TB Modeling and Translational Epi Group

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- June 2016 -

Use of Rapid, Point-of-Care Assays by Private Practitioners in Chennai, India: Priorities for Tuberculosis Diagnostic Testing. (2016). Bronner Murrison L., Ananthakrishnan R., Sukumar S., Augustine S., Krishnan N., Pai M., Dowdy DW, PloS one, 11, e0155775

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SETTING: Private practitioners are frequently the first point of healthcare contact for patients with tuberculosis (TB) in India. As new molecular tests are developed for point-of-care (POC) diagnosis of TB, it is imperative to understand these individuals' practices and preferences for POC testing. OBJECTIVE: To evaluate rapid testing practices and identify priorities for novel POC TB tests among private practitioners in Chennai. DESIGN: We conducted a cross-sectional survey of 228 practitioners practicing in the private sector from January 2014 to February 2015 who saw at least one TB patient in the previous year. Practitioners were randomly selected from both the general community and a list of practitioners who referred patients to a public-private mix program for TB treatment. We used standardized questionnaires to collect data on current practices related to point-of-care diagnosis and interest in hypothetical POC tests. We used multivariable Poisson regression with robust estimates of standard error to calculate measures of association. RESULTS: Among 228 private practitioners, about half (48%) utilized any rapid testing in their current practice, most commonly for glucose (43%), pregnancy (21%), and malaria (5%). Providers using POC tests were more likely to work in hospitals (56% vs. 43%, P = 0.05) and less likely to be chest specialists (21% vs. 54%, P<0.001). Only half (51%) of providers would use a hypothetical POC test for TB that was accurate, equipment-free, and took 20 minutes to complete. Chest specialists were half as likely to express interest in performing the hypothetical POC TB test in-house as other practitioners (aPR 0.5, 95%CI: 0.2-0.9). Key challenges to performing POC testing for TB in this study included time constraints, easy access to local private labs and lack of an attached lab facility. CONCLUSION: As novel POC tests for TB are developed and scaled up, attention must be paid to integrating these diagnostics into healthcare providers' routine practice and addressing barriers for POC testing.

Screening for active tuberculosis in a diabetes mellitus clinic in Soweto, South Africa. (2016). Majumder A., Carroll B., Bhana S., Tefu D., Syeda S., Martinson N., Golub J, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 20, 992-3

- May 2016 -

Implementation of Xpert MTB/RIF in Uganda: Missed Opportunities to Improve Diagnosis of Tuberculosis. (2016). Hanrahan CF., Haguma P., Ochom E., Kinera I., Cobelens F., Cattamanchi A., Davis L., Katamba A., Dowdy D, Open forum infectious diseases, 3, ofw068

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Background. The effect of Xpert MTB/RIF (Xpert) scale-up on patient outcomes in low-income settings with a high tuberculosis (TB) burden has not been established. We sought to characterize the effectiveness of Xpert as implemented across different levels of the healthcare system in Uganda. Methods. We reviewed laboratory records from 2012 to 2014 at 18 health facilities throughout Uganda. In 8 facilities, Xpert had been implemented onsite since 2012, and in 10 sites Xpert was available as an offsite referral test from another facility. We describe Xpert testing volumes by facility, Xpert and smear microscopy results, and downtime due to malfunction and cartridge stockouts. We compare TB treatment initiation as well as time to treatment between facilities implementing Xpert and those that did not. Results. The median number of Xpert assays run at implementing facilities was 25/month (interquartile range [IQR], 10-63), amounting to 8% of total capacity. Among 1251 assays run for a new TB diagnosis, 19% were positive. Among 1899 patients with smear-negative presumptive TB, the proportion starting TB treatment was similar between Xpert facilities (11%; 95% confidence interval [CI], 9%-13%) and non-Xpert facilities (9%; 95% CI, 8%-11%; P = .325). In Xpert facilities, a positive Xpert preceded TB treatment initiation in only 12 of 70 (17%) smear-negative patients initiated on treatment. Conclusions. Xpert was underutilized in Uganda and did not significantly increase the number of patients starting treatment for TB. Greater attention must be paid to appropriate implementation of novel diagnostic tests for TB if these new tools are to impact patient important outcomes.

- April 2016 -

Timing of Antiretroviral Treatment, Immunovirologic Status, and TB Risk: Implications for Testing and Treatment. (2016). Pettit AC., Mendes A., Jenkins C., Napravnik S., Freeman A., Shepherd BE., Dowdy D., Gill J., Rachlis A., Moore R., Sterling TR, Journal of acquired immune deficiency syndromes (1999), 72, 572-8

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BACKGROUND: Tuberculosis (TB) risk and mortality increase in the 6 months after highly active antiretroviral therapy (HAART) initiation. This short-term risk may be a consequence of HAART initiation and immune reconstitution. Alternatively, it may be due to confounding by low CD4 counts and high HIV viral loads (VLs). We assessed the TB risk before and after HAART initiation while appropriately controlling for time-updated laboratory values and HAART exposure. METHODS: We conducted an observational cohort study among persons enrolled in the North American AIDS Cohort Collaboration on Research and Design from 1998 through 2011. A marginal structural model was constructed to estimate the association of HAART initiation and TB risk. Inverse probability weights for the probability of HAART initiation were incorporated. RESULTS: Among 26,342 patients, 94 cases of TB were diagnosed during 147,557 person-years (p-y) of follow-up. The unadjusted TB rates were 93/100,000 p-y [95% confidence interval (CI): 63 to 132] before HAART initiation, 203/100,000 p-y (95% CI: 126 to 311) 6 months on HAART. After controlling for time-updated laboratory values, the adjusted odds of TB 6 months was 0.65 (95% CI: 0.28 to 1.51) and 0.29 (95% CI: 0.16 to 0.53), respectively. CONCLUSIONS: TB risk in the first 6 months after HAART initiation is not higher than that before HAART initiation after adjusting for CD4 count and VLs. These findings suggest that short-term TB risk may be related to low CD4 counts and high VLs near HAART initiation and support early HAART initiation to decrease TB risk.

- March 2016 -

Potential impact of spatially targeted adult tuberculosis vaccine in Gujarat, India. (2016). Shrestha S., Chatterjee S., Rao KD., Dowdy DW, Journal of the Royal Society, Interface, 13

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Some of the most promising vaccines in the pipeline for tuberculosis (TB) target adolescents and adults. Unlike for childhood vaccines, high-coverage population-wide vaccination is significantly more challenging for adult vaccines. Here, we aimed to estimate the impact of vaccine delivery strategies that were targeted to high-incidence geographical 'hotspots' compared with randomly allocated vaccination. We developed a spatially explicit mathematical model of TB transmission that distinguished these hotspots from the general population. We evaluated the impact of targeted and untargeted vaccine delivery strategies in India--a country that bears more than 25% of global TB burden, and may be a potential early adopter of the vaccine. We collected TB notification data and conducted a demonstration study in the state of Gujarat to validate our estimates of heterogeneity in TB incidence. We then projected the impact of randomly vaccinating 8% of adults in a single mass campaign to a spatially targeted vaccination preferentially delivered to 80% of adults in the hotspots, with both strategies augmented by continuous adolescent vaccination. In consultation with vaccine developers, we considered a vaccine efficacy of 60%, and evaluated the population-level impact after 10 years of vaccination. Spatial heterogeneity in TB notification (per 100,000/year) was modest in Gujarat: 190 in the hotspots versus 125 in the remaining population. At this level of heterogeneity, the spatially targeted vaccination was projected to reduce TB incidence by 28% after 10 years, compared with a 24% reduction projected to achieve via untargeted vaccination--a 1.17-fold augmentation in the impact of vaccination by spatially targeting. The degree of the augmentation was robust to reasonable variation in natural history assumptions, but depended strongly on the extent of spatial heterogeneity and mixing between the hotspot and general population. Identifying high-incidence hotspots and quantifying spatial mixing patterns are critical to accurate estimation of the value of targeted intervention strategies.

How do patients access the private sector in Chennai, India? An evaluation of delays in tuberculosis diagnosis. (2016). Bronner Murrison L., Ananthakrishnan R., Swaminathan A., Auguesteen S., Krishnan N., Pai M., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 20, 544-51

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SETTING: The diagnosis and treatment of tuberculosis (TB) in India are characterized by heavy private-sector involvement. Delays in treatment remain poorly characterized among patients seeking care in the Indian private sector. OBJECTIVE: To assess delays in TB diagnosis and treatment initiation among patients diagnosed in the private sector, and pathways to care in an urban setting. DESIGN: Cross-sectional survey of 289 consecutive patients diagnosed with TB in the private sector and referred for anti-tuberculosis treatment through a public-private mix program in Chennai from January 2014 to February 2015. RESULTS: Among 212 patients with pulmonary TB, 90% first contacted a formal private provider, and 78% were diagnosed by the first or second provider seen after a median of three visits per provider. Median total delay was 51 days (mean 68). Consulting an informal (rather than formally trained) provider first was associated with significant increases in total delay (absolute increase 22.8 days, 95%CI 6.2-39.5) and in the risk of prolonged delay >90 days (aRR 2.4, 95%CI 1.3-4.4). CONCLUSION: Even among patients seeking care in the formal (vs. informal) private sector in Chennai, diagnostic delays are substantial. Novel strategies are required to engage private providers, who often serve as the first point of contact.

Effect of the US National HIV/AIDS Strategy targets for improved HIV care engagement: a modelling study. (2016). Shah M., Perry A., Risher K., Kapoor S., Grey J., Sharma A., Rosenberg ES., Del Rio C., Sullivan P., Dowdy DW, The lancet. HIV, 3, e140-6

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BACKGROUND: The recently updated White House National HIV/AIDS Strategy (NHAS) includes specific progress indicators to improve the HIV care continuum in the USA, but the economic and epidemiological effect of achieving those indicators remains unclear. We aimed to project the impact of achieving NHAS goals on HIV incidence, prevalence, mortality, and costs among adults in the USA over 10 years. METHODS: We constructed a dynamic transmission model of HIV progression and care engagement based on literature sources and the most recent published US Centers for Disease Control and Prevention data. We specifically considered achievement of the 2020 targets set forth in NHAS progress indicator 1 (90% awareness of serostatus), indicator 4 (85% linkage within 1 month), and indicator 5 (90% of diagnosed individuals in care). FINDINGS: At current rates of engagement in the HIV care continuum, we project 524,000 (95% uncertainty range 442,000-712,000) new HIV infections and 375,000 deaths (364,000-578,000) between 2016 and 2025. Achievement of NHAS progress indicators 1 and 4 has modest epidemiological effect (new infections reduced by 2.0% and 3.9%, respectively). By contrast, increasing the proportion of diagnosed individuals in care (NHAS indicator 5) averts 52% (95% UR 47-56) of new infections. Achievement of all NHAS targets resulted in a 58% reduction (95% UR 52-61) in new infections and 128 000 lives saved (106,000-223,000) at an incremental health system cost of US$105 billion. INTERPRETATION: Achievement of NHAS progress indicators for screening, linkage, and particularly improving retention in care, can substantially reduce the burden of HIV in the USA, but continued and increased financial investment will be required. FUNDING: The National Institutes of Health, the B Frank and Kathleen Polk Assistant Professorship in Epidemiology, Emory University CFAR, Johns Hopkins University CFAR, and CDC/NCHHSTP Epidemiological and Economic Modeling Agreement (5U38PS004646).

- February 2016 -

How Do Urban Indian Private Practitioners Diagnose and Treat Tuberculosis? A Cross-Sectional Study in Chennai. (2016). Bronner Murrison L., Ananthakrishnan R., Sukumar S., Augustine S., Krishnan N., Pai M., Dowdy DW, PloS one, 11, e0149862

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SETTING: Private practitioners are frequently the first point of healthcare contact for patients with tuberculosis (TB) in India. Inappropriate TB management practices among private practitioners may contribute to delayed TB diagnosis and generate drug resistance. However, these practices are not well understood. We evaluated diagnostic and treatment practices for active TB and benchmarked practices against International Standards for TB Care (ISTC) among private medical practitioners in Chennai. DESIGN: A cross-sectional survey of 228 practitioners practicing in the private sector from January 2014 to February 2015 in Chennai city who saw at least one TB patient in the previous year. Practitioners were randomly selected from both the general community and a list of practitioners who referred patients to a public-private mix program for TB treatment in Chennai. Practitioners were interviewed using standardized questionnaires. RESULTS: Among 228 private practitioners, a median of 12 (IQR 4-28) patients with TB were seen per year. Of 10 ISTC standards evaluated, the median of standards adhered to was 4.0 (IQR 3.0-6.0). Chest physicians reported greater median ISTC adherence than other MD and MS practitioners (score 7.0 vs. 4.0, P<0.001), or MBBS practitioners (score 7.0 vs. 4.0, P<0.001). Only 52% of all practitioners sent >5% of patients with cough for TB testing, 83% used smear microscopy for diagnosis, 33% monitored treatment response, and 22% notified TB cases to authorities. Of 228 practitioners, 68 reported referring all patients with new pulmonary TB for treatment, while 160 listed 27 different regimens; 78% (125/160) prescribed a regimen classified as consistent with ISTC. Appropriate treatment practices differed significantly between chest physicians and other MD and MS practitioners (54% vs. 87%, P<0.001). CONCLUSION: TB management practices in India's urban private sector are heterogeneous and often suboptimal. Private providers must be better engaged to improve diagnostic capacity and decrease TB transmission in the community.

Ancient Disease, Modern Epidemiology: A Century of Progress in Understanding and Fighting Tuberculosis. (2016). Zwerling A., Hanrahan C., Dowdy DW, American journal of epidemiology, 183, 407-14

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A century's worth of efforts to better understand the epidemiology of tuberculosis (TB) and to develop new vaccines, drugs, preventive interventions, and case-finding approaches have provided important insights and helped to advance the field of epidemiology as a whole. Wade Hampton Frost developed methods for cohort analysis that formed the early basis for adjustment of confounding variables. The streptomycin trial in the United Kingdom in the 1940s introduced random allocation for participants to either the treatment or control group, ensuring blinded treatment assignment and comparable treatment groups, which is now a key element in randomized clinical trials. Research into the bacille Calmette-Guerin vaccine demonstrated the importance of comparative analyses, potential difficulties in generalizability to populations not under study, and the role of meta-analysis for discrepant data-approaches now strongly recommended prior to implementing any novel public health intervention. George Comstock's work on preventive therapy for TB demonstrated the use of epidemiologic methods to evaluate interventions on a population level. Finally, studies from the Consortium to Respond Effectively to the AIDS/TB Epidemic focused on the evaluation of real-world effectiveness and of targeting of high-risk subpopulations. In this article, we discuss how TB research in each of these domains has helped to advance epidemiologic thinking and methodology over the past 100 years.

- January 2016 -

A simplified cost-effectiveness model to guide decision-making for shortened anti-tuberculosis treatment regimens. (2016). Zwerling A., Gomez GB., Pennington J., Cobelens F., Vassall A., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 20, 257-60

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User-friendly models (UFMs) allow local decision makers to explore relationships and apply results from more detailed models of such outcomes as cost-effectiveness. When developing UFMs, modelers must decide which simplifications may be appropriate, enabling the UFM to retain accuracy while reducing complexity. We use the example of cost-effectiveness analysis (CEA) for novel shortened anti-tuberculosis treatment regimens across four settings to demonstrate how UFMs can allow decision makers to adapt published results to their local context. We simplified a complex model to produce a UFM that provides similar results, the ability to modify key parameter values, and receive customized results in seconds.

[The epidemiological advantage of preferential targeting of tuberculosis control at the poor]. (2016). Andrews JR., Basu S., Dowdy DW., Murray MB, Revista panamericana de salud publica = Pan American journal of public health, 38, 186-94

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Tuberculosis (TB) remains disproportionately concentrated among the poor, yet known determinants of TB reactivation may fail to explain observed disparities in disease rates according to wealth. Reviewing data on TB disparities in India and the wealth distribution of known TB risk factors, we describe how social mixing patterns could be contributing to TB disparities. Wealth-assortative mixing, whereby individuals are more likely to be in contact with others from similar socio-economic backgrounds, amplifies smaller differences in risk of TB, resulting in large population-level disparities. As disparities and assortativeness increase, TB becomes more difficult to control, an effect that is obscured by looking at population averages of epidemiological parameters, such as case detection rates. We illustrate how TB control efforts may benefit from preferential targeting toward the poor. In India, an equivalent-scale intervention could have a substantially greater impact if targeted at those living below the poverty line than with a population-wide strategy. In addition to potential efficiencies in targeting higher-risk populations, TB control efforts would lead to a greater reduction in secondary TB cases per primary case diagnosed if they were preferentially targeted at the poor. We highlight the need to collect programmatic data on TB disparities and explicitly incorporate equity considerations into TB control plans.

- December 2015 -

The Impact and Cost-Effectiveness of a Four-Month Regimen for First-Line Treatment of Active Tuberculosis in South Africa. (2015). Knight GM., Gomez GB., Dodd PJ., Dowdy D., Zwerling A., Wells WA., Cobelens F., Vassall A., White RG, PloS one, 10, e0145796

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BACKGROUND: A 4-month first-line treatment regimen for tuberculosis disease (TB) is expected to have a direct impact on patient outcomes and societal costs, as well as an indirect impact on Mycobacterium tuberculosis transmission. We aimed to estimate this combined impact in a high TB-burden country: South Africa. METHOD: An individual based M. tb transmission model was fitted to the TB burden of South Africa using a standard TB natural history framework. We measured the impact on TB burden from 2015-2035 of introduction of a non-inferior 4-month regimen replacing the standard 6-month regimen as first-line therapy. Impact was measured with respect to three separate baselines (Guidelines, Policy and Current), reflecting differences in adherence to TB and HIV treatment guidelines. Further scenario analyses considered the variation in treatment-related parameters and resistance levels. Impact was measured in terms of differences in TB burden and Disability Adjusted Life Years (DALYs) averted. We also examined the highest cost at which the new regimen would be cost-effective for several willingness-to-pay thresholds. RESULTS: It was estimated that a 4-month regimen would avert less than 1% of the predicted 6 million person years with TB disease in South Africa between 2015 and 2035. A similarly small impact was seen on deaths and DALYs averted. Despite this small impact, with the health systems and patient cost savings from regimen shortening, the 4-month regimen could be cost-effective at $436 [NA, 5983] (mean [range]) per month at a willingness-to-pay threshold of one GDP per capita ($6,618). CONCLUSION: The introduction of a non-inferior 4-month first-line TB regimen into South Africa would have little impact on the TB burden. However, under several scenarios, it is likely that the averted societal costs would make such a regimen cost-effective in South Africa.

A Novel Tool Improves Existing Estimates of Recent Tuberculosis Transmission in Settings of Sparse Data Collection. (2015). Kasaie P., Mathema B., Kelton WD., Azman AS., Pennington J., Dowdy DW, PloS one, 10, e0144137

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In any setting, a proportion of incident active tuberculosis (TB) reflects recent transmission ("recent transmission proportion"), whereas the remainder represents reactivation. Appropriately estimating the recent transmission proportion has important implications for local TB control, but existing approaches have known biases, especially where data are incomplete. We constructed a stochastic individual-based model of a TB epidemic and designed a set of simulations (derivation set) to develop two regression-based tools for estimating the recent transmission proportion from five inputs: underlying TB incidence, sampling coverage, study duration, clustered proportion of observed cases, and proportion of observed clusters in the sample. We tested these tools on a set of unrelated simulations (validation set), and compared their performance against that of the traditional 'n-1' approach. In the validation set, the regression tools reduced the absolute estimation bias (difference between estimated and true recent transmission proportion) in the 'n-1' technique by a median [interquartile range] of 60% [9%, 82%] and 69% [30%, 87%]. The bias in the 'n-1' model was highly sensitive to underlying levels of study coverage and duration, and substantially underestimated the recent transmission proportion in settings of incomplete data coverage. By contrast, the regression models' performance was more consistent across different epidemiological settings and study characteristics. We provide one of these regression models as a user-friendly, web-based tool. Novel tools can improve our ability to estimate the recent TB transmission proportion from data that are observable (or estimable) by public health practitioners with limited available molecular data.

Evaluating the cost of adult voluntary medical male circumcision in a mixed (surgical and PrePex) site compared to a hypothetical PrePex-only site in South Africa. (2015). Kim HY., Lebina L., Milovanovic M., Taruberekera N., Dowdy DW., Martinson NA, Global health action, 8, 29116

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BACKGROUND: Several circumcision devices have been evaluated for a safe and simplified male circumcision among adults. The PrePex device was prequalified for voluntary male medical circumcision (VMMC) in May 2013 by the World Health Organization and is expected to simplify the procedure safely while reducing cost. South Africa is scaling up VMMC. OBJECTIVE: To evaluate the overall unit cost of VMMC at a mixed site vs. a hypothetical PrePex-only site in South Africa. DESIGN: We evaluated the overall unit cost of VMMC at a mixed site where PrePex VMMC procedure was added to routine forceps-guided scalpel-based VMMC in Soweto, South Africa. We abstracted costs and then modeled these costs for a hypothetical PrePex-only site, at which 9,600 PrePex circumcisions per year could be done. We examined cost drivers and modeled costs, varying the price of the PrePex device. The healthcare system perspective was used. RESULTS: In both sites, the main contributors of cost were personnel and consumables. If 10% of all VMMC were by PrePex at the mixed site, the overall costs of the surgical method and PrePex were similar - US$59.62 and $59.53, respectively. At the hypothetical PrePex-only site, the unit cost was US$51.10 with PrePex circumcisions having markedly lower personnel and biohazardous waste management costs. In sensitivity analysis with the cost of PrePex kit reduced to US$10 and $2, the cost of VMMC was further reduced. CONCLUSIONS: Adding PrePex to an existing site did not necessarily reduce the overall costs of VMMC. However, starting a new PrePex-only site is feasible and may significantly reduce the overall cost by lowering both personnel and capital costs, thus being cost-effective in the long term. Achieving a lower cost for PrePex will be an important contributor to the scale-up of VMMC.

Sustainable HIV treatment in Africa through viral-load-informed differentiated care. (2015). Phillips A., Shroufi A., Vojnov L., Cohn J., Roberts T., Ellman T., Bonner K., Rousseau C., Garnett G., Cambiano V., Nakagawa F., Ford D., Bansi-Matharu L., Miners A., Lundgren JD., Eaton JW., Parkes-Ratanshi R., Katz Z., Maman D., Ford N., Vitoria M., Doherty M., Dowdy D., Nichols B., Murtagh M., Wareham M., Palamountain KM., Chakanyuka Musanhu C., Stevens W., Katzenstein D., Ciaranello A., Barnabas R., Braithwaite RS., Bendavid E., Nathoo KJ., van de Vijver D., Wilson DP., Holmes C., Bershteyn A., Walker S., Raizes E., Jani I., Nelson LJ., Peeling R., Terris-Prestholt F., Murungu J., Mutasa-Apollo T., Hallett TB., Revill P, Nature, 528, S68-76

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There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.

Understanding the incremental value of novel diagnostic tests for tuberculosis. (2015). Arinaminpathy N., Dowdy D, Nature, 528, S60-7

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Tuberculosis is a major source of global mortality caused by infection, partly because of a tremendous ongoing burden of undiagnosed disease. Improved diagnostic technology may play an increasingly crucial part in global efforts to end tuberculosis, but the ability of diagnostic tests to curb tuberculosis transmission is dependent on multiple factors, including the time taken by a patient to seek health care, the patient's symptoms, and the patterns of transmission before diagnosis. Novel diagnostic assays for tuberculosis have conventionally been evaluated on the basis of characteristics such as sensitivity and specificity, using assumptions that probably overestimate the impact of diagnostic tests on transmission. We argue for a shift in focus to the evaluation of such tests' incremental value, defining outcomes that reflect each test's purpose (for example, transmissions averted) and comparing systems with the test against those without, in terms of those outcomes. Incremental value can also be measured in units of outcome per incremental unit of resource (for example, money or human capacity). Using a novel, simplified model of tuberculosis transmission that addresses some of the limitations of earlier tuberculosis diagnostic models, we demonstrate that the incremental value of any novel test depends not just on its accuracy, but also on elements such as patient behaviour, tuberculosis natural history and health systems. By integrating these factors into a single unified framework, we advance an approach to the evaluation of new diagnostic tests for tuberculosis that considers the incremental value at the population level and demonstrates how additional data could inform more-effective implementation of tuberculosis diagnostic tests under various conditions.

- November 2015 -

Risk factors for transmission of tuberculosis among United States-born African Americans and Whites. (2015). Pagaoa MA., Royce RA., Chen MP., Golub JE., Davidow AL., Hirsch-Moverman Y., Marks SM., Teeter LD., Thickstun PM., Katz DJ, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 19, 1485-92

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SETTING: Tuberculosis (TB) patients and their contacts enrolled in nine states and the District of Columbia from 16 December 2009 to 31 March 2011. OBJECTIVE: To evaluate characteristics of TB patients that are predictive of tuberculous infection in their close contacts. DESIGN: The study population was enrolled from a list of eligible African-American and White TB patients from the TB registry at each site. Information about close contacts was abstracted from the standard reports of each site. RESULTS: Close contacts of African-American TB patients had twice the risk of infection of contacts of White patients (adjusted risk ratio [aRR] 2.1, 95%CI 1.3-3.4). Close contacts of patients whose sputum was positive for acid-fast bacilli on sputum smear microscopy had 1.6 times the risk of tuberculous infection compared to contacts of smear-negative patients (95%CI 1.1-2.3). TB patients with longer (>3 months) estimated times to diagnosis did not have higher proportions of infected contacts (aRR 1.2, 95%CI 0.9-1.6). CONCLUSION: African-American race and sputum smear positivity were predictive of tuberculous infection in close contacts. This study did not support previous findings that longer estimated time to diagnosis predicted tuberculous infection in contacts.

Burden of transmitted multidrug resistance in epidemics of tuberculosis: a transmission modelling analysis. (2015). Kendall EA., Fofana MO., Dowdy DW, The Lancet. Respiratory medicine, 3, 963-72

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BACKGROUND: Multidrug-resistant (MDR) tuberculosis can be acquired through de-novo mutation during tuberculosis treatment or through transmission from other individuals with active MDR tuberculosis. Understanding the balance between these two mechanisms is essential when allocating resources for MDR tuberculosis. We aimed to create a dynamic transmission model of an MDR tuberculosis epidemic to estimate the contributions of treatment-related acquisition and person-to-person transmission of resistance to incident MDR tuberculosis cases. METHODS: In this modelling analysis, we constructed a dynamic transmission model of an MDR tuberculosis epidemic, allowing for both treatment-related acquisition and person-to-person transmission of resistance. We used national tuberculosis notification data to inform Bayesian estimates of the proportion of each country's 2013 MDR tuberculosis incidence that resulted from MDR transmission rather than treatment-related MDR acquisition. FINDINGS: Global estimates of 3.5% MDR tuberculosis prevalence among new tuberculosis notifications and 20.5% among re-treatment notifications translate into an estimate that resistance transmission rather than acquisition accounts for a median 95.9% (95% uncertainty range [UR] 68.0-99.6) of all incident MDR tuberculosis, and 61.3% (16.5-95.2) of incident MDR tuberculosis in previously treated individuals. The estimated proportion of MDR tuberculosis resulting from transmission varied substantially with different countries' notification data-ranging from 48% (95% UR 30-75) in Bangladesh to 99% (91-100) in Uzbekistan. Estimates were most sensitive to estimates of the transmissibility of MDR strains, the probability of acquiring MDR during tuberculosis treatment, and the responsiveness of MDR tuberculosis to first-line treatment. INTERPRETATION: Notifications of MDR prevalence from most high-burden settings are consistent with most incident MDR tuberculosis resulting from transmission rather than new treatment-related acquisition of resistance. Merely improving the treatment of drug-susceptible tuberculosis is unlikely to greatly reduce future MDR tuberculosis incidence. Improved diagnosis and treatment of MDR tuberculosis-including new tests and drug regimens-should be highly prioritised. FUNDING: National Institutes of Health and the Bill & Melinda Gates Foundation.

Mathematical Modelling and Tuberculosis: Advances in Diagnostics and Novel Therapies. (2015). Zwerling A., Shrestha S., Dowdy DW, Advances in medicine, 2015, 907267

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As novel diagnostics, therapies, and algorithms are developed to improve case finding, diagnosis, and clinical management of patients with TB, policymakers must make difficult decisions and choose among multiple new technologies while operating under heavy resource constrained settings. Mathematical modelling can provide helpful insight by describing the types of interventions likely to maximize impact on the population level and highlighting those gaps in our current knowledge that are most important for making such assessments. This review discusses the major contributions of TB transmission models in general, namely, the ability to improve our understanding of the epidemiology of TB. We focus particularly on those elements that are important to appropriately understand the role of TB diagnosis and treatment (i.e., what elements of better diagnosis or treatment are likely to have greatest population-level impact) and yet remain poorly understood at present. It is essential for modellers, decision-makers, and epidemiologists alike to recognize these outstanding gaps in knowledge and understand their potential influence on model projections that may guide critical policy choices (e.g., investment and scale-up decisions).

Bridging the gap between evidence and policy for infectious diseases: How models can aid public health decision-making. (2015). Knight GM., Dharan NJ., Fox GJ., Stennis N., Zwerling A., Khurana R., Dowdy DW, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 42, 17-23

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The dominant approach to decision-making in public health policy for infectious diseases relies heavily on expert opinion, which often applies empirical evidence to policy questions in a manner that is neither systematic nor transparent. Although systematic reviews are frequently commissioned to inform specific components of policy (such as efficacy), the same process is rarely applied to the full decision-making process. Mathematical models provide a mechanism through which empirical evidence can be methodically and transparently integrated to address such questions. However, such models are often considered difficult to interpret. In addition, models provide estimates that need to be iteratively re-evaluated as new data or considerations arise. Using the case study of a novel diagnostic for tuberculosis, a framework for improved collaboration between public health decision-makers and mathematical modellers that could lead to more transparent and evidence-driven policy decisions for infectious diseases in the future is proposed. The framework proposes that policymakers should establish long-term collaborations with modellers to address key questions, and that modellers should strive to provide clear explanations of the uncertainty of model structure and outputs. Doing so will improve the applicability of models and clarify their limitations when used to inform real-world public health policy decisions.

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