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EXPLORE IDM’S CURRENT RESEARCH PUBLICATIONS

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Michelle A Bulterys, Bradley Wagner, Mael Redard-Jacot, Anita Suresh, Nira R. Pollock, Emmanuel Moreau, Claudia M. Denkinger, Paul K. Drain, Tobias Broger 

JOURNAL OF CLINICAL MEDICINE

Most diagnostic tests for tuberculosis (TB) rely on sputum samples, which are difficult to obtain and have low sensitivity in immunocompromised patients, patients with disseminated TB, and children, delaying treatment initiation. The World Health Organization (WHO) calls for the development of a rapid, biomarker-based, non-sputum test capable of detecting all forms of TB at the point-of-care to enable immediate treatment initiation. Lipoarabinomannan (LAM) is the only WHO-endorsed TB biomarker that can be detected in urine, an easily collected sample. This status update discusses the characteristics of LAM as a biomarker, describes the performance of first-generation urine LAM tests and reasons for slow uptake, and presents considerations for developing the next generation of more sensitive and impactful tests. Next-generation urine LAM tests have the potential to reach adult and pediatric patients regardless of HIV status or site of infection and facilitate global TB control. Implementation and scale-up of existing LAM tests and development of next-generation assays should be prioritized.

Stewart T. Chang, Violet N. Chihota, Katherine L. Fielding, Alison D. Grant, Rein M. Houben, Richard G. White, Gavin J. Churchyard, Philip A. Eckhoff, and Bradley G. Wagner

BMC MEDICINE

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.

Prof Nicolas A Menzies, PhD, Gabriela B Gomez, PhD, Fiammetta Bozzani, MSc, Susmita Chatterjee, PhD, Nicola Foster, MPH, Ines Garcia Baena, MSc, Yoko V Laurence, MSc, Prof Sun Qiang, PhD, Andrew Siroka, PhD, Sedona Sweeney, MSc, Stéphane Verguet, PhD, Nimalan Arinaminpathy, DPhil, Andrew S Azman, PhD, Eran Bendavid, MD, Stewart T Chang, PhD, Prof Ted Cohen, DPH, Justin T Denholm, PhD, David W Dowdy, MD, Philip A Eckhoff, PhD, Jeremy D Goldhaber-Fiebert, PhD, Andreas Handel, PhD, Grace H Huynh, PhD, Marek Lalli, MSc, Hsien-Ho Lin, ScD, Sandip Mandal, PhD, Emma S McBryde, PhD, Surabhi Pandey, PhD, Prof Joshua A Salomon, PhD, Sze-chuan Suen, MS, Tom Sumner, PhD, James M Trauer, MBBS, Bradley G Wagner, PhD, Prof Christopher C Whalen, MD, Chieh-Yin Wu, MS, Delia Boccia, PhD, Vineet K Chadha, MD, Salome Charalambous, PhD, Daniel P Chin, MD, Prof Gavin Churchyard, PhD, Colleen Daniels, MA, Puneet Dewan, MD, Lucica Ditiu, MD, Jeffrey W Eaton, PhD, Prof Alison D Grant, PhD, Piotr Hippner, MSc, Mehran Hosseini, MD, David Mametja, MPH, Carel Pretorius, PhD, Yogan Pillay, PhD, Kiran Rade, MD, Suvanand Sahu, MD, Lixia Wang, MS, Rein M G J Houben, PhD, Michael E Kimerling, MD, Richard G White, PhD, Anna Vassall, PhD

THE LANCET

Background
The post-2015 End TB Strategy sets global targets of reducing tuberculosis incidence by 50% and mortality by 75% by 2025. We aimed to assess resource requirements and cost-effectiveness of strategies to achieve these targets in China, India, and South Africa.

Methods
We examined intervention scenarios developed in consultation with country stakeholders, which scaled up existing interventions to high but feasible coverage by 2025. Nine independent modelling groups collaborated to estimate policy outcomes, and we estimated the cost of each scenario by synthesising service use estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health effects (ie, disability-adjusted life-years averted) and resource implications for 2016–35, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios with a base case representing continued current practice.

Findings
Incremental tuberculosis service costs differed by scenario and country, and in some cases they more than doubled existing funding needs. In general, expansion of tuberculosis services substantially reduced patient-incurred costs and, in India and China, produced net cost savings for most interventions under a societal perspective. In all three countries, expansion of access to care produced substantial health gains. Compared with current practice and conventional cost-effectiveness thresholds, most intervention approaches seemed highly cost-effective.

Interpretation
Expansion of tuberculosis services seems cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, although substantial new funding would be required. Further work to determine the optimal intervention mix for each country is necessary.

Figure 2 Incremental patient-incurred costs for 2016–35, for each intervention scenario, compared with the base case, by country and model.

Funding

Bill and Melinda Gates Foundation


Dr Rein M G J Houben, PhD, Nicolas A Menzies, PhD, Tom Sumner, PhD, Grace H Huynh, PhD, Nimalan Arinaminpathy, PhD, Jeremy D Goldhaber-Fiebert, PhD, Hsien-Ho Lin, PhD, Chieh-Yin Wu, MS, Sandip Mandal, PhD, Surabhi Pandey, PhD, Sze-chuan Suen, MS, Eran Bendavid, MD, Andrew S Azman, PhD, David W Dowdy, PhD, Nicolas Bacaër, PhD, Allison S Rhines, PhD, Prof Marcus W Feldman, PhD, Andreas Handel, PhD, Prof Christopher C Whalen, MD, Stewart T Chang, PhD, Bradley G Wagner, PhD, Philip A Eckhoff, PhD, James M Trauer, PhD, Justin T Denholm, PhD, Prof Emma S McBryde, PhD, Ted Cohen, DPH, Prof Joshua A Salomon, PhD, Carel Pretorius, PhD, Marek Lalli, MSc, Jeffrey W Eaton, PhD, Delia Boccia, PhD, Mehran Hosseini, MD, Gabriela B Gomez, PhD, Suvanand Sahu, MD, Colleen Daniels, MA, Lucica Ditiu, MD, Daniel P Chin, MD, Lixia Wang, MS, Vineet K Chadha, MD, Kiran Rade, MPhil, Puneet Dewan, MD, Piotr Hippner, MSc, Salome Charalambous, PhD, Prof Alison D Grant, Prof Gavin Churchyard, PhD, Yogan Pillay, PhD, L David Mametja, MPH, Michael E Kimerling, MD, Anna Vassall, PhD, Richard G White, PhD

THE LANCET

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-specific intervention scenarios, which included screening for symptoms, active case finding, 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-specific tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level.

Grace H Huynh, Daniel Klein, Daniel P Chin, Bradley G Wagner, Philip A Eckhoff, Renzhong Liu, and Lixia Wang

BMC MEDICINE

Background: Significant progress in tuberculosis (TB) control has been achieved worldwide over the last two decades. Global TB mortality has fallen by 45%, and TB incidence is declining. Recently, the World Health Organization (WHO) established an ambitious post-2015 global strategy, the End TB Strategy. This strategy outlines a 2025 milestone of 50% reduction in incidence and 75% reduction in mortality, and an overall 2035 target of 90% reduction in incidence and 95% reduction in mortality. In order to reach these targets, countries will likely need to redouble their TB control efforts and perhaps adopt new TB control strategies.

Between 1992 and 2012, China made impressive progress in TB control. Prior to 1992, most TB patients were treated in private hospitals, where patients typically received low-quality care - improper treatment was widespread, and only approximately 20% of patients had supervised TB treatment. In addition, nearly 50% experienced interrupted or shortened treatment and there was little follow-up of patients who dropped out or relapsed after a treatment episode. Starting in 1992, China ramped up a high-quality directly observed treatment, short-course (DOTS)-based strategy in Center for Disease Control (CDC) public health clinics in 13 provinces covering half the population, requiring hospitals to refer suspected TB patients to the CDC system. In the early 2000s, the DOTS program was expanded nationwide and an Internet-based disease reporting system was introduced [8]-[11], further increasing referrals from the hospital to the CDC system. By 2010 it was estimated that approximately 80% of all TB patients were confirmed and treated within the CDC system [8],[9], where the treatment success rate was estimated to be 85%.

Methods: The present study utilizes the Disease Transmission Kernel (DTK) model developed by the Institute for Disease Modeling group at Intellectual Ventures. The model and all necessary input files are available by request at the Institute for Disease Modeling website. Additional file 1 details the model structure, assumptions, and a complete list of model inputs. 

Conclusions: The combination of an aging demographic in China and the increasing role of reactivation disease represents a growing challenge to TB control as China considers its post-2015 strategy. We have constructed a mathematical model of TB transmission at the country level in China, taking into account aging of the population and estimating the contribution of reactivation to overall incidence. The nationwide roll-out of the DOTS program reduced the annual risk of infection(ARI) [81],[82] by improving treatment outcomes and reducing infectiousness from treatment experienced individuals. Given the high population coverage of DOTS in the CDC public health clinics, we estimate that new transmission is not the major driver of overall TB incidence. Rather, reactivation disease, combined with the growing elderly population, will be the major determinant of the decline in TB incidence and mortality over the next two decades.

BMC MEDICINE

Background

In the last 20 years, China ramped up a DOTS (directly observed treatment, short-course)-based tuberculosis (TB) control program with 80% population coverage, achieving the 2015 Millennium Development Goal of a 50% reduction in TB prevalence and mortality. Recently, the World Health Organization developed the End TB Strategy, with an overall goal of a 90% reduction in TB incidence and a 95% reduction in TB deaths from 2015–2035. As the TB burden shifts to older individuals and China’s overall population ages, it is unclear if maintaining the current DOTS strategy will be sufficient for China to reach the global targets.

Methods

We developed an individual-based computational model of TB transmission, implementing realistic age demographics and fitting to country-level data of age-dependent prevalence over time. We explored the trajectory of TB burden if the DOTS strategy is maintained or if new interventions are introduced using currently available and soon-to-be-available tools. These interventions include increasing population coverage of DOTS, reducing time to treatment, increasing treatment success, and active case finding among elders > 65 years old. We also considered preventative therapy in latently infected elders, a strategy limited by resource constraints and the risk of adverse events.

Results

Maintenance of the DOTS strategy reduces TB incidence and mortality by 42% (95% credible interval, 27-59%) and 41% (5-64%), respectively, between 2015 and 2035. A combination of all feasible interventions nears the 2035 mortality target, reducing TB incidence and mortality by 59% (50-76%) and 83% (73-94%). Addition of preventative therapy for elders would enable China to nearly reach both the incidence and mortality targets, reducing incidence and mortality by 84% (78-93%) and 92% (86-98%).

Conclusions

The current decline in incidence is driven by two factors: maintaining a low level of new infections in young individuals and the aging out of older latently infected individuals who contribute incidence due to reactivation disease. While further reducing the level of new infections has a modest effect on burden, interventions that limit reactivation have a greater impact on TB burden. Tools that make preventative therapy more feasible on a large scale and in elders will help China achieve the global targets.