78·6) of incident tuberculosis cases in China would occur in people aged 65 years or older, and 75·1% (66·8–80·7) of all cases would be due to reactivation, rather than new infection. All vaccine profiles delivered to older adults had higher population-level impact (reduction of incidence and mortality rates) and lower NNV per case and per death averted than if delivered to adolescents. For an intermediate vaccine scenario of 60% efficacy, 10-year protection, and 70% coverage, the reduction of tuberculosis incidence rates with older adult vaccination was 1·9 times (UI 1·5–2·6) to 157·5 times (119·3–225·6) greater than with adolescent vaccination, and the NNV was 0·011 times (0·008–0·014) to 0·796 times (0·632–0·970) lower. Furthermore, with older adult vaccination, post-infection vaccines provided substantially greater mortality and incidence rate reductions than pre-infection vaccines.
Interpretation
Adolescent-targeted tuberculosis vaccines, the focus of many development plans, would have only a small impact in ageing, reactivation-driven epidemics such as those in China. Instead, an efficacious post-infection vaccine delivered to older adults will be crucial to maximise population-level impact in this setting and would provide an important contribution towards achieving WHO goals. Older adults should be included in tuberculosis vaccine clinical development and implementation planning.
Author: Rebecca Harris
Posted: December 3, 2018, 6:36 pm
Background
Until recently, evidence that protection from the bacillus Calmette–Guérin (BCG) vaccination lasted beyond 10 years was limited. In the past few years, studies in Brazil and the USA (in Native Americans) have suggested that protection from BCG vaccination against tuberculosis (TB) in childhood can last for several decades. The UK’s universal school-age BCG vaccination programme was stopped in 2005 and the programme of selective vaccination of high-risk (usually ethnic minority) infants was enhanced.

Objectives
To assess the duration of protection of infant and school-age BCG vaccination against TB in the UK.

Methods
Two case–control studies of the duration of protection of BCG vaccination were conducted, the first on minority ethnic groups who were eligible for infant BCG vaccination 0–19 years earlier and the second on white subjects eligible for school-age BCG vaccination 10–29 years earlier. TB cases were selected from notifications to the UK national Enhanced Tuberculosis Surveillance system from 2003 to 2012. Population-based control subjects, frequency matched for age, were recruited. BCG vaccination status was established from BCG records, scar reading and BCG history. Information on potential confounders was collected using computer-assisted interviews. Vaccine effectiveness was estimated as a function of time since vaccination, using a case–cohort analysis based on Cox regression.

Results
In the infant BCG study, vaccination status was determined using vaccination records as recall was poor and concordance between records and scar reading was limited. A protective effect was seen up to 10 years following infant vaccination [< 5 years since vaccination: vaccine effectiveness (VE) 66%, 95% confidence interval (CI) 17% to 86%; 5–10 years since vaccination: VE 75%, 95% CI 43% to 89%], but there was weak evidence of an effect 10–15 years after vaccination (VE 36%, 95% CI negative to 77%; p = 0.396). The analyses of the protective effect of infant BCG vaccination were adjusted for confounders, including birth cohort and ethnicity. For school-aged BCG vaccination, VE was 51% (95% CI 21% to 69%) 10–15 years after vaccination and 57% (95% CI 33% to 72%) 15–20 years after vaccination, beyond which time protection appeared to wane. Ascertainment of vaccination status was based on self-reported history and scar reading.

Limitations
The difficulty in examining vaccination sites in older women in the high-risk minority ethnic study population and the sparsity of vaccine record data in the later time periods precluded robust assessment of protection from infant BCG vaccination > 10 years after vaccination.

Conclusions
Infant BCG vaccination in a population at high risk for TB was shown to provide protection for at least 10 years, whereas in the white population school-age vaccination was shown to provide protection for at least 20 years. This evidence may inform TB vaccination programmes (e.g. the timing of administration of improved TB vaccines, if they become available) and cost-effectiveness studies. Methods to deal with missing record data in the infant study could be explored, including the use of scar reading.

Author: Punam Mangtani
Posted: November 29, 2018, 9:15 am
Background
Until recently, evidence that protection from the bacillus Calmette–Guérin (BCG) vaccination lasted beyond 10 years was limited. In the past few years, studies in Brazil and the USA (in Native Americans) have suggested that protection from BCG vaccination against tuberculosis (TB) in childhood can last for several decades. The UK’s universal school-age BCG vaccination programme was stopped in 2005 and the programme of selective vaccination of high-risk (usually ethnic minority) infants was enhanced.

Objectives
To assess the duration of protection of infant and school-age BCG vaccination against TB in the UK.

Methods
Two case–control studies of the duration of protection of BCG vaccination were conducted, the first on minority ethnic groups who were eligible for infant BCG vaccination 0–19 years earlier and the second on white subjects eligible for school-age BCG vaccination 10–29 years earlier. TB cases were selected from notifications to the UK national Enhanced Tuberculosis Surveillance system from 2003 to 2012. Population-based control subjects, frequency matched for age, were recruited. BCG vaccination status was established from BCG records, scar reading and BCG history. Information on potential confounders was collected using computer-assisted interviews. Vaccine effectiveness was estimated as a function of time since vaccination, using a case–cohort analysis based on Cox regression.

Results
In the infant BCG study, vaccination status was determined using vaccination records as recall was poor and concordance between records and scar reading was limited. A protective effect was seen up to 10 years following infant vaccination [< 5 years since vaccination: vaccine effectiveness (VE) 66%, 95% confidence interval (CI) 17% to 86%; 5–10 years since vaccination: VE 75%, 95% CI 43% to 89%], but there was weak evidence of an effect 10–15 years after vaccination (VE 36%, 95% CI negative to 77%; p = 0.396). The analyses of the protective effect of infant BCG vaccination were adjusted for confounders, including birth cohort and ethnicity. For school-aged BCG vaccination, VE was 51% (95% CI 21% to 69%) 10–15 years after vaccination and 57% (95% CI 33% to 72%) 15–20 years after vaccination, beyond which time protection appeared to wane. Ascertainment of vaccination status was based on self-reported history and scar reading.

Limitations
The difficulty in examining vaccination sites in older women in the high-risk minority ethnic study population and the sparsity of vaccine record data in the later time periods precluded robust assessment of protection from infant BCG vaccination > 10 years after vaccination.

Conclusions
Infant BCG vaccination in a population at high risk for TB was shown to provide protection for at least 10 years, whereas in the white population school-age vaccination was shown to provide protection for at least 20 years. This evidence may inform TB vaccination programmes (e.g. the timing of administration of improved TB vaccines, if they become available) and cost-effectiveness studies. Methods to deal with missing record data in the infant study could be explored, including the use of scar reading.

Author: Punam Mangtani
Posted: November 26, 2018, 5:20 pm
People with pulmonary tuberculosis (TB) are at risk of developing chronic respiratory disorders due to residual lung damage. So far, the scope of the problem in high burden TB countries is relatively unknown.

Chronic respiratory symptoms (cough and phlegm lasting &gt;2 weeks) and radiological lung abnormalities were compared between adults with and without a history of TB among the general population of Uganda. Multivariable regression models were used to estimate odds ratios with adjustment for age, gender, smoking, education, setting and region. Random effects models accounted for village clustering effect.

Of 45,293 invited people from 70 villages, 41,154 (90.9%) participated in the survey. 798 had a history of TB and among them, 16% had respiratory symptoms and 41% x-ray abnormalities. Adjusted odds ratios showed strong evidence for individuals with a history of TB having increased risk of respiratory symptoms (OR=4·02, 95%CI: 3·25-4·96) and x-ray abnormalities (OR=17·52, 95%CI: 14·76-20·79); attributing 6% and 24% of the respective population risks.

In Uganda, a history of TB was a strong predictor of respiratory symptoms and lung abnormalities, before older age and smoking. Eliminating TB disease could reduce the prevalence of chronic respiratory symptoms as much as eliminating smoking.

Author: SC van Kampen
Posted: November 17, 2018, 3:09 pm
Tuberculosis (TB) is a disease of poverty. Ensuring access to health care without risk of financial hardship due to out-of-pocket health care expenditures (Universal Health Coverage; UHC) is essential for providing accessible care for underprivileged populations, but it is not enough.
The End TB Strategy promotes both patient-centred TB services and social protection measures, which aim to mitigate economic hardship on TB patients and their households due to direct medical and non-medical expenditures, as well as lost income. The Strategy includes a target that no families should face catastrophic total costs due to TB. The indicator linked to this target aims to capture the total economic burden linked to TB care, and thus differs from the “catastrophic expenditure on health” indicator, a key component of the UHC monitoring framework, aligned to the Sustainable Development Goals. Countries, especially high TB-burden countries, are expected to conduct nationally-representative TB patient cost surveys to establish baseline measurements for the catastrophic costs indicator. Findings from these surveys should also help identify entry points to develop policies to ensure better financial and social protection for TB patients. In this paper, we define the key measurable concepts for TB patient cost surveys, notably the types of costs that are captured and related affordability measures. We discuss the methods for measuring these notions in the UHC framework and contrast them with how they are measured in TB patient cost surveys.
Author: Debora Pedrazzoli
Posted: November 15, 2018, 1:38 pm
Migration is a key driver of tuberculosis (TB) in many low incidence settings, with the majority of TB cases attributed to reactivation of latent TB (LTBI) acquired overseas. A greater understanding of LTBI risk in heterogeneous migrant populations would aid health planning. We aimed to estimate the LTBI prevalence and distribution among local and overseas-born Australians.Annual risks of tuberculosis infection estimates were applied to population cohorts (by country of birth, year of arrival and age) in Australian census data in 2006, 2011 and 2016.Both the absolute number and proportion of Australian residents with LTBI increased – from 4.6% (IQR [interquartile range] 4.2-5.2%) in 2006 to 5.1% (IQR 4.7%-5.5%) in 2016 – due to the increasing proportion of the population born overseas (23.8% in 2006 to 28.3% in 2016). Of all residents estimated to have LTBI in 2016; 93.2% were overseas born, 21.6% were &lt;35 years of age and 34.4% had migrated to Australia since 2007.The overall prevalence of LTBI in Australia is low. Some residents, particularly migrants from high incidence settings, may have considerably higher risk of LTBI, and these findings allow for tailored public health interventions to reduce the risk and impact of future TB disease.
Author: KD Dale
Posted: October 30, 2018, 10:26 am
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.

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.

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.

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.

Author: FM Bozzani
Posted: October 15, 2018, 2:19 pm
The majority of tuberculosis transmission occurs in community settings. The primary aim of this study was to assess the association between exposure to community venues and multidrug-resistant tuberculosis (MDR-TB) disease. The secondary aim was to describe the social networks of MDR-TB cases and controls.

This case-control study was conducted in Lima, Peru. We recruited lab-confirmed MDR-TB cases and community controls matched on age and sex. Whole-genome sequencing was used to identify genetically-clustered cases. Venue-tracing interviews (nonblinded) were conducted to enumerate community venues frequented by participants. Logistic regression was used to assess the association between MDR-TB disease and person-time spent in community venues. A location-based social network was constructed with respondents connected if they reported frequenting the same venue and an exponential random graph model (ERGM) was fitted to model the network.

We enrolled 59 cases and 65 controls. Participants reported 729 unique venues. Mean number of venues reported was similar in both groups (P=0.92). Cases reported spending more person-time (hours) in healthcare and transportation venues than controls (P&lt;0.05). Person-time in healthcare venues (Adjusted Odds Ratio (OR)=1.67, P=0.01), schools (OR=1.53, P&lt;0.01), and transportation (OR=1.25, P=0.03) was associated with MDR-TB disease. Healthcare venues, markets, cinemas, and transportation venues were commonly shared among clustered cases. The ERGM indicated significant community segregation between cases and controls. Case networks were more densely connected.

Exposure to healthcare venues, schools and transportation was associated with MDR-TB disease. Intervention across the segregated network of case venues may be necessary to effectively stem transmission.

Author: DP Bui
Posted: September 24, 2018, 2:58 pm
Background: With an estimated 10.4 million incident tuberculosis (TB) cases in 2015, and the current trajectory of 1.5%/year incidence rate decline, new TB vaccines are urgently needed to help meet the WHO goal of tuberculosis elimination by 2050. However, insufficient epidemiological evidence exists to inform TB vaccine development strategies and to assist clinical trial site selection and design. Research to meet these data needs is critical to accelerate TB vaccine development. To maximise the future impact of new TB vaccines, estimates of the population-level impact of vaccine characteristics and implementation strategies are needed to inform design of TB vaccine target product profiles. To accelerate and de-risk clinical trials, appropriate epidemiological data are required to inform trial site selection, sample size calculations and recruitment strategy. However, data availability at trial sites is limited, and prospective studies are resource-intensive, so new methods are needed to collect appropriate data to inform TB vaccine trial design.
To inform data-driven development strategies for new TB vaccines, the aims of this thesis were to 1) estimate the epidemiological impact of new TB vaccine characteristics and implementation in China to inform design of target product profiles; and 2) to develop a novel epidemiological spatial mapping tool capable of informing clinical trial design for new TB vaccines in low-income, high-burden settings.
Methods: A deterministic, age-structured, Mycobacterium tuberculosis transmission model was developed and calibrated to age-stratified epidemiological and demographic data from China. This was employed to estimate the population-level epidemiological impact of new TB vaccines over the 2025-2050 time horizon, through an exploration of potential vaccine characteristics and implementation strategies.
A new methodology for empirical data collection to determine spatial distribution of TB notifications was developed. The electronic PArticipant Locator application (ePAL app) combined 3,243 community-identified points of interest with high resolution satellite maps, within an electronic tablet-based case report form. The app was integrated in to the National Tuberculosis Programme in Blantyre, Malawi, for collection of demographics, health status and coordinates of place of residence for patients ≥18 years initiating TB treatment. Accuracy of ePAL-recorded co-ordinates was evaluated against GPS coordinates obtained at the participant’s place of residence.
Results: Mathematical modelling predicted a shift towards a reactivation-driven, ageing TB epidemic in China by 2050. Vaccines protective against disease, effective post-infection and providing at least 5 years protection were essential for achieving higher levels of impact. Vaccination of older adults provided greater population-level impact than vaccinating adolescents for all equivalent vaccines explored, even if much lower coverage were achieved in older adult vaccination. Recommendations for post-infection vaccines were robust to substantial reductions in efficacy and duration of protection in older adults, whereas for pre-infection vaccines in some of these scenarios adolescent vaccination may be equivalent or preferred. Vaccinating older adults with post-infection vaccines provided substantially higher impact than pre-infection vaccines.
1,899 TB patients were registered using ePAL in the 12-month study period, with high patient acceptance (98.7%, 1,899/1,924). ePAL achieved clinic-based collection of patient location of residence accurate to a median of 84 metres (IQR: 35-317 metres) in a high population density urban setting without a municipal address system. Advantages of the ePAL system included real-time availability of high-resolution spatial data, low set up costs, and ease of use by health staff as part of routine TB registration. Data were used to identify areas with high TB burden, potentially suitable for TB vaccine trials.
Conclusions: The research presented in this thesis informs the development of appropriate TB vaccines and target populations to maximise future population-level impact. A prevention of disease vaccine efficacious post-infection and delivered to older adults would contribute towards maximising population-level impact in China. Adolescent-targeted tuberculosis vaccines are likely to have low impact in ageing, reactivation-driven epidemics like China, which suggests a modification of the current strategic focus on adolescents among certain funders. Clinical trials should assess disease endpoints, include M.tb-infected and older adult populations, and extend beyond the usual 2-3 years follow up. To support design of disease endpoint trials, ePAL may provide an accurate, easily implementable, low-cost tool for identification of areas of high TB burden in settings without addresses.
Author: Rebecca Harris
Posted: August 23, 2018, 2:54 pm
Mixed, polyclonal Mycobacterium tuberculosis infection occurs in natural populations. Developing an effective method for detecting such cases is important in measuring the success of treatment and reconstruction of transmission between patients. Using whole genome sequence (WGS) data, we assess two methods for detecting mixed infection: (i) a combination of the number of heterozygous sites and the proportion of heterozygous sites to total SNPs, and (ii) Bayesian model-based clustering of allele frequencies from sequencing reads at heterozygous sites.

In silico and in vitro artificially mixed and known pure M. tuberculosis samples were analysed to determine the specificity and sensitivity of each method. We found that both approaches were effective in distinguishing between pure strains and mixed infection where there was relatively high (&gt; 10%) proportion of a minor strain in the mixture. A large dataset of clinical isolates (n = 1963) from the Karonga Prevention Study in Northern Malawi was tested to examine correlations with patient characteristics and outcomes with mixed infection. The frequency of mixed infection in the population was found to be around 10%, with an association with year of diagnosis, but no association with age, sex, HIV status or previous tuberculosis.

Mixed Mycobacterium tuberculosis infection was identified in silico using whole genome sequence data. The methods presented here can be applied to population-wide analyses of tuberculosis to estimate the frequency of mixed infection, and to identify individual cases of mixed infections. These cases are important when considering the evolution and transmission of the disease, and in patient treatment.

Author: B Sobkowiak
Posted: August 17, 2018, 8:37 am
HIV and tuberculosis (TB) remain leading causes of preventable death in low- and middle-income countries (LMICs). The World Health Organization (WHO) recommends HIV testing for all individuals with TB symptoms, but implementation has been suboptimal. We conducted a systematic literature review and meta-analyses to estimate HIV and TB prevalence, and short-term (two to six months) mortality, among adults with TB symptoms at community- and facility level.

We searched Embase, Global Health and MEDLINE databases, and reviewed conference abstracts for studies reporting simultaneous HIV and TB screening of adults in LMICs published between January 2003 and December 2017. Meta-analyses were performed to estimate prevalence of HIV, undiagnosed TB and mortality risk at different health system levels.

Sixty-two studies including 260,792 symptomatic adults were identified, mostly from Africa and Asia. Median HIV prevalence was 19.2% (IQR: 8.3% to 40.4%) at community level, 55.7% (IQR: 20.9% to 71.2%) at primary care level and 80.7% (IQR: 73.8% to 84.6%) at hospital level. Median TB prevalence was 6.9% (IQR: 3.3% to 8.4%) at community, 20.5% (IQR: 11.7% to 46.4%) at primary care and 36.4% (IQR: 22.9% to 40.9%) at hospital level. Median short-term mortality was 22.6% (IQR: 15.6% to 27.7%) among inpatients, 3.1% (IQR: 1.2% to 4.2%) at primary care and 1.6% (95% CI: 0.45 to 4.13, n = 1 study) at community level.

Adults with TB symptoms have extremely high prevalence of HIV infection, even when identified through community surveys. TB prevalence and mortality increased substantially at primary care and inpatient level respectively. Strategies to expand symptom-based TB screening combined with HIV and TB testing for all symptomatic individuals should be of the highest priority for both disease programmes in LMICs with generalized HIV epidemics. Interventions to reduce short-term mortality are urgently needed.

Author: M Nliwasa
Posted: August 2, 2018, 11:33 am

 

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