TB Modeling and Translational Epi Group

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- January 2014 -

Do we need to detect isoniazid resistance in addition to rifampicin resistance in diagnostic tests for tuberculosis? (2014). Denkinger CM., Pai M., Dowdy DW, PloS one, 9, e84197

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BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is resistant to both rifampicin (RIF) and isoniazid (INH). Whereas many TB diagnostics detect RIF-resistance, few detect INH-monoresistance, which is common and may increase risk of acquired MDR-TB. Whether inclusion of INH-resistance in a first-line rapid test for TB would have an important impact on MDR-TB rates remains uncertain. METHODS: WE DEVELOPED A TRANSMISSION MODEL TO EVALUATE THREE TESTS IN A POPULATION SIMILAR TO THAT OF INDIA: a rapid molecular test for TB, the same test plus RIF-resistance detection ("TB+RIF"), and detection of RIF and INH-resistance ("TB+RIF/INH"). Our primary outcome was the prevalence of INH-resistant and MDR-TB at ten years. RESULTS: Compared to the TB test alone and assuming treatment of all diagnosed MDR cases, the TB+RIF test reduced the prevalence of MDR-TB among all TB cases from 5.5% to 3.8% (30.6% reduction, 95% uncertainty range, UR: 17-54%). Despite using liberal assumptions about the impact of INH-monoresistance on treatment outcomes and MDR-TB acquisition, expansion from TB+RIF to TB+RIF/INH lowered this prevalence only from 3.8% to 3.6% further (4% reduction, 95% UR: 3-7%) and INH-monoresistant TB from 15.8% to 15.1% (4% reduction, 95% UR: (-8)-19%). CONCLUSION: When added to a rapid test for TB plus RIF-resistance, detection of INH-resistance has minimal impact on transmission of TB, MDR-TB, and INH-monoresistant TB.

Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. (2014). Pai M., Denkinger CM., Kik SV., Rangaka MX., Zwerling A., Oxlade O., Metcalfe JZ., Cattamanchi A., Dowdy DW., Dheda K., Banaei N, Clinical microbiology reviews, 27, 3-20

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Identification and treatment of latent tuberculosis infection (LTBI) can substantially reduce the risk of developing active disease. However, there is no diagnostic gold standard for LTBI. Two tests are available for identification of LTBI: the tuberculin skin test (TST) and the gamma interferon (IFN-gamma) release assay (IGRA). Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosis exposure and indicate a cellular immune response to M. tuberculosis. Neither test can accurately differentiate between LTBI and active TB, distinguish reactivation from reinfection, or resolve the various stages within the spectrum of M. tuberculosis infection. Both TST and IGRA have reduced sensitivity in immunocompromised patients and have low predictive value for progression to active TB. To maximize the positive predictive value of existing tests, LTBI screening should be reserved for those who are at sufficiently high risk of progressing to disease. Such high-risk individuals may be identifiable by using multivariable risk prediction models that incorporate test results with risk factors and using serial testing to resolve underlying phenotypes. In the longer term, basic research is necessary to identify highly predictive biomarkers.

- November 2013 -

Rapid molecular testing for TB to guide respiratory isolation in the U.S.: a cost-benefit analysis. (2013). Millman AJ., Dowdy DW., Miller CR., Brownell R., Metcalfe JZ., Cattamanchi A., Davis JL, PloS one, 8, e79669

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BACKGROUND: Respiratory isolation of inpatients during evaluation for TB is a slow and costly process in low-burden settings. Xpert MTB/RIF (Xpert) is a novel molecular test for tuberculosis (TB) that is faster and more sensitive but substantially more expensive than smear microscopy. No previous studies have examined the costs of molecular testing as a replacement for smear microscopy in this setting. METHODS: We conducted an incremental cost-benefit analysis comparing the use of a single negative Xpert versus two negative sputum smears to release consecutive adult inpatients with presumed TB from respiratory isolation at an urban public hospital in the United States. We estimated all health-system costs and patient outcomes related to Xpert implementation, diagnostic evaluation, isolation, hospitalization, and treatment. We performed sensitivity and probabilistic uncertainty analyses to determine at what threshold the Xpert strategy would become cost-saving. RESULTS: Among a hypothetical cohort of 234 individuals undergoing evaluation for presumed active TB annually, 6.4% had culture-positive TB. Compared to smear microscopy, Xpert reduced isolation bed utilization from an average of 2.7 to 1.4 days per patient, leading to a 48% reduction in total annual isolation bed usage from 632 to 328 bed-days. Xpert saved an average of $2,278 (95% uncertainty range $1582-4570) per admission, or $533,520 per year, compared with smear microscopy. CONCLUSIONS: Molecular testing for TB could provide substantial savings to hospitals in high-income countries by reducing respiratory isolation usage and overall length of stay.

Physical complications in acute lung injury survivors: a two-year longitudinal prospective study. (2013). Fan E., Dowdy DW., Colantuoni E., Mendez-Tellez PA., Sevransky JE., Shanholtz C., Himmelfarb CR., Desai SV., Ciesla N., Herridge MS., Pronovost PJ., Needham DM, Critical care medicine, 42, 849-59

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OBJECTIVE: Survivors of severe critical illness frequently develop substantial and persistent physical complications, including muscle weakness, impaired physical function, and decreased health-related quality of life. Our objective was to determine the longitudinal epidemiology of muscle weakness, physical function, and health-related quality of life and their associations with critical illness and ICU exposures. DESIGN: A multisite prospective study with longitudinal follow-up at 3, 6, 12, and 24 months after acute lung injury. SETTING: Thirteen ICUs from four academic teaching hospitals. PATIENTS: Two hundred twenty-two survivors of acute lung injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At each time point, patients underwent standardized clinical evaluations of extremity, hand grip, and respiratory muscle strength; anthropometrics (height, weight, mid-arm circumference, and triceps skin fold thickness); 6-minute walk distance, and the Medical Outcomes Short-Form 36 health-related quality of life survey. During their hospitalization, survivors also had detailed daily evaluation of critical illness and related treatment variables. Over one third of survivors had objective evidence of muscle weakness at hospital discharge, with most improving within 12 months. This weakness was associated with substantial impairments in physical function and health-related quality of life that persisted at 24 months. The duration of bed rest during critical illness was consistently associated with weakness throughout 24-month follow-up. The cumulative dose of systematic corticosteroids and use of neuromuscular blockers in the ICU were not associated with weakness. CONCLUSIONS: Muscle weakness is common after acute lung injury, usually recovering within 12 months. This weakness is associated with substantial impairments in physical function and health-related quality of life that continue beyond 24 months. These results provide valuable prognostic information regarding physical recovery after acute lung injury. Evidence-based methods to reduce the duration of bed rest during critical illness may be important for improving these long-term impairments.

Tuberculosis control in a socially vulnerable area: a community intervention beyond DOT in a Brazilian favela. (2013). Soares EC., Vollmer WM., Cavalcante SC., Pacheco AG., Saraceni V., Silva JS., Neves GR., Golub JE., Efron AR., Durovni B., Chaisson RE, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 17, 1581-6

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OBJECTIVES: To evaluate the population-based impact of a comprehensive intervention to strengthen tuberculosis (TB) control in Rocinha, the largest urban slum in Rio de Janeiro, Brazil. DESIGN: In July 2003, 40 lay persons were hired and trained as community health workers to supervise treatment, implement educational activities and establish a supportive social network for anti-tuberculosis treatment. Between July 2005 and June 2008, a door-to-door active case finding campaign was conducted. Data were obtained from the Brazilian National Reporting System, which collects information from the TB notification form for every reported case. RESULTS: Between January 2001 and December 2008, 2623 TB cases were reported, 852 before and 1771 after the start of the program. Following the intervention, treatment success rates increased (67.6% vs. 83.2%, P < 0.001) and default rates dropped (17.8% vs. 5.5%, P < 0.001). Compared to the pre-intervention period, the TB case rate declined by an average of 39 cases per 100,000 population per 6 months (P = 0.003) in the post-intervention period, although this may have been due to secular trends already in place at the start of the intervention. Case rates declined from 591/100,000 in 2001 to 496/100,000 in 2008. CONCLUSION: With proper planning and effective community involvement, a successful intervention can lead to high cure rates and may contribute to a decrease in TB notification rates.

Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial. (2013). Theron G., Zijenah L., Chanda D., Clowes P., Rachow A., Lesosky M., Bara W., Mungofa S., Pai M., Hoelscher M., Dowdy D., Pym A., Mwaba P., Mason P., Peter J., Dheda K, Lancet (London, England), 383, 424-35

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BACKGROUND: The Xpert MTB/RIF test for tuberculosis is being rolled out in many countries, but evidence is lacking regarding its implementation outside laboratories, ability to inform same-day treatment decisions at the point of care, and clinical effect on tuberculosis-related morbidity. We aimed to assess the feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing at primary-care health-care facilities in southern Africa. METHODS: In this pragmatic, randomised, parallel-group, multicentre trial, we recruited adults with symptoms suggestive of active tuberculosis from five primary-care health-care facilities in South Africa, Zimbabwe, Zambia, and Tanzania. Eligible patients were randomly assigned using pregenerated tables to nurse-performed Xpert MTB/RIF at the clinic or sputum smear microscopy. Participants with a negative test result were empirically managed according to local WHO-compliant guidelines. Our primary outcome was tuberculosis-related morbidity (measured with the TBscore and Karnofsky performance score [KPS]) in culture-positive patients who had begun anti-tuberculosis treatment, measured at 2 months and 6 months after randomisation, analysed by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT01554384. FINDINGS: Between April 12, 2011, and March 30, 2012, we randomly assigned 758 patients to smear microscopy (182 culture positive) and 744 to Xpert MTB/RIF (185 culture positive). Median TBscore in culture-positive patients did not differ between groups at 2 months (2 [IQR 0-3] in the smear microscopy group vs 2 [0.25-3] in the MTB/RIF group; p=0.85) or 6 months (1 [0-3] vs 1 [0-3]; p=0.35), nor did median KPS at 2 months (80 [70-90] vs 90 [80-90]; p=0.23) or 6 months (100 [90-100] vs 100 [90-100]; p=0.85). Point-of-care MTB/RIF had higher sensitivity than microscopy (154 [83%] of 185 vs 91 [50%] of 182; p=0.0001) but similar specificity (517 [95%] 544 vs 540 [96%] of 560; p=0.25), and had similar sensitivity to laboratory-based MTB/RIF (292 [83%] of 351; p=0.99) but higher specificity (952 [92%] of 1037; p=0.0173). 34 (5%) of 744 tests with point-of-care MTB/RIF and 82 (6%) of 1411 with laboratory-based MTB/RIF failed (p=0.22). Compared with the microscopy group, more patients in the MTB/RIF group had a same-day diagnosis (178 [24%] of 744 vs 99 [13%] of 758; p<0.0001) and same-day treatment initiation (168 [23%] of 744 vs 115 [15%] of 758; p=0.0002). Although, by end of the study, more culture-positive patients in the MTB/RIF group were on treatment due to reduced dropout (15 [8%] of 185 in the MTB/RIF group did not receive treatment vs 28 [15%] of 182 in the microscopy group; p=0.0302), the proportions of all patients on treatment in each group by day 56 were similar (320 [43%] of 744 in the MTB/RIF group vs 317 [42%] of 758 in the microscopy group; p=0.6408). INTERPRETATION: Xpert MTB/RIF can be accurately administered by a nurse in primary-care clinics, resulting in more patients starting same-day treatment, more culture-positive patients starting therapy, and a shorter time to treatment. However, the benefits did not translate into lower tuberculosis-related morbidity, partly because of high levels of empirical-evidence-based treatment in smear-negative patients. FUNDING: European and Developing Countries Clinical Trials Partnership, National Research Foundation, and Claude Leon Foundation.

- October 2013 -

Population-level impact of active tuberculosis case finding in an Asian megacity. (2013). Dowdy DW., Lotia I., Azman AS., Creswell J., Sahu S., Khan AJ, PloS one, 8, e77517

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BACKGROUND: The potential population-level impact of private-sector initiatives for tuberculosis (TB) case finding in Southeast Asia remains uncertain. In 2011, the Indus Hospital TB Control Program in Karachi, Pakistan, undertook an aggressive case-finding campaign that doubled notification rates, providing an opportunity to investigate potential population-level effects. METHODS: We constructed an age-structured compartmental model of TB in the intervention area. We fit the model using field and literature data, assuming that TB incidence equaled the estimated nationwide incidence in Pakistan (primary analysis), or 1.5 times greater (high-incidence scenario). We modeled the intervention as an increase in the rate of formal-sector TB diagnosis and evaluated the potential impact of sustaining this rate for five years. RESULTS: In the primary analysis, the five-year intervention averted 24% (95% uncertainty range, UR: 18-30%) of five-year cumulative TB cases and 52% (95% UR: 45-57%) of cumulative TB deaths. Corresponding reductions in the high-incidence scenario were 12% (95% UR: 8-17%) and 27% (95% UR: 21-34%), although the absolute number of lives saved was higher. At the end of five years, TB notification rates in the primary analysis were below their 2010 baseline, incidence had dropped by 45%, and annual mortality had fallen by 72%. About half of the cumulative impact on incidence and mortality could be achieved with a one-year intervention. CONCLUSIONS: Sustained, multifaceted, and innovative approaches to TB case-finding in Asian megacities can have substantial community-wide epidemiological impact.

Clostridium difficile carriage and serum antitoxin responses in children with inflammatory bowel disease. (2013). Hourigan SK., Chirumamilla SR., Ross T., Golub JE., Rabizadeh S., Saeed SA., Elson CO., Kelly CP., Carroll KC., Oliva-Hemker M., Sears C, Inflammatory bowel diseases, 19, 2744-52

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BACKGROUND: Adults with inflammatory bowel disease (IBD) have a high prevalence of Clostridium difficile carriage, but little data exist regarding pediatric patients with IBD. Serum antibody responses to C. difficile toxins in correlation with organism carriage are not described in IBD. This study determines the prevalence of C. difficile carriage and compares serum antibody responses to C. difficile toxins in pediatric outpatients with IBD and controls. METHODS: Fecal and serum samples were prospectively collected from pediatric outpatients with IBD (n = 85) and age-matched controls (n = 78). Initial and follow-up stool samples were tested using cytotoxigenic C. difficile culture and PCR to detect the toxin B gene. Pulsed-field gel electrophoresis determined the strain type. Enzyme-linked immunosorbent assay determined serum immunoglobulin responses to C. difficile toxins. RESULTS: Asymptomatic C. difficile carriage was significantly greater in IBD (17%) versus controls (3%) (P = 0.012). IBD type, disease severity, IBD therapy, recent antibiotics, and hospitalizations were not associated with carriage. Proton pump inhibitor use was significantly higher in patients with C. difficile carriage (54% versus 25%, P < 0.05). North American pulsed-field (NAP) strain carriage varied over time in patients colonized with C. difficile. A significantly greater proportion of patients with IBD had a positive serum antibody response to toxin A (69%) compared with controls (53%) (P < 0.05). CONCLUSIONS: Asymptomatic toxigenic C. difficile carriage was increased in pediatric outpatients with IBD compared with controls. Proton pump inhibitor use was associated with increased carriage. Antibody responses to C. difficile toxins were increased in IBD, potentially promoting asymptomatic colonization. Future studies should identify the risk factors for symptomatic C. difficile in pediatric IBD.

AIDS-related Kaposi's sarcoma in Brazil: trends and geopolitical distribution. (2013). Saraceni V., Talhari CC., Pereira GF., Golub JE., Talhari S., Miranda AE, International journal of dermatology, 52, 1525-9

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BACKGROUND: AIDS-related Kaposi's sarcoma (KS) is a unique model of the relationship between viral infection, immunity, environmental, and genetic factors in viral cancers. The goal was to determine the distribution of KS cases among Brazilian geopolitical regions, looking at the ecological relationship with median CD4 cell count. METHODS: Ecological study using Brazilian National Diseases Reporting Databases: 1982-2009. Subjects >/= 13 years of age who have KS cited in their AIDS reporting form were selected, and demographic and HIV exposure data were collected. RESULTS: We found 11,731 KS cases in the period, with a prevalence of 2.4% among AIDS cases; 88% were male, and 68% lived in the Southeast region, which accounted for 59% of AIDS cases. The regional and national prevalence trends were similar, although the highest proportion among women was found in the North region, which has the lowest number of both AIDS and KS cases. Heterosexual transmission accounted for 87% of HIV among women compared to 18% among men. Fifty-seven percent of all KS cases were diagnosed before antiretroviral therapy (ART). Injection drug use accounted for 11% of KS cases. Median survival was 472 days before the ART era and 1482 after it (P < 0.001). Median CD4 counts increased in all regions in the period as ART coverage expanded, and a resulting correlating decline in KS cases was observed. CONCLUSIONS: Prevalence of KS declined after the introduction of ART in all regions of Brazil, suggesting individual protection conveyed by ART.

Modeling the impact of alternative strategies for rapid molecular diagnosis of tuberculosis in Southeast Asia. (2013). Sun AY., Pai M., Salje H., Satyanarayana S., Deo S., Dowdy DW, American journal of epidemiology, 178, 1740-9

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Novel diagnostic tests hold promise for improving tuberculosis (TB) control, but their epidemiologic impact remains uncertain. Using data from the World Health Organization (2011-2012), we developed a transmission model to evaluate the deployment of 3 hypothetical TB diagnostic tests in Southeast Asia under idealized scenarios of implementation. We defined diagnostics by their sensitivity for smear-negative TB and proportion of patients testing positive who initiate therapy ("point-of-care amenability"), with tests of increasing point-of-care amenability having lower sensitivity. Implemented in the public sector (35% of care-seeking attempts), each novel test reduced TB incidence by 7%-9% (95% uncertainty range: 4%-13%) and mortality by 20%-22% (95% uncertainty range: 14%-27%) after 10 years. If also deployed in the private sector (65% of attempts), these tests reduced incidence by 13%-16%, whereas a perfect test (100% sensitivity and treatment initiation) reduced incidence by 20%. Annually detecting 20% of prevalent TB cases through targeted screening (70% smear-negative sensitivity, 85% treatment initiation) also reduced incidence by 19%. Sensitivity and point-of-care amenability are equally important considerations when developing novel diagnostic tests for TB. Novel diagnostics can substantially reduce TB incidence and mortality in Southeast Asia but are unlikely to transform TB control unless they are deployed actively and in the private sector.

- September 2013 -

Fever is associated with delayed ventilator liberation in acute lung injury. (2013). Netzer G., Dowdy DW., Harrington T., Chandolu S., Dinglas VD., Shah NG., Colantuoni E., Mendez-Tellez PA., Shanholtz C., Hasday JD., Needham DM, Annals of the American Thoracic Society, 10, 608-15

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BACKGROUND: Acute lung injury (ALI) is characterized by inflammation, leukocyte activation, neutrophil recruitment, endothelial dysfunction, and epithelial injury, which are all affected by fever. Fever is common in the intensive care unit, but the relationship between fever and outcomes in ALI has not yet been studied. We evaluated the association of temperature dysregulation with time to ventilator liberation, ventilator-free days, and in-hospital mortality. METHODS: Analysis of a prospective cohort study, which recruited consecutive patients with ALI from 13 intensive care units at four hospitals in Baltimore, Maryland. The relationship of fever and hypothermia with ventilator liberation was assessed with a Cox proportional hazards model. We evaluated the association of temperature during the first 3 days after ALI with ventilator-free days, using multivariable linear regression models, and the association with mortality was evaluated by robust Poisson regression. MEASUREMENTS AND MAIN RESULTS: Of 450 patients, only 12% were normothermic during the first 3 days after ALI onset. During the first week post-ALI, each additional day of fever resulted in a 33% reduction in the likelihood of successful ventilator liberation (95% confidence interval [CI] for adjusted hazard ratio, 0.57 to 0.78; P < 0.001). Hypothermia was independently associated with decreased ventilator-free days (hypothermia during each of the first 3 d: reduction of 5.58 d, 95% CI: -9.04 to -2.13; P = 0.002) and increased mortality (hypothermia during each of the first 3 d: relative risk, 1.68; 95% CI, 1.06 to 2.66; P = 0.03). CONCLUSIONS: Fever and hypothermia are associated with worse clinical outcomes in ALI, with fever being independently associated with delayed ventilator liberation.

From Fort Lee to Phnom Penh: a journey of self-discovery. (2013). Golub JE., Diament-Golub J, Journal of the New Jersey Dental Association, 84, 24-5

- August 2013 -

Effect of improved tuberculosis screening and isoniazid preventive therapy on incidence of tuberculosis and death in patients with HIV in clinics in Rio de Janeiro, Brazil: a stepped wedge, cluster-randomised trial. (2013). Durovni B., Saraceni V., Moulton LH., Pacheco AG., Cavalcante SC., King BS., Cohn S., Efron A., Chaisson RE., Golub JE, The Lancet. Infectious diseases, 13, 852-8

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BACKGROUND: Preventive therapy for tuberculosis in patients with HIV is effective, but it has not been widely implemented in moderate or high-burden settings. We assessed the effect of widespread use of isoniazid preventive therapy on rates of tuberculosis and death in people with HIV in Brazil. METHODS: We did a stepped wedge, cluster-randomised trial with patients actively enrolled in 29 HIV clinics in Rio de Janeiro. Clinic staff were trained in tuberculosis screening, use of tuberculin skin tests, and use of isoniazid preventive therapy. Clinics were randomly allocated a date to begin the intervention period, with two clinics beginning the intervention every 2 months starting from Sept 1, 2005. The primary outcome was tuberculosis incidence alone or combined with death in the control versus intervention periods until Aug 31, 2009. This trial is registered at ClinicalTrials.gov, number NCT00107887. RESULTS: Of 17,413 patients in the cohort, 12,816 were eligible for the intervention. Overall, there were 475 tuberculosis cases and 838 deaths. The intervention increased the rate of patients receiving skin tests from 19 per 100 person-years to 59 per 100 person-years, and from 36 per 100 person-years to 144 per 100 person-years for those eligible for isoniazid preventive therapy. In the control period, 221 cases of tuberculosis were diagnosed (1.31 per 100 person-years) compared with 254 (1.10 per 100 person-years) in the intervention period (unadjusted hazard ratio [HR] 0.87; 95% CI 0.69-1.10). Rates of tuberculosis incidence or death were 3.64 and 3.04 per 100 person-years, respectively (0.76; 95% CI 0.66-0.87). When adjusted for age, sex, entry CD4 count, and use of antiretroviral therapy, the HR for tuberculosis was 0.73 (95% CI 0.54-0.99) and for tuberculosis or death was 0.69 (0.57-0.83). INTERPRETATION: Operational training aimed at increasing tuberculosis screening, provision of tuberculin skin tests, and use of isoniazid preventive therapy in Brazilian HIV clinics significantly reduced incident tuberculosis and death. Thus, scale-up of preventive therapy for HIV-infected patients in settings of moderate tuberculosis incidence is achievable and should be widely implemented in Brazil and elsewhere. FUNDING: Bill & Melinda Gates Foundation and the National Institutes of Health.

Population-level impact of same-day microscopy and Xpert MTB/RIF for tuberculosis diagnosis in Africa. (2013). Dowdy DW., Davis JL., den Boon S., Walter ND., Katamba A., Cattamanchi A, PloS one, 8, e70485

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OBJECTIVE: To compare the population-level impact of two World Health Organization-endorsed strategies for improving the diagnosis of tuberculosis (TB): same-day microscopy and Xpert MTB/RIF (Cepheid, USA). METHODS: We created a compartmental transmission model of TB in a representative African community, fit to the regional incidence and mortality of TB and HIV. We compared the population-level reduction in TB burden over ten years achievable with implementation over two years of same-day microscopy, Xpert MTB/RIF testing, and the combination of both approaches. FINDINGS: Same-day microscopy averted an estimated 11.0% of TB incidence over ten years (95% uncertainty range, UR: 3.3%-22.5%), and prevented 11.8% of all TB deaths (95% UR: 7.7%-27.1%). Scaling up Xpert MTB/RIF to all centralized laboratories to achieve 75% population coverage had similar impact on incidence (9.3% reduction, 95% UR: 1.9%-21.5%) and greater effect on mortality (23.8% reduction, 95% UR: 8.6%-33.4%). Combining the two strategies (i.e., same-day microscopy plus Xpert MTB/RIF) generated synergistic effects: an 18.7% reduction in incidence (95% UR: 5.6%-39.2%) and 33.1% reduction in TB mortality (95% UR: 18.1%-50.2%). By the end of year ten, combining same-day microscopy and Xpert MTB/RIF could reduce annual TB mortality by 44% relative to the current standard of care. CONCLUSION: Scaling up novel diagnostic tests for TB and optimizing existing ones are complementary strategies that, when combined, may have substantial impact on TB epidemics in Africa.

The eye of the beholder: tuberculosis screening for elderly long-term care residents. (2013). Schwartzman K., Dowdy D, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 17, 1121

Analysis of latent tuberculosis infection treatment adherence among refugees and other patient groups referred to the Baltimore City Health Department TB clinic, February 2009-March 2011. (2013). Nuzzo JB., Golub JE., Chaulk P., Shah M, Journal of immigrant and minority health, 17, 56-65

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We sought to determine the proportion of refugee patients at the Baltimore City Health Department Tuberculosis program (BCHD-TB) successfully completing latent tuberculosis infection (LTBI) treatment, as compared to other referral groups, and to identify factors associated with treatment completion. We completed a retrospective cohort analysis of individuals referred to BCHD-TB program for LTBI care between February 1, 2009 and March 31, 2011. Among 841 patients evaluated by BCHD-TB and diagnosed with LTBI, 81% of refugees, 50% of non-refugee foreign-born, and 35% of US-born patients completed LTBI treatment. In multivariate analysis, refugees had greater odds of LTBI treatment completion (Adjusted Odds Ratio 7.2; 95% CI 4.2-12.4, p < 0.001) compared to US-born individuals adjusting for age, gender, and treatment regimen. Overall, LTBI treatment completion remains suboptimal. At BCHD-TB, LTBI treatment completion was significantly higher among refugees than other referral groups. Additional efforts are needed to optimize LTBI care, and future efforts may need to be tailored for different risk groups.

- July 2013 -

Prevalence of tobacco smoking in adults with tuberculosis in South Africa. (2013). Lam C., Martinson N., Hepp L., Ambrose B., Msandiwa R., Wong ML., Apelberg B., Tamplin S., Golub JE, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 17, 1354-7

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We conducted a tobacco prevalence survey among 707 in-patients diagnosed with tuberculosis (TB) at the Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. Current smoking status was expanded to include both patients who self-reported at the time of TB diagnosis and patients who stopped smoking in the 2-month period before diagnosis. Six per cent reported current smoking at the time of TB diagnosis, 26% within 2 months before TB diagnosis. Human immunodeficiency virus status (73% positive) was not associated with current smoking. Classifying current smoking status among newly diagnosed TB patients should be extended to include smoking at time of the onset of TB symptoms.

- June 2013 -

Understanding the disparity: predictors of virologic failure in women using highly active antiretroviral therapy vary by race and/or ethnicity. (2013). McFall AM., Dowdy DW., Zelaya CE., Murphy K., Wilson TE., Young MA., Gandhi M., Cohen MH., Golub ET., Althoff KN, Journal of acquired immune deficiency syndromes (1999), 64, 289-98

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BACKGROUND: Stark racial/ethnic disparities in health outcomes exist among those living with HIV in the United States. One of 3 primary goals of the National HIV/AIDS Strategy is to reduce HIV-related disparities and health inequities. METHODS: Using data from HIV-infected women participating in the Women's Interagency HIV Study from April 2006 to March 2011, we measured virologic failure (HIV RNA >200 copies/mL) after suppression (HIV RNA < 80 copies/mL) on highly active antiretroviral therapy. We identified predictors of virologic failure using discrete time survival analysis and calculated racial/ethnic-specific population-attributable fractions (PAFs). RESULTS: Of 887 eligible women, 408 (46%) experienced virologic failure during the study period. Hispanic and white women had significantly lower hazards of virologic failure than African American women [Hispanic hazard ratio, (HR) = 0.8, 95% confidence interval: (0.6 to 0.9); white HR = 0.7 (0.5 to 0.9)]. The PAF of virologic failure associated with low income was higher in Hispanic [adjusted hazard ratios (aHR) = 2.2 (0.7 to 6.5), PAF = 49%] and African American women [aHR = 1.8 (1.1 to 3.2), PAF = 38%] than among white women [aHR = 1.4 (0.6 to 3.4), PAF = 16%]. Lack of health insurance compared with public health insurance was associated with virologic failure only among Hispanic [aHR = 2.0 (0.9 to 4.6), PAF = 22%] and white women [aHR = 1.9 (0.7 to 5.1), PAF = 13%]. By contrast, depressive symptoms were associated with virologic failure only among African-American women [aHR = 1.6 (1.2 to 2.2), PAF = 17%]. CONCLUSIONS: In this population of treated HIV-infected women, virologic failure was common, and correlates of virologic failure varied by race/ethnicity. Strategies to reduce disparities in HIV treatment outcomes by race/ethnicity should address racial/ethnic-specific barriers including depression and low income to sustain virologic suppression.

Challenges in evaluating the cost-effectiveness of new diagnostic tests for HIV-associated tuberculosis. (2013). Andrews JR., Lawn SD., Dowdy DW., Walensky RP, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 57, 1021-6

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With an emerging array of rapid diagnostic tests for tuberculosis, cost-effectiveness analyses are needed to inform scale-up in various populations and settings. Human immunodeficiency virus (HIV)-associated tuberculosis poses unique challenges in estimating and interpreting the cost-effectiveness of novel diagnostic tools. First, gains in sensitivity and specificity do not directly correlate with impact on clinical outcomes. Second, the cost-effectiveness of implementing tuberculosis diagnostics in HIV-infected populations is heavily influenced by downstream costs of HIV care. As a result, tuberculosis diagnostics may appear less cost-effective in this population than among HIV-uninfected individuals, raising important ethical and policy questions about the design and interpretation of cost-effectiveness analyses in this setting. Third, conventional cost-effectiveness benchmarks may be inadequate for making decisions about whether to adopt new diagnostics. If we are to appropriately deploy novel diagnostics for tuberculosis to people living with HIV in resource-constrained settings, these challenges in measuring cost-effectiveness must be more widely recognized and addressed.

Economic evaluations of point of care testing strategies for active tuberculosis. (2013). Zwerling A., Dowdy D, Expert review of pharmacoeconomics & outcomes research, 13, 313-25

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Point of care (POC) diagnostics are often hailed as having the potential to transform tuberculosis (TB) control efforts. However, POC testing is better conceptualized as a system of diagnosis and treatment, not simply a test that can provide rapid, deployable results. Economic evaluations may help decision makers allocate scarce resources for TB control, but evaluations of POC testing face unique challenges that include evaluating the full diagnostic system, incorporating implementation costs, translating diagnostic results into health and accounting for downstream treatment costs. For economic evaluations to reach their full potential as decision-making tools for POC testing in TB, these challenges must be understood and addressed.

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