TB Modeling and Translational Epi Group

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- April 2020 -

Study protocol: a cluster randomized trial to evaluate the effectiveness and implementation of onsite GeneXpert testing at community health centers in Uganda (XPEL-TB). (2020). Reza TF., Nalugwa T., Farr K., Nantale M., Oyuku D., Nakaweesa A., Musinguzi J., Vangala M., Shete PB., Tucker A., Ferguson O., Fielding K., Sohn H., Dowdy D., Moore DAJ., Davis JL., Ackerman SL., Handley MA., Katamba A., Cattamanchi A, Implementation science : IS, 15, 24

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BACKGROUND: Delays in diagnosis and treatment of tuberculosis (TB) remain common in high-burden countries. To improve case detection, substantial investments have been made to scale-up Xpert MTB/RIF (Xpert), a cartridge-based nucleic acid amplification test that can detect TB within 2 hours, as a replacement for sputum smear microscopy. However, the optimal strategy for implementation of Xpert testing remains unclear. METHODS: The Xpert Performance Evaluation for Linkage to Tuberculosis Care (XPEL-TB) trial uses an ultra-pragmatic, hybrid type II effectiveness-implementation design to assess the effectiveness and implementation of a streamlined strategy for delivery of Xpert testing in real-world settings. Twenty health centers with TB microscopy units were selected to participate in the trial, with ten health centers randomized to the intervention strategy (onsite molecular testing using GeneXpert Edge, process redesign to facilitate same-day TB diagnosis and treatment, and performance feedback) or routine care (onsite sputum smear microscopy plus referral of sputum samples to Xpert testing sites). The primary outcome is the number of patients with microbiologically confirmed TB who were initiated on treatment within 14 days of presentation to the health center, which reflects successful completion of the TB diagnostic evaluation process. Secondary outcomes include health outcomes (6-month vital status), as well as measures of the reach, adoption, and implementation of the intervention strategy. DISCUSSION: The design elements and implementation approach for the XPEL-TB trial were intentionally selected to minimize disruptions to routine care procedures, with the goal of limiting their influence on key primary and secondary outcomes. Trial findings may result in increased support and funding for rapid, onsite molecular testing as the standard-of-care for all patients being evaluated for TB. TRIAL REGISTRATION: US National Institutes of Health's ClinicalTrials.gov, NCT03044158. Registered 06 February 2017. Pan African Clinical Trials Registry, PACTR201610001763265. Registered 03 September 2016.

The urgent need to improve clinical practice guidelines for pediatric tuberculosis. (2020). Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 24, 264

- March 2020 -

Prevalence and risk factors for latent tuberculosis infection among household contacts of index cases in two South African provinces: Analysis of baseline data from a cluster-randomised trial. (2020). MacPherson P., Lebina L., Motsomi K., Bosch Z., Milovanovic M., Ratsela A., Lala S., Variava E., Golub JE., Webb EL., Martinson NA, PloS one, 15, e0230376

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INTRODUCTION: Household contacts of patients with active pulmonary tuberculosis (TB) often have latent TB infection, and are at risk of progression to disease. We set out to investigate whether index TB case HIV status was linked to a higher probability of latent TB infection among household contacts. MATERIALS AND METHODS: Data were collected prospectively from participants in the intervention arm of a household cluster-randomised trial in two South Africa provinces (Mangaung, Free State, and Capricorn, Limpopo). In intervention group households, TB contacts underwent HIV testing and tuberculin skin testing (TST). TST induration was estimated at two cut-offs (≥5mm, ≥10mm). Multilevel Bayesian regression models estimated posterior distributions of the percentage of household contacts with TST induration ≥5mm and ≥10mm by age group, and compared the odds of latent TB infection by key risk factors including HIV status index case age and study province. RESULTS: A total of 2,985 household contacts of 924 index cases were assessed, with most 2,725 (91.3%) undergoing TST. HIV prevalence in household contacts was 14% and 10% in Mangaung and Capricorn respectively. Overall, 16.8% (458/2,725) had TST induration of ≥5mm and 13.1% (359/2,725) ≥10mm. In Mangaung, children aged 0-4 years had a high TST positivity prevalence compared to their peers in Capricorn (22.0% vs. 7.6%, and 20.5% vs. 2.3%, using TST thresholds of ≥5mm and ≥10mm respectively). Compared to contacts from Capricorn, household contacts living in Mangaung were more likely to have TST induration ≥5mm (odds ratio [OR]: 3.08, 95% credibility interval [CI]: 2.13-4.58) and ≥10mm (OR: 4.52, 95% CI: 3.03-6.97). There was a 90% and 92% posterior probability that the odds of TST induration ≥5mm (OR: 0.79, 95% CI: 0.56-1.14) and ≥10mm (OR: 0.77, 95% CI: 0.53-1.10) respectively were lower in household contacts of HIV-positive compared to HIV-negative index cases. CONCLUSIONS: High TST induration positivity, especially among young children and people living in Mangaung indicates considerable TB transmission despite high antiretroviral therapy coverage. Household contact of HIV-positive index TB cases were less likely to have evidence of latent TB infection than contacts of HIV-negative index cases.

Challenges with scale-up of GeneXpert MTB/RIF® in Uganda: a health systems perspective. (2020). Nalugwa T., Shete PB., Nantale M., Farr K., Ojok C., Ochom E., Mugabe F., Joloba M., Dowdy DW., Moore DAJ., Davis JL., Cattamanchi A., Katamba A, BMC health services research, 20, 162

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BACKGROUND: Many high burden countries are scaling-up GeneXpert® MTB/RIF (Xpert) testing for tuberculosis (TB) using a hub-and-spoke model. However, the effect of scale up on reducing TB has been limited. We sought to characterize variation in implementation of referral-based Xpert TB testing across Uganda, and to identify health system factors that may enhance or prevent high-quality implementation of Xpert testing services. METHODS: We conducted a cross-sectional study triangulating quantitative and qualitative data sources at 23 community health centers linked to one of 15 Xpert testing sites between November 2016 and May 2017 to assess health systems infrastructure for hub-and-spoke Xpert testing. Data sources included a standardized site assessment survey, routine TB notification data, and field notes from site visits. RESULTS: Challenges with Xpert implementation occurred at every step of the diagnostic evaluation process, leading to low overall uptake of testing. Of 2192 patients eligible for TB testing, only 574 (26%) who initiated testing were referred for Xpert testing. Of those, 54 (9.4%) were Xpert confirmed positive just under half initiated treatment within 14 days (n = 25, 46%). Gaps in required infrastructure at 23 community health centers to support the hub-and-spoke system included lack of refrigeration (n = 14, 61%) for sputum testing and lack of telephone/mobile communication (n = 21, 91%). Motorcycle riders responsible for transporting sputum to Xpert sites operated variable with trips once, twice, or three times a week at 10 (43%), nine (39%) and four (17%) health centers, respectively. Staff recorded Xpert results in the TB laboratory register at only one health center and called patients with positive results at only two health centers. Of the 15 Xpert testing sites, five (33%) had at least one non-functioning module. The median number of tests per day was 3.57 (IQR 2.06-4.54), and 10 (67%) sites had error/invalid rates > 5%. CONCLUSIONS: Although Xpert devices are now widely distributed throughout Uganda, health system factors across the continuum from test referral to results reporting and treatment initiation preclude effective implementation of Xpert testing for patients presenting to peripheral health centers. Support for scale up of innovative technologies should include support for communication, coordination and health systems integration.

- February 2020 -

Redefining and revisiting cost estimates of routine ART care in Zambia: an analysis of ten clinics. (2020). Tucker A., Tembo T., Tampi RP., Mutale J., Mukumba-Mwenechanya M., Sharma A., Dowdy DW., Moore CB., Geng E., Holmes CB., Sikazwe I., Sohn H, Journal of the International AIDS Society, 23, e25431

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INTRODUCTION: Accurate costing is key for programme planning and policy implementation. Since 2011, there have been major changes in eligibility criteria and treatment regimens with price reductions in ART drugs, programmatic changes resulting in clinical task-shifting and decentralization of ART delivery to peripheral health centres making existing evidence on ART care costs in Zambia out-of-date. As decision makers consider further changes in ART service delivery, it is important to understand the current drivers of costs for ART care. This study provides updates on costs of ART services for HIV-positive patients in Zambia. METHODS: We evaluated costs, assessed from the health systems perspective and expressed in 2016 USD, based on an activity-based costing framework using both top-down and bottom-up methods with an assessment of process and capacity. We collected primary site-level costs and resource utilization data from government documents, patient chart reviews and time-and-motion studies conducted in 10 purposively selected ART clinics. RESULTS: The cost of providing ART varied considerably among the ten clinics. The average per-patient annual cost of ART service was $116.69 (range: $59.38 to $145.62) using a bottom-up method and $130.32 (range: $94.02 to $162.64) using a top-down method. ART drug costs were the main cost driver (67% to 7% of all costs) and are highly sensitive to the types of patient included in the analysis (long-term vs. all ART patients, including those recently initiated) and the data sources used (facility vs. patient level). Missing capacity costs made up 57% of the total difference between the top-down and bottom-up estimates. Variability in cost across the ten clinics was associated with operational characteristics. CONCLUSIONS: Real-world costs of current routine ART services in Zambia are considerably lower than previously reported estimates and sensitive to operational factors and methods used. We recommend collection and monitoring of resource use and capacity data to periodically update cost estimates.

Patient-incurred cost of inpatient treatment for Tuberculosis in rural Malawi. (2020). Shin H., Ngwira LG., Tucker A., Chaisson RE., Corbett EL., Dowdy DW, Tropical medicine & international health : TM & IH, 25, 624-634

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OBJECTIVES: To mitigate the economic burden of tuberculosis (TB), it is important to fully understand the costs of TB treatment from the patient perspective. We therefore sought to quantify the patient-incurred cost of TB treatment in rural Malawi, with specific focus on costs borne by patients requiring inpatient hospitalisation. METHODS: We conducted a cross-sectional survey of 197 inpatients and 156 outpatients being treated for TB in rural Malawi. We collected data on out-of-pocket costs and lost wages, including costs to guardians. Costs for inpatient TB treatment were estimated and compared to costs for outpatient TB treatment. We then explored the equity distribution of inpatient TB treatment cost using concentration curves. RESULTS: Despite free government services, inpatients were estimated to incur a mean of $137 (standard deviation: $147) per initial TB episode, corresponding to >50% of annual household spending among patients in the lowest expenditure quintile. Non-medical hospitalisation costs accounted for 88% of this total. Patients treated entirely as outpatients incurred estimated costs of $25 (standard deviation: $15) per episode. The concentration curves showed that, among individuals hospitalised for an initial TB episode, poorer patients shouldered a much greater proportion of inpatient TB treatment costs than wealthier ones (concentration index: -0.279). CONCLUSION: Patients hospitalised for TB in resource-limited rural Malawi experience devastating costs of TB treatment. Earlier diagnosis and treatment must be prioritised if we are to meet goals of effective TB control, avoidance of catastrophic costs and provision of appropriate patient-centred care in such settings.

Risk of hearing loss among multidrug-resistant tuberculosis patients according to cumulative aminoglycoside dose. (2020). Hong H., Dowdy DW., Dooley KE., Francis HW., Budhathoki C., Han HR., Farley JE, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 24, 65-72

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SETTING: The ototoxic effects of aminoglycosides (AGs) lead to permanent hearing loss, which is one of the devastating consequences of multidrug-resistant tuberculosis (MDR-TB) treatment. As AG ototoxicity is dose-dependent, the impact of a surrogate measure of AG exposure on AG-induced hearing loss warrants close attention for settings with limited therapeutic drug monitoring.OBJECTIVE: To explore the prognostic impact of cumulative AG dose on AG ototoxicity in patients following initiation of AG-containing treatment for MDR-TB.DESIGN: This prospective cohort study was nested within an ongoing cluster-randomized trial of nurse case management intervention across 10 MDR-TB hospitals in South Africa.RESULTS: The adjusted hazard of AG regimen modification due to ototoxicity in the high-dose group (≥75 mg/kg/week) was 1.33 times higher than in the low-dose group (<75 mg/kg/week, 95%CI 1.09-1.64). The adjusted hazard of developing audiometric hearing loss was 1.34 times higher than in the low-dose group (95%CI 1.01-1.77). Pre-existing hearing loss (adjusted hazard ratio [aHR] 1.71, 95%CI 1.29-2.26) and age (aHR 1.16 per 10 years of age, 95%CI 1.01-1.33) were also associated with an increased risk of hearing loss.CONCLUSION: MDR-TB patients with high AG dose, advanced age and pre-existing hearing loss have a significantly higher risk of AG-induced hearing loss. Those at high risk may be candidates for more frequent monitoring or AG-sparing regimens.

- January 2020 -

Levofloxacin versus placebo for the treatment of latent tuberculosis among contacts of patients with multidrug-resistant tuberculosis (the VQUIN MDR trial): a protocol for a randomised controlled trial. (2020). Fox GJ., Nguyen CB., Nguyen TA., Tran PT., Marais BJ., Graham SM., Nguyen BH., Velen K., Dowdy DW., Mason P., Britton WJ., Behr MA., Benedetti A., Menzies D., Nguyen VN., Marks GB, BMJ open, 10, e033945

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INTRODUCTION: Treatment of latent tuberculosis infection (LTBI) plays a substantial role in the prevention of drug-susceptible tuberculosis (TB). However, clinical trials to evaluate the efficacy of preventive therapy for presumed multidrug-resistant (MDR) LTBI are lacking. This trial aims to evaluate the efficacy of the antibiotic levofloxacin in preventing the development of active TB among latently infected contacts of index patients with MDR-TB. METHODS AND ANALYSIS: A double-blind placebo-controlled parallel group randomised controlled trial will be conducted in 10 provinces of Vietnam. Household contacts living with patients with bacteriologically confirmed rifampicin-resistant or MDR-TB will be eligible for recruitment if they have a positive tuberculin skin test or are known to be immunosuppressed, and do not have active TB. Participants will be randomised to receive either levofloxacin or placebo tablets once per day for 6 months. Screening for incident TB will be performed at 6 months intervals. The primary study outcome is the incidence of bacteriologically confirmed TB within 30 months after randomisation. Analysis will be by intention to treat, using Poisson regression. ETHICS: Ethical approval from the University of Sydney Human Research Ethics Committee was obtained on 29 April 2015 (2014/929), and from the Vietnam Ministry of Health Institutional Review Board on 30 September 2015 (4040/QD-BYT). DISSEMINATION: Findings of the study will be published in peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12616000215426.

- December 2019 -

Clinical Impact of Rapid Drug Susceptibility Testing to Accompany Fluoroquinolone-Containing Universal Tuberculosis Regimens: A Markov Model. (2019). Kendall EA., Malhotra S., Cook-Scalise S., Dowdy DW., Denkinger CM, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 71, 2889-2896

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BACKGROUND: To appropriately treat tuberculosis (TB) with regimens that combine novel and older drugs, evidence-based, context-specific strategies for drug-susceptibility testing (DST) will be required. METHODS: We created a Markov state-transition model of 100 000 adults with TB receiving a novel, fluoroquinolone (FQ)-containing regimen. We estimated clinical outcomes and resource utilization with no FQ-DST, universal FQ-DST, or FQ-DST only for patients with rifampin-resistant TB ("targeted FQ-DST"). We considered scenarios of stronger (South Africa) and weaker (Southeast Asia) correlation of fluoroquinolone resistance with rifampin resistance, with sensitivity analysis for other setting and regimen characteristics. RESULTS: Relative to no FQ-DST, targeted FQ-DST increased cure of FQ-resistant TB by 7.5% (interquartile range [IQR], 6.7%-9.2%) in South Africa and 1.7% (IQR, 0.7%-2.5%) in Southeast Asia. However, rare FQ resistance among the more prevalent rifampin-susceptible TB accounted for 50% of FQ-resistant TB in South Africa and 83% in Southeast Asia. As a result, universal FQ-DST further increased cure of FQ-resistant TB by 3.4% (IQR, 2.3%-5.4%) in South Africa and 5.8% (IQR, 5.1%-6.3%) in Southeast Asia. With targeted FQ-DST, 1 additional patient was cured per 50 (IQR, 42-70) tests in South Africa and 44 (IQR, 37-51) in Southeast Asia. When expanding from targeted to universal FQ-DST, 1 additional cure required 3500 (IQR, 2300-5500) tests in South Africa and 410 (IQR, 370-450) in Southeast Asia. CONCLUSIONS: FQ-DST improved patient outcomes and was particularly important for high-risk patient groups and less robust regimens. A universal strategy was favored in generalized epidemics of fluoroquinolone resistance.

Correction: 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, e0226389

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[This corrects the article DOI: 10.1371/journal.pone.0217289.].

Overcoming limitations of tuberculosis information systems: researcher and clinician perspectives. (2019). van der Heijden YF., Hughes J., Dowdy DW., Streicher E., Chihota V., Jacobson KR., Warren R., Theron G, Public health action, 9, 120-127

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SETTING: Tuberculosis (TB) diagnosis and treatment requires patients to have multiple encounters with health care systems and the different stakeholders who play a role in curing them to coordinate their efforts. To optimize this process, high-quality, readily available data are required. Data systems to facilitate these linkages are a neglected priority which, if weak, fundamentally undermine TB control interventions. OBJECTIVE: To describe lessons learnt from the use of programmatic data for TB patient care and research. DESIGN: We did a survey of researcher and clinical provider experiences with information systems and developed a tiered approach to addressing frequently reported barriers to high-quality care. RESULTS: Unreliable linkages, incomplete data, lack of a reliable unique patient identifier, and lack of data management expertise were the most important data-related barriers to high-quality patient care and research. We propose the creation of health service delivery environments that facilitate, prioritize, and evaluate high-quality data entry during patient or specimen registration. CONCLUSION: An integrated approach, focused on high-quality data, and centered on unique patient identification will form the foundation for linkages across health systems that reduce patient management errors, bolster surveillance, and enhance the quality of research based on programmatic data.

Projecting the impact of variable MDR-TB transmission efficiency on long-term epidemic trends in South Africa and Vietnam. (2019). Salvatore PP., Kendall EA., Seabrook D., Brown J., Durham GH., Dowdy DW, Scientific reports, 9, 18099

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Whether multidrug-resistant tuberculosis (MDR-TB) is less transmissible than drug-susceptible (DS-)TB on a population level is uncertain. Even in the absence of a genetic fitness cost, the transmission potential of individuals with MDR-TB may vary by infectiousness, frequency of contact, or duration of disease. We used a compartmental model to project the progression of MDR-TB epidemics in South Africa and Vietnam under alternative assumptions about the relative transmission efficiency of MDR-TB. Specifically, we considered three scenarios: consistently lower transmission efficiency for MDR-TB than for DS-TB; equal transmission efficiency; and an initial deficit in the transmission efficiency of MDR-TB that closes over time. We calibrated these scenarios with data from drug resistance surveys and projected epidemic trends to 2040. The incidence of MDR-TB was projected to expand in most scenarios, but the degree of expansion depended greatly on the future transmission efficiency of MDR-TB. For example, by 2040, we projected absolute MDR-TB incidence to account for 5% (IQR: 4-9%) of incident TB in South Africa and 14% (IQR: 9-26%) in Vietnam assuming consistently lower MDR-TB transmission efficiency, versus 15% (IQR: 8-27%)and 41% (IQR: 23-62%), respectively, assuming shrinking transmission efficiency deficits. Given future uncertainty, specific responses to halt MDR-TB transmission should be prioritized.

- November 2019 -

Lipid mediators of inflammation and Resolution in individuals with tuberculosis and tuberculosis-Diabetes. (2019). Shivakoti R., Dalli J., Kadam D., Gaikwad S., Barthwal M., Colas RA., Mazzacuva F., Lokhande R., Dharmshale S., Bharadwaj R., Kagal A., Pradhan N., Deshmukh S., Atre S., Sahasrabudhe T., Kakrani A., Kulkarni V., Raskar S., Suryavanshi N., Chon S., Gupte A., Gupta A., Gupte N., Arriaga MB., Fukutani KF., Andrade BB., Golub JE., Mave V, Prostaglandins & other lipid mediators, 147, 106398

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Individuals with concurrent tuberculosis (TB) and Type 2 diabetes (DM) have a higher risk of adverse outcomes. To better understand potential immunological differences, we utilized a comprehensive panel to characterize pro-inflammatory and pro-resolving (i.e., mediators involved in the resolution of inflammation) lipid mediators in individuals with TB and TB-DM. A nested cross-sectional study of 40 individuals (20 newly diagnosed DM and 20 without DM) was conducted within a cohort of individuals with active drug-susceptible treatment-naïve pulmonary TB. Lipid mediators were quantified in serum samples through lipid mediator profiling. We conducted correlation-based analysis of these mediators. Overall, the arachidonic acid-derived leukotriene and prostaglandin families were the most abundant pro-inflammatory lipid mediators, while lipoxins and maresins families were the most abundant pro-resolving lipid mediators in individuals with TB and TB-DM. Individuals with TB-DM had increased correlations and connectivity with both pro-inflammatory and pro-resolving lipid mediators compared to those with TB alone. We identified the most abundant lipid mediator metabolomes in circulation among individuals with TB and TB-DM; in addition, our data shows a substantial number of significant correlations between both pro-inflammatory and pro-resolving lipid mediators in individuals with TB-DM, delineating a molecular balance that potentially defines this comorbidity.

Cost-effectiveness of QuantiFERON-TB Gold In-Tube versus tuberculin skin test for diagnosis and treatment of Latent Tuberculosis Infection in primary health care workers in Brazil. (2019). Loureiro RB., Maciel ELN., Caetano R., Peres RL., Fregona G., Golub JE., Braga JU, PloS one, 14, e0225197

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OBJECTIVES: The goal of this study was to perform a cost-effectiveness analysis from the public health system perspective, comparing five strategies for Latent Tuberculosis Infection (LTBI) diagnosis in primary health care workers in Brazil. DESIGN: Analytical model for decision making, characterized by cost-effectiveness analysis. SETTING: Primary Care Level, considering primary health care workers in Brazil. PARTICIPANTS: An analytical model for decision making, characterized by a tree of probabilities of events, was developed considering a hypothetical cohort of 10,000 primary health care workers, using the software TreeAge Pro™ 2013 to simulate the clinical and economic impacts of new diagnostic technology (QuantiFERON®-TB Gold in-Tube) versus the traditional tuberculin skin test. METHODS: This model simulated five diagnostic strategies for LTBI in primary health care workers (HCW) in Brazil: tuberculin skin testing using ≥5 mm cut-off, tuberculin skin testing ≥10 mm cut-off, QuantiFERON®-TB Gold in-Tube, tuberculin skin testing using ≥5 mm cut-off confirmed by QuantiFERON®-TB Gold In-Tube if TST positive, tuberculin skin testing using ≥10 mm cut-off confirmed by QuantiFERON®-TB Gold In-Tube if TST positive. PRIMARY AND SECONDARY OUTCOME MEASURES: The outcome measures are the number of individuals correctly classified by the test and the number of Tuberculosis cases avoided. RESULTS: The most cost-effective strategy was the tuberculin skin test considering ≥10mm cut-off. The isolated use of the QuantiFERON®-TB Gold In-Tube revealed the strategy of lower efficiency with incremental cost-effectiveness ratio (ICER) of US$ 146.05 for each HCW correctly classified by the test. CONCLUSIONS: The tuberculin skin test using ≥10 mm cut-off was the most cost-effective strategy in the diagnosis of Latent Tuberculosis Infection in primary health care works in Brazil.

Quality of care for patients evaluated for tuberculosis in the context of Xpert MTB/RIF scale-up. (2019). Farr K., Nalugwa T., Ojok C., Nantale M., Nabwire S., Oyuku D., Shete PB., Han AH., Fielding K., Joloba M., Mugabe F., Dowdy DW., Moore D., Davis JL., Katamba A., Cattamanchi A, Journal of clinical tuberculosis and other mycobacterial diseases, 15, 100099

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RATIONALE: Many high-burden countries are scaling-up Xpert MTB/RIF using a hub-and-spoke model. We evaluated the quality of care for patients undergoing TB evaluation at microscopy centers (spokes) linked to Xpert testing sites (hubs) in Uganda. OBJECTIVES: To characterize the extent to which patients were receiving care in accordance with international and national guidelines. METHODS: We conducted a prospective cohort study of all adults with presumptive pulmonary TB at 24 health centers linked to Xpert testing sites. Health center staff photographed TB registers, and uploaded photos to a secure server bi-weekly. We assessed the proportion of patients (1) initiating testing; (2) completing testing; and (3) treated for confirmed TB within 14 days. MEASUREMENTS AND MAIN RESULTS: Between January to December 2017, 6744 patients underwent evaluation for pulmonary TB. Only 1316 patients had sputum referred for Xpert testing, including 1075/3229 (33.3%) people living with HIV and 241/3515 (6.9%) without HIV. Of 119 patients confirmed to have TB by Xpert testing, 44 (36%) did not initiate treatment. There were significant losses along the entire diagnostic cascade of care, with only 5330/6744 (79.0%) patients having samples referred for sputum-based testing, 2978/5330 (55.9%) patients completing recommended testing if referred, and 313/418 (74.9%) patients initiating treatment within 14 days if confirmed to have TB. CONCLUSIONS: Although coverage of Xpert testing services across Uganda is high, the quality of care delivered to patients undergoing TB evaluation remains poor. Further research is needed to identify health system interventions to facilitate uptake of Xpert testing and high-quality care.

Correction: 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., Yogendra Shivakumar SVB., 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, e0224914

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[This corrects the article DOI: 10.1371/journal.pone.0220507.].

- October 2019 -

Incidence of tuberculosis in HIV-infected adults on first- and second-line antiretroviral therapy in India. (2019). Gupte AN., Kadam D., Sangle S., Rewari BB., Salvi S., Chavan A., Nimkar S., Golub J., Gupte N., Gupta A., Marbaniang I., Mave V, BMC infectious diseases, 19, 914

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BACKGROUND: Programmatic data on the baseline risk of tuberculosis in people living with HIV (PLHIV) are needed to evaluate long-term effectiveness of the ongoing isoniazid preventive therapy (IPT) roll-out in India. METHODS: We estimated the incidence rate and risk factors of tuberculosis disease in adult PLHIV initiating first- and second-line anti-retroviral therapy (ART) prior to widespread IPT in a public ART center in Pune, India. RESULTS: 4067 participants contributing 5205.7 person-years of follow-up on first-line ART and 871 participants contributing 1031.7 person-years of follow-up on second-line ART were included in the analysis. The incidence rate of tuberculosis was 4.39 cases (95%CI 3.86-5.00) per 100 person-years on first-line ART and 1.64 cases (95%CI 1.01-2.63) per 100 person-years on second-line ART (p < 0.001). After adjusting for competing risks, male sex (aSHR = 1.33, 95%CI 1.02-1.74, p = 0.03), urban residence (aSHR = 1.53, 95%CI 1.13-2.07, p = 0.006) and CD4+ counts < 350 cells/mm(3) (aSHR = 3.06 vs CD4 > 350 cells/mm(3), 95%CI 1.58-5.94, p < 0.001) at ART initiation were associated with higher risk of tuberculosis independent of ART regimen. CONCLUSION: Risk of tuberculosis was lower in PLHIV receiving second-line ART compared to first-line ART. Prioritizing IPT in PLHIV with low CD4+ counts, urban residence and in males may further mitigate the risk of tuberculosis during ART.

CD4+ cell count stratification to guide tuberculosis preventive therapy for people living with HIV. (2019). Chaisson LH., Saraceni V., Cohn S., Seabrook D., Cavalcante SC., Chaisson RE., Golub JE., Durovni B, AIDS (London, England), 34, 139-147

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OBJECTIVES: In 2018, Brazilian guidelines changed to recommend tuberculosis (TB) preventive therapy for all people with HIV and a CD4 cell count 350 cells/μl or less, but only for those with a positive tuberculin skin test (TST) if CD4 cell count is than 350 cells/μl. We determined the potential effectiveness of CD4-based guidelines for TB testing and preventive therapy. DESIGN: Secondary analysis of the stepped-wedge, cluster-randomized THRio trial for isoniazid preventive therapy (IPT). METHODS: We analyzed data from 4114 newly registered patients with HIV in 29 clinics followed until TB diagnosis, death, or administrative censoring. We compared incidence rates of TB and TB/death between CD4, TST, IPT, and antiretroviral therapy categories. RESULTS: Initial CD4 cell count was 350 cells/μl or less in 2138 (52%) and more than 350 cells/μl in 1976 (48%) patients. TST was performed for 2922 (71%), of whom 657 (16%) were TST-positive [278 (13%) CD4 ≤ 350 vs. 379 (19%) CD4 > 350]. A total of 619 (15%) received IPT and 2806 (68%) received antiretroviral therapy. For patients with CD4 cell count 350 cells/μl or less who did not receive IPT, the incidence rate of TB was 1.79/100 person-years (pys) and TB/death was 3.89/100 pys. For patients with CD4 cell count more than 350 who did not receive IPT, the incidence rates of TB and TB/death were 0.57/100 and 1.49/100 pys for TST-negatives, and 1.05/100 and 1.64/100 pys for TST-unknowns. CONCLUSION: TB incidence was high among all patients who did not receive IPT, including those with CD4 cell count more than 350 cells/μl and negative or unknown TST results. TB preventive therapy should be provided to all people living with HIV in medium burden settings, regardless of CD4 cell count and TST status.

Implementation of Xpert(®) MTB/RIF: real challenges, real promise. (2019). Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 1123

Delays and barriers to early treatment initiation for childhood tuberculosis in India. (2019). Valvi C., Chandanwale A., Khadse S., Kulkarni R., Kadam D., Kinikar A., Joshi S., Lokhande R., Pardeshi G., Garg P., Gupte N., Jain D., Suryavanshi N., Golub JE., Shankar A., Gupta A., Dhumal G., Deluca A., Bollinger RC, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 1090-1099

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BACKGROUND: India accounts for 27% of global childhood tuberculosis (TB) burden. Understanding barriers to early diagnosis and treatment in children may improve care and outcomes.METHODS: A cross-sectional study was performed among 89 children initiated on anti-TB treatment from a public hospital in Pune during 2016, using a structured questionnaire and hospital records. Health care providers (HCPs) were defined as medical personnel consulted about the child's TB symptoms. Time-to-treatment initiation (TTI) was defined as the number of days between onset of TB symptoms and anti-TB treatment initiation. Based on Revised National TB Control Programme recommendations, delayed TTI was defined as >28 days.RESULTS: Sixty-seven (75%) of 89 enrolled children had significant TTI delays (median 51 days, interquartile range [IQR] 27-86). Sixty-six (74%) children visited 1-8 HCPs in the private sector before approaching the public sector. The median HCP delay was 28 days (IQR 10-75). Bacille Calmette-Guérin vaccination (aOR 10.96, P = 0.04) and loss of appetite (aOR 4.44, P = 0.04) were associated with delayed TTI.CONCLUSION: The majority of the children had TTI delays due to delays by HCPs in the private sector. Strengthening HCP competency in TB symptom screening and encouraging early referrals are crucial for rapid scaling up of early treatment initiation in childhood TB.

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