TB Modeling and Translational Epi Group

Group Publications

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- October 2015 -

Stopping the body count: a comprehensive approach to move towards zero tuberculosis deaths. (2015). Keshavjee S., Dowdy D., Swaminathan S, Lancet (London, England), 386, e46-7

Data for action: collection and use of local data to end tuberculosis. (2015). Theron G., Jenkins HE., Cobelens F., Abubakar I., Khan AJ., Cohen T., Dowdy DW, Lancet (London, England), 386, 2324-33

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Accelerating progress in the fight against tuberculosis will require a drastic shift from a strategy focused on control to one focused on elimination. Successful disease elimination campaigns are characterised by locally tailored responses that are informed by appropriate data. To develop such a response to tuberculosis, we suggest a three-step process that includes improved collection and use of existing programmatic data, collection of additional data (eg, geographic information, drug resistance, and risk factors) to inform tailored responses, and targeted collection of novel data (eg, sequencing data, targeted surveys, and contact investigations) to improve understanding of tuberculosis transmission dynamics. Development of a locally targeted response for tuberculosis will require substantial investment to reconfigure existing systems, coupled with additional empirical data to evaluate the effectiveness of specific approaches. Without adoption of an elimination strategy that uses local data to target hotspots of transmission, ambitious targets to end tuberculosis will almost certainly remain unmet.

Toward the optical "magic carpet": reducing the divergence of a light sheet below the diffraction limit. (2015). Golub I., Chebbi B., Golub J, Optics letters, 40, 5121-4

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In 3D, diffraction-free or Bessel beams are well known and have found applications in diverse fields. An analog in 2D, or pseudonondiffracting (PND) beams, is a nontrivial problem, and existing methods suffer from deficiencies. For example, Airy beams are not highly localized, some PND beams have significant side lobes, and a cosine beam has to be truncated by a very narrow aperture thus discarding most of the energy. We show, both theoretically and experimentally, that it is possible to generate a quasi-nondiffracting 2D light beam in a simple and efficient fashion. This is achieved by placing a mask consisting of a pair of double slits on a cylindrical lens. The applications include light sheet microscopy/optical sectioning and particle manipulation.

In reply. (2015). Johnston JC., Khan FA., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 19, 1264

Directly observed therapy of tuberculosis in Brazil: associated determinants and impact on treatment outcome. (2015). Reis-Santos B., Pellacani-Posses I., Macedo LR., Golub JE., Riley LW., Maciel EL, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 19, 1188-93

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SETTING: All Brazilian states. OBJECTIVES: To assess the determinants of tuberculosis (TB) in patients undergoing directly observed therapy (DOT) and the impact of DOT on treatment outcomes. DESIGN: This is a cross-sectional study among TB patients aged 18 years conducted in 2011. The primary outcome was the status of DOT received, while the secondary was the outcome of anti-tuberculosis treatment. RESULTS: In 2011, 35 775 (38.3%) subjects received DOT. The odds of receiving DOT were higher in patients with the following characteristics: brown/mestizo patients (OR 1.18, 95%CI 1.14-1.22) and those of other ethnic groups (OR 2.01, 95%CI 1.79-2.27) compared to Whites, alcohol users (OR 1.37, 95%CI 1.28-1.47) and those with mental disorders (OR 1.88, 95%CI 1.54-2.29). The odds of receiving DOT were lower in human immunodeficiency virus positive patients (OR 0.64, 95%CI 0.60-0.68). Patients who did not receive DOT were more likely to default from anti-tuberculosis treatment (OR 0.62, 95%CI 0.57-0.66), die due to TB (OR 0.68, 95%CI 0.61-0.77) and to have unknown treatment outcomes (OR 0.71, 95%CI 0.66-0.76). The adjusted preventable fraction of DOT in the reduction of unfavorable outcomes was 25%. CONCLUSION: Sociodemographic and clinical characteristics are determinants of anti-tuberculosis treatment outcomes in patients undergoing DOT; DOT use led to a 25% reduction in unfavorable outcomes.

Economic and epidemiological impact of early antiretroviral therapy initiation in India. (2015). Maddali MV., Dowdy DW., Gupta A., Shah M, Journal of the International AIDS Society, 18, 20217

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INTRODUCTION: Recent WHO guidance advocates for early antiretroviral therapy (ART) initiation at higher CD4 counts to improve survival and reduce HIV transmission. We sought to quantify how the cost-effectiveness and epidemiological impact of early ART strategies in India are affected by attrition throughout the HIV care continuum. METHODS: We constructed a dynamic compartmental model replicating HIV transmission, disease progression and health system engagement among Indian adults. Our model of the Indian HIV epidemic compared implementation of early ART initiation (i.e. initiation above CD4 >/=350 cells/mm(3)) with delayed initiation at CD4

- September 2015 -

The Distribution of Fitness Costs of Resistance-Conferring Mutations Is a Key Determinant for the Future Burden of Drug-Resistant Tuberculosis: A Model-Based Analysis. (2015). Knight GM., Colijn C., Shrestha S., Fofana M., Cobelens F., White RG., Dowdy DW., Cohen T, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 61Suppl 3, S147-54

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BACKGROUND: Drug resistance poses a serious challenge for the control of tuberculosis in many settings. It is well established that the expected future trend in resistance depends on the reproductive fitness of drug-resistant Mycobacterium tuberculosis. However, the variability in fitness between strains with different resistance-conferring mutations has been largely ignored when making these predictions. METHODS: We developed a novel approach for incorporating the variable fitness costs of drug resistance-conferring mutations and for tracking this distribution of fitness costs over time within a transmission model. We used this approach to describe the effects of realistic fitness cost distributions on the future prevalence of drug-resistant tuberculosis. RESULTS: The shape of the distribution of fitness costs was a strong predictor of the long-term prevalence of resistance. While, as expected, lower average fitness costs of drug resistance-conferring mutations were associated with more severe epidemics of drug-resistant tuberculosis, fitness distributions with greater variance also led to higher levels of drug resistance. For example, compared to simulations in which the fitness cost of resistance was fixed, introducing a realistic amount of variance resulted in a 40% increase in prevalence of drug-resistant tuberculosis after 20 years. CONCLUSIONS: The differences in the fitness costs associated with drug resistance-conferring mutations are a key determinant of the future burden of drug-resistant tuberculosis. Future studies that can better establish the range of fitness costs associated with drug resistance-conferring mutations will improve projections and thus facilitate better public health planning efforts.

The Epidemiologic and Economic Impact of Improving HIV Testing, Linkage, and Retention in Care in the United States. (2015). Shah M., Risher K., Berry SA., Dowdy DW, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 62, 220-229

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BACKGROUND: Recent guidelines advocate early antiretroviral therapy (ART) to decrease human immunodeficiency virus (HIV) morbidity and prevent transmission, but suboptimal engagement in care may compromise impact. We sought to determine the economic and epidemiologic impact of incomplete engagement in HIV care in the United States. METHODS: We constructed a dynamic transmission model of HIV among US adults (aged 15-65 years) and conducted a cost-effectiveness analysis of improvements along the HIV care continuum : We evaluated enhanced HIV testing (annual for high-risk groups), increased 3-month linkage to care (to 90%), and improved retention (50% relative reduction in yearly disengagement and 50% increase in reengagement). Our primary outcomes were HIV incidence, mortality, costs and quality-adjusted life-years (QALYs). RESULTS: Despite early ART initiation, a projected 1.39 million (95% uncertainty range [UR], 0.91-2.2 million) new HIV infections will occur at a (discounted) cost of $256 billion ($199-298 billion) over 2 decades at existing levels of HIV care engagement. Enhanced testing with increased linkage has modest epidemiologic benefits and could reduce incident HIV infections by 21% (95% UR, 13%-26%) at a cost of $65 700 per QALY gained ($44 500-111 000). By contrast, comprehensive improvements that couples enhanced testing and linkage with improved retention would reduce HIV incidence by 54% (95% UR, 37%-68%) and mortality rate by 64% (46%-78%), at a cost-effectiveness ratio of $45 300 per QALY gained ($27 800-72 300). CONCLUSIONS: Failure to improve engagement in HIV care in the United States leads to excess infections, treatment costs, and deaths. Interventions that improve not just HIV screening but also retention in care are needed to optimize epidemiologic impact and cost-effectiveness.

- August 2015 -

Tobacco smoking and tuberculosis treatment outcomes: a prospective cohort study in Georgia. (2015). Gegia M., Magee MJ., Kempker RR., Kalandadze I., Chakhaia T., Golub JE., Blumberg HM, Bulletin of the World Health Organization, 93, 390-9

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OBJECTIVE: To assess the effect of tobacco smoking on the outcome of tuberculosis treatment in Tbilisi, Georgia. METHODS: We conducted a prospective cohort study of adults with laboratory-confirmed tuberculosis from May 2011 to November 2013. History of tobacco smoking was collected using a standardized questionnaire adapted from the global adult tobacco survey. We considered tuberculosis therapy to have a poor outcome if participants defaulted, failed treatment or died. We used multivariable regressions to estimate the risk of a poor treatment outcome. FINDINGS: Of the 591 tuberculosis patients enrolled, 188 (31.8%) were past smokers and 271 (45.9%) were current smokers. Ninety (33.2%) of the current smokers and 24 (18.2%) of the participants who had never smoked had previously been treated for tuberculosis (P < 0.01). Treatment outcome data were available for 524 of the participants, of whom 128 (24.4%) - including 80 (32.9%) of the 243 current smokers and 21 (17.2%) of the 122 individuals who had never smoked - had a poor treatment outcome. Compared with those who had never smoked, current smokers had an increased risk of poor treatment outcome (adjusted relative risk, aRR: 1.70; 95% confidence interval, CI: 1.00-2.90). Those who had ceased smoking more than two months before enrolment did not have such an increased risk (aRR: 1.01; 95% CI: 0.51-1.99). CONCLUSION: There is a high prevalence of smoking among patients with tuberculosis in Georgia and smoking increases the risk of a poor treatment outcome.

- July 2015 -

Pathways and costs of care for patients with tuberculosis symptoms in rural Uganda. (2015). Shete PB., Haguma P., Miller CR., Ochom E., Ayakaka I., Davis JL., Dowdy DW., Hopewell P., Katamba A., Cattamanchi A, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 19, 912-7

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SETTING: Six district-level government health centers in rural Uganda and the surrounding communities. OBJECTIVE: To determine pathways to care and associated costs for patients with chronic cough referred for tuberculosis (TB) evaluation in Uganda. DESIGN: We conducted a cross-sectional study, surveying 64 patients presenting with chronic cough and undergoing first-time sputum evaluation at government clinics. We also surveyed a random sample of 114 individuals with chronic cough in surrounding communities. We collected information on previous health visits for the cough as well as costs associated with the current visit. RESULTS: Eighty per cent of clinic patients had previously sought care for their cough, with a median of three previous visits (range 0-32, interquartile range [IQR] 2-5). Most (n = 203, 88%) visits were to a health facility that did not provide TB microscopy services, and the majority occurred in the private sector. The cost of seeking care for the current visit alone represented 28.8% (IQR 9.1-109.5) of the patients' median monthly household income. CONCLUSION: Most patients seek health care for chronic cough, but do so first in the private sector. Engagement of the private sector and streamlining TB diagnostic evaluation are critical for improving case detection and meeting global TB elimination targets.

Optimal Timing of Antiretroviral Therapy Initiation for HIV-Infected Adults With Newly Diagnosed Pulmonary Tuberculosis: A Systematic Review and Meta-analysis. (2015). Uthman OA., Okwundu C., Gbenga K., Volmink J., Dowdy D., Zumla A., Nachega JB, Annals of internal medicine, 163, 32-9

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BACKGROUND: Initiation of antiretroviral therapy (ART) during tuberculosis (TB) treatment remains challenging. PURPOSE: To assess evidence from randomized, controlled trials of the timing of ART initiation in HIV-infected adults with newly diagnosed pulmonary TB. DATA SOURCES: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, conference abstracts, and ClinicalTrials.gov (from January 1980 to May 2015). STUDY SELECTION: Randomized, controlled trials evaluating early versus delayed ART initiation (1 to 4 weeks vs. 8 to 12 weeks after initiation of TB treatment) or deferred ART initiation (after the end of TB treatment). DATA EXTRACTION: Three reviewers independently extracted data and assessed risk of bias. The main outcome measures were all-cause mortality and the TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). DATA SYNTHESIS: The 8 included trials (n = 4568) were conducted in Africa, Asia, and the United States and were generally at low risk of bias for the assessed domains. Overall, early ART reduced mortality compared with delayed ART (relative risk [RR], 0.81 [95% CI, 0.66 to 0.99]; I2 = 0%). In a prespecified subgroup analysis, early ART reduced mortality compared with delayed ART among patients with baseline CD4+ T-cell counts less than 0.050 x 109 cells/L (RR, 0.71 [CI, 0.54 to 0.93]; I2 = 0%). However, a mortality benefit from early ART was not found among those with CD4+ T-cell counts greater than 0.050 x 109 cells/L (RR, 1.05 [CI, 0.68 to 1.61]; I2 = 56%). Early ART was associated with a higher incidence of TB-IRIS than delayed ART (RR, 2.31 [CI, 1.87 to 2.86]; I2 = 19%). LIMITATION: Few trials provided sufficient data for subgroup analysis. CONCLUSION: Early ART in HIV-infected adults with newly diagnosed TB improves survival in those with CD4+ T-cell counts less than 0.050 x 109 cells/L, although this is associated with a 2-fold higher frequency of TB-IRIS. In patients with CD4+ T-cell counts greater than 0.050 x 109 cells/L, evidence is insufficient to support or refute a survival benefit conferred by early versus delayed ART initiation. PRIMARY FUNDING SOURCE: None. (PROSPERO registration: CRD42012001884).

- June 2015 -

Screening for Tuberculosis Among Adults Newly Diagnosed With HIV in Sub-Saharan Africa: A Cost-Effectiveness Analysis. (2015). Zwerling AA., Sahu M., Ngwira LG., Khundi M., Harawa T., Corbett EL., Chaisson RE., Dowdy DW, Journal of acquired immune deficiency syndromes (1999), 70, 83-90

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OBJECTIVE: New tools, including light-emitting diode (LED) fluorescence microscopy and the molecular assay Xpert MTB/RIF, offer increased sensitivity for tuberculosis (TB) in persons with HIV but come with higher costs. Using operational data from rural Malawi, we explored the potential cost-effectiveness of on-demand screening for TB in low-income countries of Sub-Saharan Africa. DESIGN AND METHODS: Costs were empirically collected in 4 clinics and in 1 hospital using a microcosting approach, through direct interview and observation from the national TB program perspective. Using decision analysis, newly diagnosed persons with HIV were modeled as being screened by 1 of the 3 strategies: Xpert, LED, or standard of care (ie, at the discretion of the treating physician). RESULTS: Cost-effectiveness of TB screening among persons newly diagnosed with HIV was largely determined by 2 factors: prevalence of active TB among patients newly diagnosed with HIV and volume of testing. In facilities screening at least 50 people with a 6.5% prevalence of TB, or at least 500 people with a 2.5% TB prevalence, Xpert is likely to be cost-effective. At lower prevalence-including that observed in Malawi-LED microscopy may be the preferred strategy, whereas in settings of lower TB prevalence or small numbers of eligible patients, no screening may be reasonable (such that resources can be deployed elsewhere). CONCLUSIONS: TB screening at the point of HIV diagnosis may be cost-effective in low-income countries of Sub-Saharan Africa, but only if a relatively large population with high prevalence of TB can be identified for screening.

- May 2015 -

Reducing relapse in tuberculosis treatment: is it time to reassess WHO treatment guidelines? (2015). Johnston JC., Khan FA., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 19, 624

- April 2015 -

Costs and Consequences of Using Interferon-gamma Release Assays for the Diagnosis of Active Tuberculosis in India. (2015). Little KM., Pai M., Dowdy DW, PloS one, 10, e0124525

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BACKGROUND: There is growing concern that interferon-gamma release assays (IGRAs) are being used off-label for the diagnosis of active tuberculosis (TB) disease in many high-burden settings, including India, where the background prevalence of latent TB infection is high. We analyzed the costs and consequences of using IGRAs for the diagnosis of active TB in India from the perspective of the Indian TB control sector. METHODS AND FINDINGS: We constructed a decision analytic model to estimate the incremental cost and effectiveness of IGRAs for the diagnosis of active TB in India. We compared a reference scenario of clinical examination and non-microbiological tests against scenarios in which clinical diagnosis was augmented by the addition of either sputum smear microscopy, IGRA, or Xpert MTB/RIF. We examined costs (in 2013 US dollars) and consequences from the perspective of the Indian healthcare sector. Relative to sputum smear microscopy, use of IGRA for active TB resulted in 23,700 (95% uncertainty range, UR: 3,800 - 38,300) additional true-positive diagnoses, but at the expense of 315,700 (95% UR: 118,300 - 388,400) additional false-positive diagnoses and an incremental cost of US$49.3 million (95% UR: $34.9 - $58.0 million) (2.9 billion Indian Rupees). Relative to Xpert MTB/RIF (including the cost of treatment for drug resistant TB), use of IGRA led to 400 additional TB cases treated (95% UR: [-8,000] - 16,200), 370,600 (95% UR: 252,200 - 441,700) more false-positive diagnoses, 70,400 (95% UR: [-7,900] - 247,200) fewer disability-adjusted life years averted, and US$14.6 million (95%UR: [-$7.2] - $28.7 million) (854 million Indian Rupees) in additional costs. CONCLUSION: Using IGRAs for diagnosis of active TB in a setting like India results in tremendous overtreatment of people without TB, and substantial incremental cost with little gain in health. These results support the policies by WHO and Standards for TB Care in India, which discourage the use of IGRAs for the diagnosis of active TB in India and similar settings.

The epidemiological advantage of preferential targeting of tuberculosis control at the poor. (2015). Andrews JR., Basu S., Dowdy DW., Murray MB, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 19, 375-80

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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.

Performance of a Novel Algorithm Using Automated Digital Microscopy for Diagnosing Tuberculosis. (2015). Ismail NA., Omar SV., Lewis JJ., Dowdy DW., Dreyer AW., van der Meulen H., Nconjana G., Clark DA., Churchyard GJ, American journal of respiratory and critical care medicine, 191, 1443-9

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RATIONALE: TBDx automated microscopy is a novel technology that processes digital microscopic images to identify acid-fast bacilli (AFB). Use of TBDx as part of a diagnostic algorithm could improve the diagnosis of tuberculosis (TB), but its performance characteristics have not yet been formally tested. OBJECTIVES: To evaluate the performance of the TBDx automated microscopy system in algorithms for diagnosis of TB. METHODS: Prospective samples from patients with presumed TB were processed in parallel with conventional smear microscopy, TBDx microscopy, and liquid culture. All TBDx-positive specimens were also tested with the Xpert MTB/RIF (GXP) assay. We evaluated the sensitivity and specificity of two algorithms-(1) TBDx-GXP (TBDx with positive specimens tested by Xpert MTB/RIF) and (2) TBDx alone-against the gold standard liquid media culture. MEASUREMENTS AND MAIN RESULTS: Of 1,210 samples, 1,009 were eligible for evaluation, of which 109 were culture positive for Mycobacterium tuberculosis. The TBDx system identified 70 specimens (68 culture positive) as having 10 or more putative AFB (high positive) and 207 (19 culture positive) as having 1-9 putative AFB (low positive). An algorithm in which "low-positive" results on TBDx were confirmed by GXP had 78% sensitivity (85 of 109) and 99.8% specificity (889 of 900), requiring 21% (207 of 1,009) specimens to be processed by GXP. As a stand-alone test, a "high-positive" result on TBDx had 62% sensitivity and 99.7% specificity. CONCLUSIONS: TBDx used in diagnostic algorithms with GXP provided reasonable sensitivity and high specificity for active TB while dramatically reducing the number GXP tests performed. As a stand-alone microscopy system, its performance was equivalent to that of a highly experienced TB microscopist.

- March 2015 -

Drivers and trajectories of resistance to new first-line drug regimens for tuberculosis. (2015). Shrestha S., Knight GM., Fofana M., Cohen T., White RG., Cobelens F., Dowdy DW, Open forum infectious diseases, 1, ofu073

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BACKGROUND: New first-line drug regimens for treatment of tuberculosis (TB) are in clinical trials: emergence of resistance is a key concern. Because population-level data on resistance cannot be collected in advance, epidemiological models are important tools for understanding the drivers and dynamics of resistance before novel drug regimens are launched. METHODS: We developed a transmission model of TB after launch of a new drug regimen, defining drug-resistant TB (DR-TB) as resistance to the new regimen. The model is characterized by (1) the probability of acquiring resistance during treatment, (2) the transmission fitness of DR-TB relative to drug-susceptible TB (DS-TB), and (3) the probability of treatment success for DR-TB versus DS-TB. We evaluate the effect of each factor on future DR-TB prevalence, defined as the proportion of incident TB that is drug-resistant. RESULTS: Probability of acquired resistance was the strongest predictor of the DR-TB proportion in the first 5 years after the launch of a new drug regimen. Over a longer term, however, the DR-TB proportion was driven by the resistant population's transmission fitness and treatment success rates. Regardless of uncertainty in acquisition probability and transmission fitness, high levels (>10%) of drug resistance were unlikely to emerge within 50 years if, among all cases of TB that were detected, 85% of those with DR-TB could be appropriately diagnosed as such and then successfully treated. CONCLUSIONS: Short-term surveillance cannot predict long-term drug resistance trends after launch of novel first-line TB regimens. Ensuring high treatment success of drug-resistant TB through early diagnosis and appropriate second-line therapy can mitigate many epidemiological uncertainties and may substantially slow the emergence of drug-resistant TB.

- February 2015 -

C-reactive protein (CRP), interferon gamma-inducible protein 10 (IP-10), and lipopolysaccharide (LPS) are associated with risk of tuberculosis after initiation of antiretroviral therapy in resource-limited settings. (2015). Tenforde MW., Gupte N., Dowdy DW., Asmuth DM., Balagopal A., Pollard RB., Sugandhavesa P., Lama JR., Pillay S., Cardoso SW., Pawar J., Santos B., Riviere C., Mwelase N., Kanyama C., Kumwenda J., Hakim JG., Kumarasamy N., Bollinger R., Semba RD., Campbell TB., Gupta A, PloS one, 10, e0117424

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OBJECTIVE: The association between pre-antiretroviral (ART) inflammation and immune activation and risk for incident tuberculosis (TB) after ART initiation among adults is uncertain. DESIGN: Nested case-control study (n = 332) within ACTG PEARLS trial of three ART regimens among 1571 HIV-infected, treatment-naive adults in 9 countries. We compared cases (participants with incident TB diagnosed by 96 weeks) to a random sample of controls (participants who did not develop TB, stratified by country and treatment arm). METHODS: We measured pre-ART C-reactive protein (CRP), EndoCab IgM, ferritin, interferon gamma (IFN-gamma), interleukin 6 (IL-6), interferon gamma-inducible protein 10 (IP-10), lipopolysaccharide (LPS), soluble CD14 (sCD14), tumor necrosis factor alpha (TNF-alpha), and CD4/DR+/38+ and CD8/DR+/38+ T cells. Markers were defined according to established cutoff definitions when available, 75th percentile of measured values when not, and detectable versus undetectable for LPS. Using logistic regression, we measured associations between biomarkers and incident TB, adjusting for age, sex, study site, treatment arm, baseline CD4 and log10 viral load. We assessed the discriminatory value of biomarkers using receiver operating characteristic (ROC) analysis. RESULTS: Seventy-seven persons (4.9%) developed incident TB during follow-up. Elevated baseline CRP (aOR 3.25, 95% CI: 1.55-6.81) and IP-10 (aOR 1.89, 95% CI: 1.05-3.39), detectable plasma LPS (aOR 2.39, 95% CI: 1.13-5.06), and the established TB risk factors anemia and hypoalbuminemia were independently associated with incident TB. In ROC analysis, CRP, albumin, and LPS improved discrimination only modestly for TB risk when added to baseline routine patient characteristics including CD4 count, body mass index, and prior TB. CONCLUSION: Incident TB occurs commonly after ART initiation. Although associated with higher post-ART TB risk, baseline CRP, IP-10, and LPS add limited value to routine patient characteristics in discriminating who develops active TB. Besides determining ideal cutoffs for these biomarkers, additional biomarkers should be sought that predict TB disease in ART initiators.

- January 2015 -

Postarrival Tuberculosis Screening of High-Risk Immigrants at a Local Health Department. (2015). Nuzzo JB., Golub JE., Chaulk P., Shah M, American journal of public health, 105, 1432-8

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OBJECTIVES: We sought to characterize postimmigration tuberculosis (TB) care for Class B immigrants and refugees at the Baltimore City Health Department TB program (BCHD), and to determine the proportion of immigrants with active TB or latent TB infection (LTBI) in this high-risk population. METHODS: We conducted a retrospective chart review of Class B immigrants and refugees who reported to the BCHD for postimmigration TB evaluation from 2010 to 2012. RESULTS: We reviewed the clinical records of 153 Class B immigrants; 4% were diagnosed with active TB and 53% were diagnosed with LTBI. Fifty percent of active TB cases were culture positive, and 67% were asymptomatic; 100% received and completed active TB therapy at the BCHD. Among those diagnosed with LTBI, 87% initiated LTBI therapy and 91% completed treatment. CONCLUSIONS: The high prevalence of active TB and LTBI found among Class B immigrants underscore the importance for postarrival TB screening. The absence of reported symptoms among the majority of active cases identified during this study suggest that reliance on symptom-based screening protocols to prompt sputa testing may be inadequate for identifying active TB among this high-risk group.

- December 2014 -

Cost-effectiveness of tuberculosis screening and isoniazid treatment in the TB/HIV in Rio (THRio) Study. (2014). Azadi M., Bishai DM., Dowdy DW., Moulton LH., Cavalcante S., Saraceni V., Pacheco AG., Cohn S., Chaisson RE., Durovni B., Golub JE, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 18, 1443-8

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OBJECTIVE: To estimate the incremental cost-effectiveness of tuberculosis (TB) screening and isoniazid preventive therapy (IPT) among human immunodeficiency virus (HIV) infected adults in Rio de Janeiro, Brazil. DESIGN: We used decision analysis, populated by data from a cluster-randomized trial, to project the costs (in 2010 USD) and effectiveness (in disability-adjusted life years [DALYs] averted) of training health care workers to implement the tuberculin skin test (TST), followed by IPT for TST-positive patients with no evidence of active TB. This intervention was compared to a baseline of usual care. We used time horizons of 1 year for the intervention and 20 years for disease outcomes, with all future DALYs and medical costs discounted at 3% per year. RESULTS: Providing this intervention to 100 people would avert 1.14 discounted DALYs (1.57 undiscounted DALYs). The median estimated incremental cost-effectiveness ratio was $2273 (IQR $1779-$3135) per DALY averted, less than Brazil's 2010 per capita gross domestic product (GDP) of $11,700. Results were most sensitive to the cost of providing the training. CONCLUSION: Training health care workers to screen HIV-infected adults with TST and provide IPT to those with latent tuberculous infection can be considered cost-effective relative to the Brazilian GDP per capita.

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