TB Modeling and Translational Epi Group

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- August 2019 -

Tuberculosis fatality rates in the city of Campinas - São Paulo, Brazil, from 2001 to 2009. (2019). Oliveira HB., Marin-Léon L., Saita NM., Golub JE, Revista brasileira de epidemiologia = Brazilian journal of epidemiology, 22, e190043

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INTRODUCTION: The mortality rate among tuberculosis patients (TB fatality) has been attributed to irregular chemotherapy, delay in diagnosis, multidrug resistance, and HIV coinfection. OBJECTIVE: To analyze TB fatality rates by sex, clinical presentation and HIV coinfection in Campinas, São Paulo, Brazil. METHODS: Cohorts of residents in the city of Campinas who either died during treatment for tuberculosis or had the disease confirmed after death were divided into three intervals: 2001-2003, 2004-2006, and 2007-2009. Data were obtained from the database of the Tuberculosis Surveillance System of the University of Campinas, and notifications were gathered through TB-WEB Health São Paulo Secretary. Statistical significance was determined using a chi-square test, considering p < 0.05. RESULTS: Between 2001 and 2009, 3,416 TB patients were diagnosed: 2,827 (82.8%) were new TB cases and 589 (17.2%) were retreatments. Between the first and second triennium, the number of new patients decreased by 18%, and 23% among retreatments. Between the second and third intervals, the reduction was 5% and 21%, respectively. General case fatality rate declined from 11.4% to 9.9% across intervals, and was most significant among patients that had previously abandoned treatment (17.3% to 5.1%). Fatality rates among patients coinfected with TB-AIDS were 2-3 times that of patients not infected with TB-AIDS throughout the intervals. Fatality between the first and third triennium among TB-AIDS co-infected patients declined (24.8% to 19.5%), while increasing slightly among non-AIDS TB patients (7.3% to 8%) during this period. CONCLUSION: Though mortality among TB-AIDS patients declined from 2001-2009, rates among non-AIDS TB remained stagnant. Improved TB diagnosis and treatment is needed to further decrease TB mortality in Campinas.

Mobile phone access and comfort: implications for HIV and tuberculosis care in India and South Africa. (2019). Cox SN., Elf JL., Lokhande R., Ogale YP., DiAndreth L., Dupuis E., Milovanovic M., Mpungose N., Mave V., Suryavanshi N., Gupta A., Martinson N., Golub JE., Mathad JS, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 865-872

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SETTING: India and South Africa shoulder the greatest burden of tuberculosis (TB) and human immunodeficiency virus (HIV) infection respectively, but care retention is suboptimal.OBJECTIVE: We conducted a study in Pune, India, and Matlosana, South Africa, 1) to identify the factors associated with mobile phone access and comfort of use, 2) to assess access patterns.DESIGN: A cross-sectional study assessed mobile phone access, and comfort; a longitudinal study assessed access patterns.RESULTS: We enrolled 261 participants: 136 in India and 125 in South Africa. Between 1 week and 6 months, participant contact decreased from 90% (n = 122) to 57% (n = 75) in India and from 93% (n = 116) to 70% (n = 88) in South Africa. In the latter, a reason for a clinic visit for HIV management was associated with 63% lower odds of contact than other priorities (e.g., diabetes mellitus, maternal health, TB). In India, 57% (n = 78) reported discomfort with texting; discomfort was higher in the unemployed (adjusted OR [aOR] 4.97, 95%CI 1.12-22.09) and those aged ≥35 years (aOR 1.10, 95%CI 1.04-1.16) participants, but lower in those with higher education (aOR 0.04, 95% CI 0.01-1.14). In South Africa, 91% (n = 114) reported comfort with texting.CONCLUSION: Mobile phone contact was poor at 6 months. While mHealth could transform TB-HIV care, alternative approaches may be needed for certain subpopulations.

Informing decision-making for universal access to quality tuberculosis diagnosis in India: an economic-epidemiological model. (2019). Sohn H., Kasaie P., Kendall E., Gomez GB., Vassall A., Pai M., Dowdy D, BMC medicine, 17, 155

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BACKGROUND: India and many other high-burden countries have committed to providing universal access to high-quality diagnosis and drug susceptibility testing (DST) for tuberculosis (TB), but the most cost-effective approach to achieve this goal remains uncertain. Centralized testing at district-level hub facilities with a supporting sample transport network can generate economies of scale, but decentralization to the peripheral level may provide faster diagnosis and reduce losses to follow-up (LTFU). METHODS: We generated functions to evaluate the costs of centralized and decentralized molecular testing for tuberculosis with Xpert MTB/RIF (Xpert), a WHO-endorsed test which can be performed at centralized and decentralized levels. We merged the cost estimates with an agent-based simulation of TB transmission in a hypothetical representative region in India to assess the impact and cost-effectiveness of each strategy. RESULTS: Compared against centralized Xpert testing, decentralization was most favorable when testing volume at decentralized facilities and pre-treatment LTFU were high, and specimen transport network was exclusively established for TB. Assuming equal quality of centralized and decentralized testing, decentralization was cost-saving, saving a median $338,000 (interquartile simulation range [IQR] - $222,000; $889,000) per 20 million people over 10 years, in the most cost-favorable scenario. In the most cost-unfavorable scenario, decentralized testing would cost a median $3161 [IQR $2412; $4731] per disability-adjusted life year averted relative to centralized testing. CONCLUSIONS: Decentralization of Xpert testing is likely to be cost-saving or cost-effective in most settings to which these simulation results might generalize. More decentralized testing is more cost-effective in settings with moderate-to-high peripheral testing volumes, high existing clinical LTFU, inability to share specimen transport costs with other disease entities, and ability to ensure high-quality peripheral Xpert testing. Decision-makers should assess these factors when deciding whether to decentralize molecular testing for tuberculosis.

Home-based tuberculosis contact investigation in Uganda: a household randomised trial. (2019). Davis JL., Turimumahoro P., Meyer AJ., Ayakaka I., Ochom E., Ggita J., Mark D., Babirye D., Okello DA., Mugabe F., Fair E., Vittinghoff E., Armstrong-Hough M., Dowdy D., Cattamanchi A., Haberer JE., Katamba A, ERJ open research, 5

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INTRODUCTION: The World Health Organization (WHO) recommends household tuberculosis (TB) contact investigation in low-income countries, but most contacts do not complete a full clinical and laboratory evaluation. METHODS: We performed a randomised trial of home-based, SMS-facilitated, household TB contact investigation in Kampala, Uganda. Community health workers (CHWs) visited homes of index patients with pulmonary TB to screen household contacts for TB. Entire households were randomly allocated to clinic (standard-of-care) or home (intervention) evaluation. In the intervention arm, CHWs offered HIV testing to adults; collected sputum from symptomatic contacts and persons living with HIV (PLWHs) if ≥5 years; and transported sputum for microbiologic testing. CHWs referred PLWHs, children <5 years, and anyone unable to complete sputum testing to clinic. Sputum testing results and/or follow-up instructions were returned by automated SMS texts. The primary outcome was completion of a full TB evaluation within 14 days; secondary outcomes were TB and HIV diagnoses and treatments among screened contacts. RESULTS: There were 471 contacts of 190 index patients allocated to the intervention and 448 contacts of 182 index patients allocated to the standard-of-care. CHWs identified 190/471 (40%) intervention and 213/448 (48%) standard-of-care contacts requiring TB evaluation. In the intervention arm, CHWs obtained sputum from 35/91 (39%) of sputum-eligible contacts and SMSs were sent to 95/190 (50%). Completion of TB evaluation in the intervention and standard-of-care arms at 14 days (14% versus 15%; difference -1%, 95% CI -9% to 7%, p=0.81) and yields of confirmed TB (1.5% versus 1.1%, p=0.62) and new HIV (2.0% versus 1.8%, p=0.90) diagnoses were similar. CONCLUSIONS: Home-based, SMS-facilitated evaluation did not improve completion or yield of household TB contact investigation, likely due to challenges delivering the intervention components.

Smoking, alcohol use disorder and tuberculosis treatment outcomes: A dual co-morbidity burden that cannot be ignored. (2019). Thomas BE., Thiruvengadam K., S R., Kadam D., Ovung S., Sivakumar S., Bala Yogendra Shivakumar SV., Paradkar M., Gupte N., Suryavanshi N., Dolla CK., Gupte AN., Kohli R., Pradhan N., Sivaramakrishnan GN., Gaikwad S., Kagal A., Dhanasekaran K., Deluca A., Golub JE., Mave V., Chandrasekaran P., Gupta A, PloS one, 14, e0220507

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BACKGROUND: More than 20% of tuberculosis (TB) disease worldwide may be attributable to smoking and alcohol abuse. India is the second largest consumer of tobacco products, a major consumer of alcohol particularly among males, and has the highest burden of TB globally. The impact of increasing tobacco dose, relevance of alcohol misuse and past versus current or never smoking status on TB treatment outcomes remain inadequately defined. METHODS: We conducted a multi-centric prospective cohort study of newly diagnosed adult pulmonary TB patients initiated on TB treatment and followed for a minimum of 6 months to assess the impact of smoking status with or without alcohol abuse on treatment outcomes. Smokers were defined as never smokers, past smokers or current smokers. Alcohol Use Disorder Identification Test (AUDIT) scores were used to assess alcohol misuse. The association between smoking status and treatment outcomes was assessed in univariate and multivariate random effects poisson regression models. RESULTS: Of 455 enrolled, 129 (28%) had a history of smoking with 94 (20%) current smokers and 35 (8%) past smokers. Unfavourable treatment outcomes were significantly higher among past and current smokers as compared to never smokers. Specifically, the risk of treatment failure was significantly higher among past smokers (aIRR = 2.66, 95% CI: 1.41-4.90, p = 0.002), recurrent TB among current smokers (aIRR = 2.94, 95% CI: 1.30-6.67, p = 0.010) and death among both past (2.63, 95% CI: 1.11-6.24, p = 0.028) and current (aIRR = 2.59, 95% CI: 1.29-5.18, p = 0.007) smokers. Furthermore, the combined effect of alcohol misuse and smoking on unfavorable treatment outcomes was significantly higher among past smokers (aIRR: 4.67, 95% CI: 2.17-10.02, p<0.001) and current smokers (aIRR: 3.58, 95% CI: 1.89-6.76, p<0.001). CONCLUSION: Past and current smoking along with alcohol misuse have combined effects on increasing the risk of unfavourable TB treatment outcomes. Innovative interventions that can readily address both co-morbidities are urgently needed.

Seventy Years of Tuberculosis Prevention: Efficacy, Effectiveness, Toxicity, Durability, and Duration. (2019). Salazar-Austin N., Dowdy DW., Chaisson RE., Golub JE, American journal of epidemiology, 188, 2078-2085

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Tuberculosis (TB) has been a leading infectious cause of death worldwide for much of human history, with 1.6 million deaths estimated in 2017. The Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health has played an important role in understanding and responding to TB, and it has made particularly substantial contributions to prevention of TB with chemoprophylaxis. TB preventive therapy is highly efficacious in the prevention of TB disease, yet it remains underutilized by TB programs worldwide despite strong evidence to support its use in high-risk groups, such as people living with HIV and household contacts, including those under 5 years of age. We review the evidence for TB preventive therapy and discuss the future of TB prevention.

- July 2019 -

Empiric treatment of pulmonary TB in the Xpert era: Correspondence of sputum culture, Xpert MTB/RIF, and clinical diagnoses. (2019). Kendall EA., Kamoga C., Kitonsa PJ., Nalutaaya A., Salvatore PP., Robsky K., Nakasolya O., Mukiibi J., Isooba D., Cattamanchi A., Kato-Maeda M., Katamba A., Dowdy DW, PloS one, 14, e0220251

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BACKGROUND: Clinical tuberculosis diagnosis and empiric treatment have traditionally been common among patients with negative bacteriologic test results. Increasing availability of rapid molecular diagnostic tests, including Xpert MTB/RIF and the new Xpert Ultra cartridge, may alter the role of empiric treatment. METHODS: We prospectively enrolled outpatients age > = 15 who were evaluated for pulmonary tuberculosis at three health facilities in Kampala, Uganda. Using sputum mycobacterial culture, interviews, and clinical record abstraction, we estimated the accuracy of clinical diagnosis relative to Xpert and sputum culture and assessed the contribution of clinical diagnosis to case detection. RESULTS: Over a period of 9 months, 99 patients were diagnosed with pulmonary tuberculosis and subsequently completed sputum culture; they were matched to 196 patients receiving negative tuberculosis evaluations in the same facilities. Xpert was included in the evaluation of 291 (99%) patients. Compared to culture, Xpert had a sensitivity of 92% (95% confidence interval 83-97%) and specificity of 95% (92-98%). Twenty patients with negative Xpert were clinically diagnosed with tuberculosis and subsequently had their culture status determined; two (10%) were culture-positive. Considering all treated patients regardless of Xpert and culture data completeness, and considering treatment initiations before a positive Xpert (N = 4) to be empiric, 26/101 (26%) tuberculosis treatment courses were started empirically. Compared to sputum smear- or Xpert-positive patients with positive cultures, empirically-treated, Xpert-negative patients with negative cultures had higher prevalence of HIV (67% versus 37%), shorter duration of cough (median 4 versus 8 weeks), and lower inflammatory markers (median CRP 7 versus 101 mg/L). CONCLUSION: Judged against sputum culture in a routine care setting of high HIV prevalence, the accuracy of Xpert was high. Clinical judgment identified a small number of additional culture-positive cases, but with poor specificity. Although clinicians should continue to prescribe tuberculosis treatment for Xpert-negative patients whose clinical presentations strongly suggest pulmonary tuberculosis, they should also carefully consider alternative diagnoses.

Infection free "resisters" among household contacts of adult pulmonary tuberculosis. (2019). Mave V., Chandrasekaran P., Chavan A., Shivakumar SVBY., Danasekaran K., Paradkar M., Thiruvengadam K., Kinikar A., Murali L., Gaikwad S., Hanna LE., Kulkarni V., Pattabiraman S., Suryavanshi N., Thomas B., Kohli R., Sivaramakrishnan GN., Pradhan N., Bhanu B., Kagal A., Golub J., Gandhi N., Gupte A., Gupte N., Swaminathan S., Gupta A, PloS one, 14, e0218034

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Despite substantial exposure to infectious pulmonary tuberculosis (TB) cases, some household contacts (HHC) never acquire latent TB infection (LTBI). Characterizing these "resisters" can inform who to study immunologically for the development of TB vaccines. We enrolled HHCs of culture-confirmed adult pulmonary TB in India who underwent LTBI testing using tuberculin skin test (TST) and QuantiFERON TB Gold Test-in-tube (QFT-GIT) at baseline and, if negative by both (<5mm TST and <0.35IU/mL QFT-GIT), underwent follow-up testing at 4-6 and/or 12 months. We defined persons with persistently negative LTBI tests at both baseline and followup as pLTBI- and resisters as those who had a high exposure to TB using a published score and remained pLTBI-. We calculated the proportion of resisters overall and resisters with complete absence of response to LTBI tests (0mm TST and/or QFT-GIT <0.01 IU/ml). Using random effects Poisson regression, we assessed factors associated with pLTBI-. Of 799 HHCs in 355 households, 67 (8%) were pLTBI- at 12 months; 52 (6.5%) pLTBI- in 39 households were resisters. Complete absence of response to LTBI tests was found in 27 (53%) resisters. No epidemiological characteristics were associated with the pLTBI- phenotype. LTBI free resisters among HHC exist but are uncommon and are without distinguishing epidemiologic characteristics. Assessing the genetic and immunologic features of such resister individuals is likely to elucidate mechanisms of protective immunity to TB.

Formative research for an mHealth program to improve the HIV care continuum in South Africa. (2019). DiAndreth L., Krishnan N., Elf JL., Cox S., Tilchin C., Nthulana M., Jarrett B., Kronis N., Dupuis E., Motlhaoleng K., Chon S., Martinson N., Golub JE, AIDS care, 32, 744-748

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In South Africa, high attrition rates throughout the care continuum present major barriers to controlling the HIV epidemic. Mobile health (mHealth) interventions may provide innovative opportunities for efficient healthcare delivery and improving retention in care. In this formative research, we interviewed 11 patients and 28 healthcare providers in North West Province, South Africa, to identify perceived benefits, concerns and suggestions for a future mHealth program to deliver HIV Viral Load and CD4 Count test results directly to patients via mobile phone. Thematic analysis found that reduced workload for providers, reduced wait times for patients, potential expanded uses and patient empowerment were the main perceived benefits of an mHealth program. Perceived concerns included privacy, disseminating distressing results through text messages and patients' inability to interpret results. Participants felt that an mHealth program should complement face-to-face interactions and educational information to interpret results is needed. Providers identified logistical considerations and suggested protocols be developed. An mHealth program to deliver HIV test results directly to patients could mitigate multiple barriers to care but needs to be tested for efficacy. Concerns identified by patients and providers must be addressed in designing the program to successfully integrate with health facility workflow and ensure its sustainability.

High risk for latent tuberculosis infection among medical residents and nursing students in India. (2019). Kinikar A., Chandanwale A., Kadam D., Joshi S., Basavaraj A., Pardeshi G., Girish S., Shelke S., DeLuca A., Dhumal G., Golub J., Lokhande N., Gupte N., Gupta A., Bollinger R., Mave V, PloS one, 14, e0219131

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Defining occupational latent tuberculosis infection (LTBI) risk among healthcare workers is needed to support implementation of prevention guidelines. Prospective cohort study of 200 medical residents and nursing students in India was conducted May 2016-December 2017. Tuberculin skin test (TST) and QuantiFERON TB Gold Test-in-tube (QFT-GIT) were performed at study entry and 12 months. Primary outcome was incident LTBI (≥10mm TST induration and/or ≥0.35IU/mL QFT-GIT) at 12 months; secondary outcomes included baseline LTBI prevalence and risk factors for incident and prevalent LTBI using Poisson regression. Among 200, [90 nursing students and 110 medical residents], LTBI prevalence was 30% (95% CI, 24-37); LTBI incidence was 26.8 (95% CI, 18.6-37.2) cases per 100 person-years and differed by testing method (28.7 [95% CI, 20.6-38.9] vs 17.4 [95% CI, 11.5-25.4] cases per 100 person-years using TST and QFT-GIT, respectively). Medical residents had two-fold greater risk of incident LTBI than nursing students (Relative Risk, 2.16; 95% CI, 1.05-4.42). During study period 6 (3%) HCWs were diagnosed with active TB disease. Overall, median number of self-reported TB exposures was 5 (Interquartile Range, 1-15). Of 60 participants with prevalent and incident LTBI who were offered free isoniazid preventive therapy (IPT), only 2 participants initiated and completed IPT. High risk for LTBI was noted among medical residents compared to nursing students. Self-reported TB exposure is underreported, and uptake of LTBI prevention therapy remains low. New approaches are needed to identify HCWs at highest risk for LTBI.

- June 2019 -

A Systematic Review to Evaluate the Association between Clean Cooking Technologies and Time Use in Low- and Middle-Income Countries. (2019). Simkovich SM., Williams KN., Pollard S., Dowdy D., Sinharoy S., Clasen TF., Puzzolo E., Checkley W, International journal of environmental research and public health, 16

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Interventions implementing clean fuels to mitigate household air pollution in low- and middle-income countries have focused on environmental and health outcomes, but few have evaluated time savings. We performed a systematic review, searching for studies of clean fuel interventions that measured time use. A total of 868 manuscripts were identified that met the search criteria, but only 2 met the inclusion criteria. Both were cross-sectional and were conducted in rural India. The first surveyed the female head of household (141 using biogas and 58 using biomass) and reported 1.2 h saved per day collecting fuel and 0.7 h saved cooking, resulting in a combined 28.9 days saved over an entire year. The second surveyed the head of household (37 using biogas and 68 using biomass, 13% female) and reported 1.5 h saved per day collecting fuel, or 22.8 days saved over a year. Based on these time savings, we estimated that clean fuel use could result in a 3.8% or 4.7% increase in daily income, respectively, not including time or costs for fuel procurement. Clean fuel interventions could save users time and money. Few studies have evaluated this potential benefit, suggesting that prospective studies or randomized controlled trials are needed to adequately measure gains.

Impact and Effectiveness of State-Level Tuberculosis Interventions in California, Florida, New York, and Texas: A Model-Based Analysis. (2019). Shrestha S., Cherng S., Hill AN., Reynolds S., Flood J., Barry PM., Readhead A., Oxtoby M., Lauzardo M., Privett T., Marks SM., Dowdy DW, American journal of epidemiology, 188, 1733-1741

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The incidence of tuberculosis (TB) in the United States has stabilized, and additional interventions are needed to make progress toward TB elimination. However, the impact of such interventions depends on local demography and the heterogeneity of populations at risk. Using state-level individual-based TB transmission models calibrated to California, Florida, New York, and Texas, we modeled 2 TB interventions: 1) increased targeted testing and treatment (TTT) of high-risk populations, including people who are non-US-born, diabetic, human immunodeficiency virus (HIV)-positive, homeless, or incarcerated; and 2) enhanced contact investigation (ECI) for contacts of TB patients, including higher completion of preventive therapy. For each intervention, we projected reductions in active TB incidence over 10 years (2016-2026) and numbers needed to screen and treat in order to avert 1 case. We estimated that TTT delivered to half of the non-US-born adult population could lower TB incidence by 19.8%-26.7% over a 10-year period. TTT delivered to smaller populations with higher TB risk (e.g., HIV-positive persons, homeless persons) and ECI were generally more efficient but had less overall impact on incidence. TTT targeted to smaller, highest-risk populations and ECI can be highly efficient; however, major reductions in incidence will only be achieved by also targeting larger, moderate-risk populations. Ultimately, to eliminate TB in the United States, a combination of these approaches will be necessary.

Treatment of latent infection to achieve tuberculosis elimination in low-incidence countries. (2019). Campbell JR., Dowdy D., Schwartzman K, PLoS medicine, 16, e1002824

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In a Perspective for the Tuberculosis Special Issue, Kevin Schwartzman and colleagues discuss the choices and implications for personal versus public health benefits when pursuing tuberculosis elimination in low-incidence countries.

- May 2019 -

Reply to Chen, Song, and Liu. (2019). Hong H., Dowdy DW, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 70, 547-548

The economic case for typhoid conjugate vaccines in countries with medium and high incidence of infection. (2019). Jo Y., Dowdy DW, The Lancet. Infectious diseases, 19, 675-676

Assessment of lung function in successfully treated tuberculosis reveals high burden of ventilatory defects and COPD. (2019). Gupte AN., Paradkar M., Selvaraju S., Thiruvengadam K., Shivakumar SVBY., Sekar K., Marinaik S., Momin A., Gaikwad A., Natrajan P., Prithivi M., Shivaramakrishnan G., Pradhan N., Kohli R., Raskar S., Jain D., Velu R., Karthavarayan B., Lokhande R., Suryavanshi N., Gupte N., Murali L., Salvi S., Checkley W., Golub J., Bollinger R., Mave V., Padmapriyadarasini C., Gupta A, PloS one, 14, e0217289

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BACKGROUND: Burden, phenotype and risk-factors of lung function defects in successfully treated tuberculosis cases are unclear. METHODS: We performed spirometry with bronchodilators in new drug-sensitive adult (≥18 years) pulmonary tuberculosis cases during the 12 months following successful treatment in India. Airflow obstruction was defined as pre-bronchodilator FEV1/FVC<5th percentile of Global Lung Initiative mixed-ethnicity reference (lower limit of normal [LLN]). Chronic obstructive pulmonary disease (COPD) was defined as post-bronchodilator FEV1/FVC

Point of care Xpert MTB/RIF versus smear microscopy for tuberculosis diagnosis in southern African primary care clinics: a multicentre economic evaluation. (2019). Pooran A., Theron G., Zijenah L., Chanda D., Clowes P., Mwenge L., Mutenherwa F., Lecesse P., Metcalfe J., Sohn H., Hoelscher M., Pym A., Peter J., Dowdy D., Dheda K, The Lancet. Global health, 7, e798-e807

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BACKGROUND: Rapid on-site diagnosis facilitates tuberculosis control. Performing Xpert MTB/RIF (Xpert) at point of care is feasible, even when performed by minimally trained health-care workers, and when compared with point-of-care smear microscopy, reduces time to diagnosis and pretreatment loss to follow-up. However, whether Xpert is cost-effective at point of care remains unclear. METHODS: We empirically collected cost (US$, 2014) and clinical outcome data from participants presenting to primary health-care facilities in four African countries (South Africa, Zambia, Zimbabwe, and Tanzania) during the TB-NEAT trial. Costs were determined using an bottom-up ingredients approach. Effectiveness measures from the trial included number of cases diagnosed, initiated on treatment, and completing treatment. The primary outcome was the incremental cost-effectiveness of point-of-care Xpert relative to smear microscopy. The study was performed from the perspective of the health-care provider. FINDINGS: Using data from 1502 patients, we calculated that the mean Xpert unit cost was lower when performed at a centralised laboratory (Lab Xpert) rather than at point of care ($23·00 [95% CI 22·12-23·88] vs $28·03 [26·19-29·87]). Per 1000 patients screened, and relative to smear microscopy, point-of-care Xpert cost an additional $35 529 (27 054-40 025) and was associated with an additional 24·3 treatment initiations ([-20·0 to 68·5]; $1464 per treatment), 63·4 same-day treatment initiations ([27·3-99·4]; $511 per same-day treatment), and 29·4 treatment completions ([-6·9 to 65·6]; $1211 per completion). Xpert costs were most sensitive to test volume, whereas incremental outcomes were most sensitive to the number of patients initiating and completing treatment. The probability of point-of-care Xpert being cost-effective was 90% at a willingness to pay of $3820 per treatment completion. INTERPRETATION: In southern Africa, although point-of-care Xpert unit cost is higher than Lab Xpert, it is likely to offer good value for money relative to smear microscopy. With the current availability of point-of-care nucleic acid amplification platforms (eg, Xpert Edge), these data inform much needed investment and resource allocation strategies in tuberculosis endemic settings. FUNDING: European Union European and Developing Countries Clinical Trials Partnership.

What will it take to eliminate drug-resistant tuberculosis? (2019). Kendall EA., Sahu S., Pai M., Fox GJ., Varaine F., Cox H., Cegielski JP., Mabote L., Vassall A., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 535-546

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Drug-resistant tuberculosis (DR-TB) is challenging to diagnose, treat, and prevent, but this situation is slowly changing. If the world is to drastically reduce the incidence of DR-TB, we must stop creating new DR-TB as an essential first step. The DR-TB epidemic that is ongoing should also be directly addressed. First-line drug resistance must be rapidly detected using universal molecular testing for resistance to at least rifampin and, preferably, other key drugs at initial TB diagnosis. DR-TB treatment outcomes must also improve dramatically. Effective use of currently available, new, and repurposed drugs, combined with patient-centered treatment that aids adherence and reduces catastrophic costs, are essential. Innovations within sight, such as short, highly effective, broadly indicated regimens, paired with point-of-care drug susceptibility testing, could accelerate progress in treatment outcomes. Preventing or containing resistance to second-line and novel drugs is also critical and will require high-quality systems for diagnosis, regimen selection, and treatment monitoring. Finally, earlier detection and/or prevention of DR-TB is necessary, with particular attention to airborne infection control, case finding, and preventive therapy for contacts of patients with DR-TB. Implementing these strategies can overcome the barrier that DR-TB represents for global TB elimination efforts, and could ultimately make global elimination of DR-TB (fewer than one annual case per million population worldwide) attainable. There is a strong cost-effectiveness case to support pursuing DR-TB elimination; however, achieving this goal will require substantial global investment plus political and societal commitment at national and local levels.

Subtherapeutic Rifampicin Concentration Is Associated With Unfavorable Tuberculosis Treatment Outcomes. (2019). Ramachandran G., Chandrasekaran P., Gaikwad S., Agibothu Kupparam HK., Thiruvengadam K., Gupte N., Paradkar M., Dhanasekaran K., Sivaramakrishnan GN., Kagal A., Thomas B., Pradhan N., Kadam D., Hanna LE., Balasubramanian U., Kulkarni V., Murali L., Golub J., Gupte A., Shivakumar SVBY., Swaminathan S., Dooley KE., Gupta A., Mave V, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 70, 1463-1470

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BACKGROUND: The relationships between first-line drug concentrations and clinically important outcomes among patients with tuberculosis (TB) remain poorly understood. METHODS: We enrolled a prospective cohort of patients with new pulmonary TB receiving thrice-weekly treatment in India. The maximum plasma concentration of each drug was determined at months 1 and 5 using blood samples drawn 2 hours postdose. Subtherapeutic cutoffs were: rifampicin <8 µg/mL, isoniazid <3 µg/mL, and pyrazinamide <20 µg/mL. Factors associated with lower log-transformed drug concentrations, unfavorable outcomes (composite of treatment failure, all-cause mortality, and recurrence), and individual outcomes were examined using Poisson regression models. RESULTS: Among 404 participants, rifampicin, isoniazid, and pyrazinamide concentrations were subtherapeutic in 85%, 29%, and 13%, respectively, at month 1 (with similar results for rifampicin and isoniazid at month 5). Rifampicin concentrations were lower with human immunodeficiency virus coinfection (median, 1.6 vs 4.6 µg/mL; P = .015). Unfavorable outcome was observed in 19%; a 1-μg/mL decrease in rifampicin concentration was independently associated with unfavorable outcome (adjusted incidence rate ratio [aIRR], 1.21 [95% confidence interval {CI}, 1.01-1.47]) and treatment failure (aIRR, 1.16 [95% CI, 1.05-1.28]). A 1-μg/mL decrease in pyrazinamide concentration was associated with recurrence (aIRR, 1.05 [95% CI, 1.01-1.11]). CONCLUSIONS: Rifampicin concentrations were subtherapeutic in most Indian patients taking a thrice-weekly TB regimen, and low rifampicin and pyrazinamide concentrations were associated with poor outcomes. Higher or more frequent dosing is needed to improve TB treatment outcomes in India.

Diabetes mellitus and tuberculosis in Korean adults: impact on tuberculosis incidence, recurrence and mortality. (2019). Golub JE., Mok Y., Hong S., Jung KJ., Jee SH., Samet JM, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 507-513

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SETTING The prevalence of diabetes mellitus (DM) worldwide is increasing markedly, and many countries with rising rates also have a high incidence rate of tuberculosis (TB). OBJECTIVE To investigate the relationships of fasting serum glucose (FSG) and DM with TB incidence, recurrence and mortality risk in a prospective cohort study in South Korea. DESIGN Our study comprised 1 267 564 Koreans who received health insurance from the National Health Insurance System, had an initial medical evaluation between 1997 and 2000 and were prospectively followed biennially. RESULTS Participants with DM had a higher risk for incident TB (hazard ratio [HR] 1.81, 95%CI 1.71-1.91 in males, HR 1.33; 95%CI 1.20-1.47 in females) than those without DM. There was a strong positive trend for TB risk with rising FSG among males. The risk for recurrent TB among those with previous TB was significantly higher in males (HR 1.58, 95%CI 1.43-1.75) and in females with DM (HR 1.38, 95%CI 1.08-1.76). The increased risk of death from TB during follow-up was also significant in men (HR 1.91, 95%CI 1.87-1.95) and in women (HR 1.71, 95%CI 1.65-1.77). CONCLUSIONS A diagnosis of DM is a risk factor for TB, TB recurrence and death from TB. Screening for TB should be considered among people living with DM in Korea, particularly those with severe DM. .

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