TB Modeling and Translational Epi Group

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- November 2016 -

Tobacco Smoking and Tuberculosis among Men Living with HIV in Johannesburg, South Africa: A Case-Control Study. (2016). Bronner Murrison L., Martinson N., Moloney RM., Msandiwa R., Mashabela M., Samet JM., Golub JE, PloS one, 11, e0167133

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SETTING: Although there is ample evidence that smoking increases the risk of tuberculosis (TB), the magnitude of impact on TB risk among HIV-infected persons is poorly described. Given that a high proportion of patients with TB are co-infected with HIV in South Africa, the risks arising from the intersection of smoking, TB, and HIV/AIDS have key relevance for tobacco control policies. OBJECTIVE: To evaluate the association of pulmonary tuberculosis (PTB) with current tobacco smoking among men with HIV in South Africa. DESIGN: Case-control study of antiretroviral therapy naive men with confirmed HIV-infection in Johannesburg. Cases had laboratory-confirmed PTB and controls had no evidence of active TB. Participants were interviewed to collect detailed smoking histories. RESULTS: We enrolled 146 men diagnosed with PTB and 133 controls. Overall, 33% of participants were currently smoking, defined as smoking a cigarette within 2 months (34% cases vs. 32% controls, p = 0.27). Median CD4 count was lower (60 vs. 81 cells/mm3, P = 0.03) and median viral load was higher (173 vs. 67 copies/ul per thousand, P<0.001) among cases versus controls. In adjusted analyses, current smoking tripled the odds of PTB (aOR 3.2; 95%CI: 1.3-7.9, P = 0.01) and former smoking nearly doubled the odds of PTB (aOR 1.8; 95%CI 0.8-4.4, P = 0.18) compared to never smoking. CONCLUSIONS: Males with HIV that smoke are at greater odds for developing PTB than non-smokers. Extensive smoking cessation programs are needed to reduce odds of TB and promote health among adults living with HIV.

- October 2016 -

Tuberculosis. (2016). Pai M., Behr MA., Dowdy D., Dheda K., Divangahi M., Boehme CC., Ginsberg A., Swaminathan S., Spigelman M., Getahun H., Menzies D., Raviglione M, Nature reviews. Disease primers, 2, 16076

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Tuberculosis (TB) is an airborne infectious disease caused by organisms of the Mycobacterium tuberculosis complex. Although primarily a pulmonary pathogen, M. tuberculosis can cause disease in almost any part of the body. Infection with M. tuberculosis can evolve from containment in the host, in which the bacteria are isolated within granulomas (latent TB infection), to a contagious state, in which the patient will show symptoms that can include cough, fever, night sweats and weight loss. Only active pulmonary TB is contagious. In many low-income and middle-income countries, TB continues to be a major cause of morbidity and mortality, and drug-resistant TB is a major concern in many settings. Although several new TB diagnostics have been developed, including rapid molecular tests, there is a need for simpler point-of-care tests. Treatment usually requires a prolonged course of multiple antimicrobials, stimulating efforts to develop shorter drug regimens. Although the Bacillus Calmette-Guerin (BCG) vaccine is used worldwide, mainly to prevent life-threatening TB in infants and young children, it has been ineffective in controlling the global TB epidemic. Thus, efforts are underway to develop newer vaccines with improved efficacy. New tools as well as improved programme implementation and financing are necessary to end the global TB epidemic by 2035.

Cost-effectiveness and resource implications of aggressive action on tuberculosis in China, India, and South Africa: a combined analysis of nine models. (2016). Menzies NA., Gomez GB., Bozzani F., Chatterjee S., Foster N., Baena IG., Laurence YV., Qiang S., Siroka A., Sweeney S., Verguet S., Arinaminpathy N., Azman AS., Bendavid E., Chang ST., Cohen T., Denholm JT., Dowdy DW., Eckhoff PA., Goldhaber-Fiebert JD., Handel A., Huynh GH., Lalli M., Lin HH., Mandal S., McBryde ES., Pandey S., Salomon JA., Suen SC., Sumner T., Trauer JM., Wagner BG., Whalen CC., Wu CY., Boccia D., Chadha VK., Charalambous S., Chin DP., Churchyard G., Daniels C., Dewan P., Ditiu L., Eaton JW., Grant AD., Hippner P., Hosseini M., Mametja D., Pretorius C., Pillay Y., Rade K., Sahu S., Wang L., Houben RMGJ., Kimerling ME., White RG., Vassall A, The Lancet. Global health, 4, e816-e826

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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. FUNDING: Bill & Melinda Gates Foundation.

Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India: a combined analysis of 11 mathematical models. (2016). Houben RMGJ., Menzies NA., Sumner T., Huynh GH., Arinaminpathy N., Goldhaber-Fiebert JD., Lin HH., Wu CY., Mandal S., Pandey S., Suen SC., Bendavid E., Azman AS., Dowdy DW., Bacaer N., Rhines AS., Feldman MW., Handel A., Whalen CC., Chang ST., Wagner BG., Eckhoff PA., Trauer JM., Denholm JT., McBryde ES., Cohen T., Salomon JA., Pretorius C., Lalli M., Eaton JW., Boccia D., Hosseini M., Gomez GB., Sahu S., Daniels C., Ditiu L., Chin DP., Wang L., Chadha VK., Rade K., Dewan P., Hippner P., Charalambous S., Grant AD., Churchyard G., Pillay Y., Mametja LD., Kimerling ME., Vassall A., White RG, The Lancet. Global health, 4, e806-e815

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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. FUNDING: Bill and Melinda Gates Foundation.

Cost-effectiveness of Diagnostic Algorithms for Tuberculosis in Children Less Than 5 Years of Age. (2016). Debes AK., Gilman RH., Onyango-Makumbi C., Ruff A., Oberhelman R., Dowdy DW, The Pediatric infectious disease journal, 36, 36-43

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BACKGROUND: The objective of this analysis was to assess the cost-effectiveness of TB diagnosis using microscopic observation drug susceptibility (MODS), Xpert MTB/RIF (Xpert) and empiric treatment for all patients, in addition to current clinical diagnostic practices in children less than 5 years of age in a national tuberculosis (TB) referral hospital in Uganda. METHODS: A decision analysis was conducted from the healthcare perspective, with a primary outcome of incremental cost-effectiveness expressed as cost per year of life gained (YLG). RESULTS: Cost-effectiveness of the algorithms depended strongly on 3 variables: the prevalence of TB, probability of death if TB was untreated and accuracy of existing diagnostic algorithms. Xpert and MODS had similar cost-effectiveness profiles and were preferred in settings where the prevalence of TB and probability of death from untreated TB were low. As the underlying probability of TB disease and death increased, treating all children with clinically suspected disease became more cost-effective. In settings where the probability that an untreated child will die of TB-whether a result of high prevalence of TB or high mortality from untreated TB-treating all children for TB is likely to be the most cost-effective approach until better diagnostic tests can be developed. CONCLUSIONS: The cost-effectiveness of diagnostic tools for TB in children depends on the population, natural history of untreated TB and existing diagnostic practices. In settings where the risk of TB death is high, empiric treatment of all children for TB should be considered until a more sensitive, low-cost diagnostic test is available.

- July 2016 -

Serial testing for latent tuberculosis using QuantiFERON-TB Gold In-Tube: A Markov model. (2016). Moses MW., Zwerling A., Cattamanchi A., Denkinger CM., Banaei N., Kik SV., Metcalfe J., Pai M., Dowdy D, Scientific reports, 6, 30781

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Healthcare workers (HCWs) in low-incidence settings are often serially tested for latent TB infection (LTBI) with the QuantiFERON-TB Gold In-Tube (QFT) assay, which exhibits frequent conversions and reversions. The clinical impact of such variability on serial testing remains unknown. We used a microsimulation Markov model that accounts for major sources of variability to project diagnostic outcomes in a simulated North American HCW cohort. Serial testing using a single QFT with the recommended conversion cutoff (IFN-g > 0.35 IU/mL) resulted in 24.6% (95% uncertainty range, UR: 23.8-25.5) of the entire population testing false-positive over ten years. Raising the cutoff to >1.0 IU/mL or confirming initial positive results with a (presumed independent) second test reduced this false-positive percentage to 2.3% (95%UR: 2.0-2.6%) or 4.1% (95%UR: 3.7-4.5%), but also reduced the proportion of true incident infections detected within the first year of infection from 76.5% (95%UR: 66.3-84.6%) to 54.8% (95%UR: 44.6-64.5%) or 61.5% (95%UR: 51.6-70.9%), respectively. Serial QFT testing of HCWs in North America may result in tremendous over-diagnosis and over-treatment of LTBI, with nearly thirty false-positives for every true infection diagnosed. Using higher cutoffs for conversion or confirmatory tests (for initial positives) can mitigate these effects, but will also diagnose fewer true infections.

- June 2016 -

Cost-Effectiveness of Automated Digital Microscopy for Diagnosis of Active Tuberculosis. (2016). Jha S., Ismail N., Clark D., Lewis JJ., Omar S., Dreyer A., Chihota V., Churchyard G., Dowdy DW, PloS one, 11, e0157554

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BACKGROUND: Automated digital microscopy has the potential to improve the diagnosis of tuberculosis (TB), particularly in settings where molecular testing is too expensive to perform routinely. The cost-effectiveness of TB diagnostic algorithms using automated digital microscopy remains uncertain. METHODS: Using data from a demonstration study of an automated digital microscopy system (TBDx, Applied Visual Systems, Inc.), we performed an economic evaluation of TB diagnosis in South Africa from the health system perspective. The primary outcome was the incremental cost per new TB diagnosis made. We considered costs and effectiveness of different algorithms for automated digital microscopy, including as a stand-alone test and with confirmation of positive results with Xpert MTB/RIF ('Xpert', Cepheid, Inc.). Results were compared against both manual microscopy and universal Xpert testing. RESULTS: In settings willing to pay $2000 per incremental TB diagnosis, universal Xpert was the preferred strategy. However, where resources were not sufficient to support universal Xpert, and a testing volume of at least 30 specimens per day could be ensured, automated digital microscopy with Xpert confirmation of low-positive results could facilitate the diagnosis of 79-84% of all Xpert-positive TB cases, at 50-60% of the total cost. The cost-effectiveness of this strategy was $1280 per incremental TB diagnosis (95% uncertainty range, UR: $340-$3440) in the base case, but improved under conditions likely reflective of many settings in sub-Saharan Africa: $677 per diagnosis (95% UR: $450-$935) when sensitivity of manual smear microscopy was lowered to 0.5, and $956 per diagnosis (95% UR: $40-$2910) when the prevalence of multidrug-resistant TB was lowered to 1%. CONCLUSIONS: Although universal Xpert testing is the preferred algorithm for TB diagnosis when resources are sufficient, automated digital microscopy can identify the majority of cases and halve the cost of diagnosis and treatment when resources are more scarce and multidrug-resistant TB is not common.

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.

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