Accuracy of Cytologic vs Histologic Specimens for Assessment of Programmed Cell Death Ligand-1 Expression in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Programmed cell death ligand-1 (PD-L1) expression on tumor cells, evaluated by immunohistochemistry, guides the use of immunotherapy in advanced non-small cell lung cancer (NSCLC). RESEARCH QUESTION: What is the sensitivity and specificity of PD-L1 testing performed in cytologic vs paired histologic specimens in patients with NSCLC? STUDY DESIGN AND METHODS: The MEDLINE, Embase, Web of Science, and Cochrane Library databases were searched through June 1, 2021. The primary outcome was pooled sensitivity and specificity of PD-L1 testing performed on cytologic specimens compared with the reference standard of histologic specimens, analyzed at the PD-L1 expression cutoffs (tumor proportion score) ≥ 1% and ≥ 50%. Pooled sensitivity and specificity, and associated 95% CIs, were estimated using bivariate generalized linear mixed models. RESULTS: Twenty-six articles were included, encompassing a total of 1,064 pairs of histology specimens and cytology cell blocks, and 267 pairs of histology specimens and direct smears. Among these, 946 paired specimens were acquired without interval treatment between the collection of histology and cytology samples. The pooled sensitivity and specificity of cytology specimens compared with paired histology specimens at the PD-L1 expression cutoff ≥ 1% were 0.84 (95% CI, 0.77-0.89) and 0.88 (95% CI, 0.82-0.93), respectively, whereas the pooled sensitivity and specificity at cutoff ≥ 50% were 0.78 (95% CI, 0.69-0.86) and 0.94 (95% CI, 0.91-0.96), respectively. When only paired specimens acquired without interval treatment were considered, the pooled sensitivity and specificity of cytology specimens at PD-L1 expression cutoff ≥ 1% were 0.84 (95% CI, 0.76-0.90) and 0.89 (95% CI, 0.82-0.94), respectively, whereas the pooled sensitivity and specificity at cutoff ≥ 50% were 0.80 (95% CI, 0.71-0.89) and 0.94 (95% CI, 0.91-0.96), respectively. INTERPRETATION: Cytologic specimens provide an accurate assessment of PD-L1 expression in most patients with NSCLC, at both ≥ 1% and ≥ 50% cutoffs, when compared with histologic specimens. TRIAL REGISTRATION: PROSPERO; No.: CRD42020153279; URL: https://www.crd.york.ac.uk/prospero/.

GeneXpert or chest-X-ray or tuberculin skin testing for household contact assessment (GXT): protocol for a cluster-randomized trial.

BACKGROUND: The World Health Organization recommends tuberculosis (TB) preventive treatment (TPT) for all people living with HIV (PLH) and household contacts (HHC) of index TB patients. Tests for TB infection (TBI) or to rule out TB disease (TBD) are preferred, but if not available, this should not be a barrier if access to these tests is limited for high-risk people, such as PLH and HHC under 5 years old. There is equipoise on the need for these tests in different risk populations, especially HHC aged over 5. METHODS: This superiority cluster-randomized multicenter trial with three arms of equal size compares, in Benin and Brazil, three strategies for HHC investigation aged 0-50: (i) tuberculin skin testing (TST) or interferon gamma release assay (IGRA) for TBI and if positive, chest X-Ray (CXR) to rule out TBD in persons with positive TST or IGRA; (ii) same as (i) but GeneXpert (GX) replaces CXR; and (iii) no TBI testing. CXR for all; if CXR is normal, TPT is recommended. All strategies start with symptom screening. Clusters are defined as HHC members of the same index patients with newly diagnosed pulmonary TBD. The main outcome is the proportion of HHC that are TPT eligible who start TPT within 3 months of the index TB patient starting TBD treatment. Societal costs, incidence of severe adverse events, and prevalence of TBD are among secondary outcomes. Stratified analyses by age (under versus over 5) and by index patient microbiological status will be conducted. All participants provide signed informed consent. The study was approved by the Research Ethic Board of the Research Institute of the McGill University Health Centre, the Brazilian National Ethical Board CONEP, and the "Comité Local d'Éthique Pour la Recherche Biomédicale (CLERB) de l'Université de Parakou," Benin. Findings will be submitted for publication in major medical journals and presented in conferences, to WHO and National and municipal TB programs of the involved countries. DISCUSSION: This randomized trial is meant to provide high-quality evidence to inform WHO recommendations on investigation of household contacts, as currently these are based on very low-quality evidence. TRIAL REGISTRATION: ClinicalTrials.gov NCT04528823.

Systematic on-site testing for SARS-CoV-2 infection among asymptomatic essential workers in Montréal, Canada: a prospective observational and cost-assessment study.

BACKGROUND: Essential workers are at increased risk for SARS-CoV-2 infection. We aimed to estimate the yield, acceptability and cost of systematic workplace-based testing of asymptomatic essential workers for SARS-CoV-2 infection. METHODS: From Jan. 27 to Mar. 12, 2021, we prospectively recruited non-health care essential businesses in Montréal, Canada, through email or telephone contact. Two trained mobile teams, each composed of 2 non-health care professionals, visited businesses. Consenting asymptomatic employees provided saline gargle samples under supervision. Samples were analyzed by means of reverse transcription polymerase chain reaction (RT-PCR). At businesses with outbreaks (≥ 2 participants with a positive result), we retested all participants with a negative result on initial testing. Our primary outcomes were yield (proportion of test results that were positive), acceptability (proportion of participants estimated to be present at the business who agreed to participate) and costs (including training, sample collection and analysis, and communicating results). Our secondary outcome was identification of factors associated with a positive test result on multivariable logistic regression. RESULTS: Of the 366 businesses contacted, 69 (18.8%) agreed to participate. Nineteen businesses (28%) were manufacturers or suppliers, 12 (17%) were in auto sales or repair, and 11 (16%) were in childcare; the corresponding number of employees was 1225, 242 and 113. The median number of participants per business was 13 (interquartile range [IQR] 8-22). Of an estimated 2348 employees on site, 2128 (90.6%) participated (808 [38.0%] female, median age 48 [IQR 37-57] yr). Of the 2626 tests performed, 53 (2.0%) gave a positive result. Self-reported nonwhite ethnicity (adjusted odds ratio [OR] 3.7, 95% confidence interval [CI] 1.4-9.9) and a negative SARS-CoV-2 test result before the study (adjusted OR 0.4, 95% CI 0.2-0.8) were associated with a positive test result. Five businesses were experiencing an outbreak; at these businesses, 40/917 participants (4.4%) had a positive result on the initial test. We repeated testing for employees with initially negative results at 3 of these businesses over 2-3 weeks: 8/350 participants (2.3%) had a positive result on the second test, and none had a positive result on the third and fourth tests; no employer reported new positive results after our final visit (up to Mar. 26, 2021). At the remaining 64 businesses, 1211 participants were tested once, of whom 5 (0.4%) had a positive result. The per-person RT-PCR cost was $34, and all other costs, $8.67. INTERPRETATION: On-site saline gargle sampling of essential workers for SARS-CoV-2 testing was acceptable and of modest cost, and appears most useful in the context of outbreaks. This sampling strategy should be evaluated further as a component of efforts to prevent SARS-CoV-2 transmission. PREPRINT: medRxiv - doi:10.1101/2021.05.12.21256956.

Scaling up investigation and treatment of household contacts of tuberculosis patients in Brazil: a cost-effectiveness and budget impact analysis.

Background: In Brazil, investigation and treatment of tuberculosis infection (TBI) in households contacts (HHC) of TB patients is not a priority. We estimated the cost-effectiveness and budget-impact of scaling-up an enhanced HHC management in Brazil. Methods: We conceptualized a cascade-of-care that captures how HHC of tuberculosis patients are investigated in Brazil (status quo) and two enhanced strategies for management of HHC focusing on: (1) only tuberculosis disease (TBD) detection and, (2) TBD and TBI detection and treatment. Effectiveness was the number of HHC diagnosed with TBD and completing TBI treatment. Proportions in the cascades-of-care were derived from a meta-analysis. Health-system costs (2019 US$) were based on literature and official data from Brazil. The impact of enhanced strategies was extrapolated using reported data from 2019. Findings: With the status quo, 0 (95% uncertainty interval: 0-1) HHC are diagnosed with TBD and 2 (0-16) complete TBI treatment. With strategy(1), an additional 15 (3-45) HHC would be diagnosed with TBD at a cost of US$346 each. With strategy(2), 81 (19-226) additional HHC would complete TBI treatment at a cost of US$84 each. A combined strategy, implemented nationally to enhance TBD detection and TBI treatment would result in an additional 9,711 (845-28,693) TBD being detected, and 51,277 (12,028-143,495) more HHC completing TBI treatment each year, utilizing 10.9% and 11.6% of the annual national tuberculosis program budget, respectively. Interpretation: Enhanced detection and treatment of TBD and TBI among HHC in Brazil can be achieved at a national level using current tools at reasonable cost. Funding: None.

Triage of Persons With Tuberculosis Symptoms Using Artificial Intelligence-Based Chest Radiograph Interpretation: A Cost-Effectiveness Analysis.

BACKGROUND: In settings without access to rapid expert radiographic interpretation, artificial intelligence (AI)-based chest radiograph (CXR) analysis can triage persons presenting with possible tuberculosis (TB) symptoms, to identify those who require additional microbiological testing. However, there is limited evidence of the cost-effectiveness of this technology as a triage tool. METHODS: A decision analysis model was developed to evaluate the cost-effectiveness of triage strategies with AI-based CXR analysis for patients presenting with symptoms suggestive of pulmonary TB in Karachi, Pakistan. These strategies were compared to the current standard of care using microbiological testing with smear microscopy or GeneXpert, without prior triage. Positive triage CXRs were considered to improve referral success for microbiologic testing, from 91% to 100% for eligible persons. Software diagnostic accuracy was based on a prospective field study in Karachi. Other inputs were obtained from the Pakistan TB Program. The analysis was conducted from the healthcare provider perspective, and costs were expressed in 2020 US dollars. RESULTS: Compared to upfront smear microscopy for all persons with presumptive TB, triage strategies with AI-based CXR analysis were projected to lower costs by 19%, from $23233 per 1000 persons, and avert 3%-4% disability-adjusted life-years (DALYs), from 372 DALYs. Compared to upfront GeneXpert, AI-based triage strategies lowered projected costs by 37%, from $34346 and averted 4% additional DALYs, from 369 DALYs. Reinforced follow-up for persons with positive triage CXRs but negative microbiologic tests was particularly cost-effective. CONCLUSIONS: In lower-resource settings, the addition of AI-based CXR triage before microbiologic testing for persons with possible TB symptoms can reduce costs, avert additional DALYs, and improve TB detection.

Economic and modeling evidence for tuberculosis preventive therapy among people living with HIV: A systematic review and meta-analysis.

BACKGROUND: Human immunodeficiency virus (HIV) is the strongest known risk factor for tuberculosis (TB) through its impairment of T-cell immunity. Tuberculosis preventive treatment (TPT) is recommended for people living with HIV (PLHIV) by the World Health Organization, as it significantly reduces the risk of developing TB disease. We conducted a systematic review and meta-analysis of modeling studies to summarize projected costs, risks, benefits, and impacts of TPT use among PLHIV on TB-related outcomes. METHODS AND FINDINGS: We searched MEDLINE, Embase, and Web of Science from inception until December 31, 2020. Two reviewers independently screened titles, abstracts, and full texts; extracted data; and assessed quality. Extracted data were summarized using descriptive analysis. We performed quantile regression and random effects meta-analysis to describe trends in cost, effectiveness, and cost-effectiveness outcomes across studies and identified key determinants of these outcomes. Our search identified 6,615 titles; 61 full texts were included in the final review. Of the 61 included studies, 31 reported both cost and effectiveness outcomes. A total of 41 were set in low- and middle-income countries (LMICs), while 12 were set in high-income countries (HICs); 2 were set in both. Most studies considered isoniazid (INH)-based regimens 6 to 2 months long (n = 45), or longer than 12 months (n = 11). Model parameters and assumptions varied widely between studies. Despite this, all studies found that providing TPT to PLHIV was predicted to be effective at averting TB disease. No TPT regimen was substantially more effective at averting TB disease than any other. The cost of providing TPT and subsequent downstream costs (e.g. post-TPT health systems costs) were estimated to be less than $1,500 (2020 USD) per person in 85% of studies that reported cost outcomes (n = 36), regardless of study setting. All cost-effectiveness analyses concluded that providing TPT to PLHIV was potentially cost-effective compared to not providing TPT. In quantitative analyses, country income classification, consideration of antiretroviral therapy (ART) use, and TPT regimen use significantly impacted cost-effectiveness. Studies evaluating TPT in HICs suggested that TPT may be more effective at preventing TB disease than studies evaluating TPT in LMICs; pooled incremental net monetary benefit, given a willingness-to-pay threshold of country-level per capita gross domestic product (GDP), was $271 in LMICs (95% confidence interval [CI] -$81 to $622, p = 0.12) and was $2,568 in HICs (-$32,115 to $37,251, p = 0.52). Similarly, TPT appeared to be more effective at averting TB disease in HICs; pooled percent reduction in active TB incidence was 20% (13% to 27%, p < 0.001) in LMICs and 37% (-34% to 100%, p = 0.13) in HICs. Key limitations of this review included the heterogeneity of input parameters and assumptions from included studies, which limited pooling of effect estimates, inconsistent reporting of model parameters, which limited sample sizes of quantitative analyses, and database bias toward English publications. CONCLUSIONS: The body of literature related to modeling TPT among PLHIV is large and heterogeneous, making comparisons across studies difficult. Despite this variability, all studies in all settings concluded that providing TPT to PLHIV is potentially effective and cost-effective for preventing TB disease.

Effectiveness and cost-effectiveness of a health systems intervention for latent tuberculosis infection management (ACT4): a cluster-randomised trial.

BACKGROUND: Reaching the UN General Assembly High-Level Meeting on Tuberculosis target of providing tuberculosis preventive treatment to at least 30 million people by 2022, including 4 million children under the age of 5 years and 20 million other household contacts, will require major efforts to strengthen health systems. The aim of this study was to evaluate the effectiveness and cost-effectiveness of a health systems intervention to strengthen management for latent tuberculosis infection (LTBI) in household contacts of confirmed tuberculosis cases. METHODS: ACT4 was a cluster-randomised, open-label trial involving 24 health facilities in Benin, Canada, Ghana, Indonesia, and Vietnam randomly assigned to either a three-phase intervention (LTBI programme evaluation, local decision making, and strengthening activities) or control (standard LTBI care). Tuberculin and isoniazid were provided to control and intervention sites if not routinely available. Randomisation was stratified by country and restricted to ensure balance of index patients with tuberculosis by arm and country. The primary outcome was the number of household contacts who initiated tuberculosis preventive treatment at each health facility within 4 months of the diagnosis of the index case, recorded in the first or last 6 months of our 20-month study. To ease interpretation, this number was standardised per 100 newly diagnosed index patients with tuberculosis. Analysis was by intention to treat. Masking of staff at the coordinating centre and sites was not possible; however, those analysing data were masked to assignment of intervention or control. An economic analysis of the intervention was done in parallel with the trial. ACT4 is registered at ClinicalTrials.gov, NCT02810678. FINDINGS: The study was done between Aug 1, 2016, and March 31, 2019. During the first 6 months of the study the crude overall proportion of household contacts initiating tuberculosis preventive treatment out of those eligible at intervention sites was 0·21. After the implementation of programme strengthening activities, the proportion initiating tuberculosis preventive treatment increased to 0·35. Overall, the number of household contacts initiating tuberculosis preventive treatment per 100 index patients with tuberculosis increased between study phases in intervention sites (adjusted rate difference 60, 95% CI 4 to 116), while control sites showed no statistically significant change (-12, -33 to 10). There was a difference in rate differences of 72 (95% CI 10 to 134) contacts per 100 index patients with tuberculosis initiating preventive treatment associated with the intervention. The total cost for the intervention, plus LTBI clinical care per additional contact initiating treatment was estimated to be CA$1348 (range 724 to 9708). INTERPRETATION: A strategy of standardised evaluation, local decision making, and implementation of health systems strengthening activities can provide a mechanism for scale-up of tuberculosis prevention, particularly in low-income and middle-income countries. FUNDING: Canadian Institutes of Health Research.

The Sensitivity and Costs of Testing for SARS-CoV-2 Infection With Saliva Versus Nasopharyngeal Swabs : A Systematic Review and Meta-analysis.

BACKGROUND: Nasopharyngeal swabs are the primary sampling method used for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but they require a trained health care professional and extensive personal protective equipment. PURPOSE: To determine the difference in sensitivity for SARS-CoV-2 detection between nasopharyngeal swabs and saliva and estimate the incremental cost per additional SARS-CoV-2 infection detected with nasopharyngeal swabs. DATA SOURCES: Embase, Medline, medRxiv, and bioRxiv were searched from 1 January to 1 November 2020. Cost inputs were from nationally representative sources in Canada and were converted to 2020 U.S. dollars. STUDY SELECTION: Studies including at least 5 paired nasopharyngeal swab and saliva samples and reporting diagnostic accuracy for SARS-CoV-2 detection. DATA EXTRACTION: Data were independently extracted using standardized forms, and study quality was assessed using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2). DATA SYNTHESIS: Thirty-seven studies with 7332 paired samples were included. Against a reference standard of a positive result on either sample, the sensitivity of saliva was 3.4 percentage points lower (95% CI, 9.9 percentage points lower to 3.1 percentage points higher) than that of nasopharyngeal swabs. Among persons with previously confirmed SARS-CoV-2 infection, saliva's sensitivity was 1.5 percentage points higher (CI, 7.3 percentage points lower to 10.3 percentage points higher) than that of nasopharyngeal swabs. Among persons without a previous SARS-CoV-2 diagnosis, saliva was 7.9 percentage points less (CI, 14.7 percentage points less to 0.8 percentage point more) sensitive. In this subgroup, if testing 100 000 persons with a SARS-CoV-2 prevalence of 1%, nasopharyngeal swabs would detect 79 more (95% uncertainty interval, 5 fewer to 166 more) persons with SARS-CoV-2 than saliva, but with an incremental cost per additional infection detected of $8093. LIMITATION: The reference standard was imperfect, and saliva collection procedures varied. CONCLUSION: Saliva sampling seems to be a similarly sensitive and less costly alternative that could replace nasopharyngeal swabs for collection of clinical samples for SARS-CoV-2 testing. PRIMARY FUNDING SOURCE: McGill Interdisciplinary Initiative in Infection and Immunity. (PROSPERO: CRD42020203415).

Ease and equity of access to free DR-TB services in Nigeria- a qualitative analysis of policies, structures and processes.

INTRODUCTION: Persistent low rates of case notification and treatment coverage reflect that accessing diagnosis and treatment for drug-resistant tuberculosis (DR-TB) in Nigeria remains a challenge, even though it is provided free of charge to patients. Equity in health access requires availability of comparable, appropriate services to all, based on needs, and irrespective of socio-demographic characteristics. Our study aimed to identify the reasons for Nigeria's low rates of case-finding and treatment for DR-TB. To achieve this, we analyzed elements that facilitate or hinder equitable access for different groups of patients within the current health system to support DR-TB management in Nigeria. METHODS: We conducted documentary review of guidelines and workers manuals, as well as 57 qualitative interviews, including 10 focus group discussions, with a total of 127 participants, in Nigeria. Between August and November 2017, we interviewed patients who were on treatment, their treatment supporter, and providers in Ogun and Plateau States, as well as program managers in Benue and Abuja. We adapted and used Levesque's patient-centered access to care framework to analyze DR-TB policy documents and interview data. RESULTS: Thematic analysis revealed inequitable access to DR-TB care for some patient socio-demographic groups. While patients were mostly treated equally at the facility level, some patients experienced more difficulty accessing care based on their gender, age, occupation, educational level and religion. Health system factors including positive provider attitudes and financial support provided to the patients facilitated equity and ease of access. However, limited coverage and the absence of patients' access rights protection and considerations in the treatment guidelines and workers manuals likely hampered access. CONCLUSION: In the context of Nigeria's low case-finding and treatment coverage, applying an equity of access framework was necessary to highlight gaps in care. Differing social contexts of patients adversely affected their access to DR-TB care. We identified several strengths in DR-TB care delivery, including the current financial support that should be sustained. Our findings highlight the need for government's commitment and continued interventions.

Active testing of groups at increased risk of acquiring SARS-CoV-2 in Canada: costs and human resource needs.

BACKGROUND: Testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely passive, which impedes epidemic control. We defined active testing strategies for SARS-CoV-2 using reverse transcription polymerase chain reaction (RT-PCR) for groups at increased risk of acquiring SARS-CoV-2 in all Canadian provinces. METHODS: We identified 5 groups who should be prioritized for active RT-PCR testing: contacts of people who are positive for SARS-CoV-2, and 4 at-risk populations - hospital employees, community health care workers and people in long-term care facilities, essential business employees, and schoolchildren and staff. We estimated costs, human resources and laboratory capacity required to test people in each group or to perform surveillance testing in random samples. RESULTS: During July 8-17, 2020, across all provinces in Canada, an average of 41 751 RT-PCR tests were performed daily; we estimated this required 5122 personnel and cost $2.4 million per day ($67.8 million per month). Systematic contact tracing and testing would increase personnel needs 1.2-fold and monthly costs to $78.9 million. Conducted over a month, testing all hospital employees would require 1823 additional personnel, costing $29.0 million; testing all community health care workers and persons in long-term care facilities would require 11 074 additional personnel and cost $124.8 million; and testing all essential employees would cost $321.7 million, requiring 25 965 added personnel. Testing the larger population within schools over 6 weeks would require 46 368 added personnel and cost $816.0 million. Interventions addressing inefficiencies, including saliva-based sampling and pooling samples, could reduce costs by 40% and personnel by 20%. Surveillance testing in population samples other than contacts would cost 5% of the cost of a universal approach to testing at-risk populations. INTERPRETATION: Active testing of groups at increased risk of acquiring SARS-CoV-2 appears feasible and would support the safe reopening of the economy and schools more broadly. This strategy also appears affordable compared with the $169.2 billion committed by the federal government as a response to the pandemic as of June 2020.

Health System Costs of Treating Latent Tuberculosis Infection With Four Months of Rifampin Versus Nine Months of Isoniazid in Different Settings.

BACKGROUND: Four months of rifampin treatment for latent tuberculosis infection is safer, has superior treatment completion rates, and is as effective as 9 months of isoniazid. However, daily medication costs are higher for a 4-month rifampin regimen than a 9-month isoniazid regimen. OBJECTIVE: To compare health care use and associated costs of 4 months of rifampin and 9 months of isoniazid. DESIGN: Health system cost comparison using all health care activities recorded during 2 randomized clinical trials. (ClinicalTrials.gov: NCT00931736 and NCT00170209). SETTING: High-income countries (Australia, Canada, Saudi Arabia, and South Korea), middle-income countries (Brazil and Indonesia), and African countries (Benin, Ghana, and Guinea). PARTICIPANTS: Adults and children with clinical or epidemiologic factors associated with increased risk for developing tuberculosis that warranted treatment for latent tuberculosis infection. MEASUREMENTS: Health system costs per participant. RESULTS: A total of 6012 adults and 829 children were included. In both adults and children, greater health system use and higher costs were observed with 9 months of isoniazid than with 4 months of rifampin. In adults, the ratios of costs of 4 months of rifampin versus 9 months of isoniazid were 0.76 (95% CI, 0.70 to 0.82) in high-income countries, 0.90 (CI, 0.85 to 0.96) in middle-income countries, and 0.80 (CI, 0.78 to 0.81) in African countries. Similar findings were observed in the pediatric population. LIMITATION: Costs may have been overestimated because the trial protocol required a minimum number of follow-up visits, although fewer than recommended by many authoritative guidelines. CONCLUSION: A 4-month rifampin regimen was safer and less expensive than 9 months of isoniazid in all settings. This regimen could be adopted by tuberculosis programs in many countries as first-line therapy for latent tuberculosis infection. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Solutions to improve the latent tuberculosis Cascade of Care in Ghana: a longitudinal impact assessment.

BACKGROUND: Loss of patients in the latent tuberculosis infection (LTBI) cascade of care is a major barrier to LTBI management. We evaluated the impact and acceptability of local solutions implemented to strengthen LTBI management of household contacts (HHCs) at an outpatient clinic in Ghana. METHODS: Local solutions to improve LTBI management were informed by a baseline evaluation of the LTBI cascade and questionnaires administered to index patients, HHCs, and health care workers at the study site in Offinso, Ghana. Solutions aimed to reduce patient costs and improve knowledge. We evaluated the impact and acceptability of the solutions. Specific objectives were to: 1) Compare the proportion of eligible HHCs completing each step in the LTBI cascade of care before and after solution implementation; 2) Compare knowledge, attitude, and practices (KAP) before and after solution implementation, based on responses of patients and health care workers (HCW) to structured questionnaires; 3) Evaluate patient and HCW acceptability of solutions using information obtained from these questionnaires. RESULTS: Pre and Post-Solution LTBI Cascades included 58 and 125 HHCs, respectively. Before implementation, 39% of expected < 5-year-old HHCs and 66% of ≥5-year-old HHCs were identified. None completed any further cascade steps. Post implementation, the proportion of eligible HHCs who completed identification, assessment, evaluation, and treatment initiation increased for HHCs < 5 to 94, 100, 82, 100%, respectively, and for HHCs ≥5 to 96, 69, 67, 100%, respectively. Pre and Post-Solutions questionnaires were completed by 80 and 95 respondents, respectively. Study participants most frequently mentioned financial support and education as the solutions that supported LTBI management. CONCLUSION: Implementation of locally selected solutions was associated with an increase in the proportion of HHCs completing all steps in the LTBI cascade. Tuberculosis programs should consider prioritizing financial support, such as payment for chest x-rays, to support LTBI cascade completion.

Treatment with isoniazid or rifampin for latent tuberculosis infection: population-based study of hepatotoxicity, completion and costs.

Clinical trials suggest less hepatotoxicity and better adherence with 4 months rifampin (4R) versus 9 months isoniazid (9H) for treating latent tuberculosis infection (LTBI). Our objectives were to compare frequencies of severe hepatic adverse events and treatment completion, and direct health system costs of LTBI regimens 4R and 9H, in the general population of the province of Quebec, Canada, using provincial health administrative data.Our retrospective cohort included all patients starting rifampin or isoniazid regimens between 2003 and 2007. We estimated hepatotoxicity from hospitalisation records, treatment completion from community pharmacy records and direct costs from billing records and fee schedules. We compared rifampin to isoniazid using logistic (hepatotoxicity), log-binomial (completion), and gamma (costs) regression, with adjustment for age, co-morbidities and other confounders.10 559 individuals started LTBI treatment (9684 isoniazid; 875 rifampin). Rifampin patients were older with more baseline co-morbidities. Severe hepatotoxicity risk was higher with isoniazid (n=15) than rifampin (n=1), adjusted OR=2.3 (95% CI: 0.3-16.1); there were two liver transplants and one death with isoniazid and none with rifampin. Overall, patients without co-morbidities had lower hepatotoxicity risk (0.1% versus 1.0%). 4R completion (53.5%) was higher than 9H (36.9%), adjusted RR=1.5 (95% CI: 1.3-1.7). Mean costs per patient were lower for rifampin than isoniazid: adjusted cost ratio=0.7 (95% CI: 0.5-0.9).Risk of severe hepatotoxicity and direct costs were lower, and completion was higher, for 4R than 9H, after adjustment for age and co-morbidities. Severe hepatotoxicity resulted in death or liver transplant in three patients receiving 9H, compared with no patients receiving 4R.

Emergence of drug resistance in patients with tuberculosis cared for by the Indian health-care system: a dynamic modelling study.

BACKGROUND: India has the highest number of patients with tuberculosis and multidrug-resistant tuberculosis in the world. We used a transmission model to project the emergence of drug resistance in India due to incorrect tuberculosis management practices in multiple sectors, including public and private providers, chemists, and non-allopathic practitioners. METHODS: We constructed a dynamic Markov model to represent India's tuberculosis epidemic, including a probabilistic framework reflecting complex treatment-seeking pathways. Underlying drug resistance and the acquisition of drug resistance during treatment were included. India-specific epidemiological data, including tuberculosis management practices, were obtained from published literature. Outcomes, which included annual risk of infection, incidence of new disease, prevalence of untreated tuberculosis, and tuberculosis-related mortality, were stratified by underlying drug resistance, as well as by health sector to understand how each sector contributes to the emergence of drug resistance. FINDINGS: If tuberculosis management practices across sectors in India remain unchanged over the next 20 years, we estimated a 47% increase in the incidence of isoniazid resistance, a 152% increase in multidrug-resistant tuberculosis incidence, a 242% increase in prevalent untreated multidrug-resistant tuberculosis, and a 275% increase in the risk of multidrug-resistant tuberculosis infection. By 2032, an estimated 85% of multidrug-resistant tuberculosis will be primary multidrug-resistant tuberculosis compared with only 15% in 2012. The public sector contributed 87% of acquired multidrug-resistant tuberculosis, related to irregular adherence; the remainder came from the private sector, related to treatment non-completion. Chemists and non-allopathic practitioners do not treat with rifampicin, but because of the high rates of inappropriate isoniazid-containing regimens, and treatment non-adherence, this would generate isoniazid resistance. INTERPRETATION: We predict a gradual transformation from the current epidemic of drug-susceptible tuberculosis to a drug-resistant epidemic. Evidence-based strategies to improve provider practices and patient adherence across health sectors are urgently needed to prevent this. FUNDING: United States Agency for International Development and the Canadian Institutes for Health Research.

Knowledge about tuberculosis transmission and prevention and perceptions of health service utilization among index cases and contacts in Brazil: Understanding losses in the latent tuberculosis cascade of care.

INTRODUCTION: Tuberculosis contacts are candidates for active and latent tuberculosis infection screening and eventual treatment. However, many losses occur in the different steps of the contacts' cascade of care. Reasons for this are poorly understood. OBJECTIVE: To describe the different steps where losses in the contact cascade occur and to explore knowledge and attitudes regarding tuberculosis transmission/prevention and perceptions about tuberculosis services in order to understand the reasons for losses from the tuberculosis service users' perspective. DESIGN: We collected routine data from the index case and contact registry books and from patients' records to build the cascade of care of contacts in 12 health facilities in three Brazilian cities with high tuberculosis incidence rates. During a knowledge, attitudes and practices (KAP) survey, trained interviewers administered a semi-structured questionnaire to 138 index cases and 98 contacts. RESULTS: Most of the losses in the cascade occurred in the first two steps (contact identification, 43% and tuberculin skin testing placement, 91% of the identified contacts). Among KAP-interviewed contacts, 67% knew how tuberculosis is transmitted, 87% knew its key symptoms and 81% declared they would take preventive therapy if prescribed. Among KAP-interviewed index cases, 67% knew they could spread tuberculosis, 70% feared for the health of their families and 88% would like their family to be evaluated in the same services. CONCLUSION: Only a small proportion of contacts are evaluated for active and latent tuberculosis, despite their-and their index cases'-reasonable knowledge, positive attitudes towards prevention and satisfaction with tuberculosis services. In these services, education of service users would not be a sufficient solution. Healthcare workers' and managers' perspective, not explored in this study, may bring more light to this subject.

The impact of the Brazilian family health strategy on selected primary care sensitive conditions: A systematic review.

BACKGROUND: Brazil has the largest public health-system in the world, with 120 million people covered by its free primary care services. The Family Health Strategy (FHS) is the main primary care model, but there is no consensus on its impact on health outcomes. We systematically reviewed published evidence regarding the impact of the Brazilian FHS on selective primary care sensitive conditions (PCSC). METHODS: We searched Medline, Web of Science and Lilacs in May 2016 using key words in Portuguese and English, without language restriction. We included studies if intervention was the FHS; comparison was either different levels of FHS coverage or other primary health care service models; outcomes were the selected PCSC; and results were adjusted for relevant sanitary and socioeconomic variables, including the national conditional cash transfer program (Bolsa Familia). Due to differences in methods and outcomes reported, pooling of results was not possible. RESULTS: Of 1831 records found, 31 met our inclusion criteria. Of these, 25 were ecological studies. Twenty-one employed longitudinal quasi-experimental methods, 27 compared different levels the FHS coverage, whilst four compared the FHS versus other models of primary care. Fourteen studies found an association between higher FHS coverage and lower post-neonatal and child mortality. When the effect of Bolsa Familia was accounted for, the effect of the FHS on child mortality was greater. In 13 studies about hospitalizations due to PCSC, no clear pattern of association was found. In four studies, there was no effect on child and elderly vaccination or low-birth weight. No included studies addressed breast-feeding, dengue, HIV/AIDS and other neglected infectious diseases. CONCLUSIONS: Among these ecological studies with limited quality evidence, increasing coverage by the FHS was consistently associated with improvements in child mortality. Scarce evidence on other health outcomes, hospitalization and synergies with cash transfer was found.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis.

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.

Modeling the impact of tuberculosis interventions on epidemiologic outcomes and health system costs.

BACKGROUND: Tuberculosis (TB) programs must invest in a variety of TB specific activities in order to reach ambitious global targets. Uncertainty exists surrounding the potential impact of each of these activities. The objective of our study was to model different interventions and quantify their impact on epidemiologic outcomes and costs from the health system perspective. METHODS: Decision analysis was used to define the TB patient trajectory within the health system of three different countries. We considered up to seven different interventions that could affect either the natural history of TB, or patient trajectories within the health system. The expected impact of interventions were derived from published studies where possible. Epidemiologic outcomes and associated health system costs were projected for each scenario. RESULTS: With no specific intervention, TB related death rates are high and less than 10% of the population starts on correct treatment. Interventions that either prevent cases or affect all patients with TB disease early in their trajectory are expected to have the biggest impact, regardless of underlying epidemiologic characteristics of the setting. In settings with a private sector, improving diagnosis and appropriate treatment across all sectors is expected to have a major impact on outcomes. CONCLUSION: In all settings, the greatest benefit will come from early diagnosis of all forms of TB. Once this has been achieved more specific interventions, such as those targeting HIV, drug resistance or the private sector can be integrated to increase impact.

Fluoroquinolone Therapy for the Prevention of Multidrug-Resistant Tuberculosis in Contacts. A Cost-Effectiveness Analysis.

RATIONALE: Fluoroquinolone (FQN) therapy of latent tuberculosis infection among contacts of individuals with multidrug-resistant tuberculosis (MDR-TB) is controversial. OBJECTIVES: To determine the potential benefits, risks (including acquired FQN resistance), and cost-effectiveness of FQN therapy to prevent TB in contacts of individuals with MDR-TB. METHODS: We used decision analysis to estimate costs and outcomes associated with no therapy compared with a 6-month course of daily FQN therapy to treat latent TB infection in contacts of individuals with MDR-TB. Outcomes modeled were the incidence of MDR-TB, MDR-TB with FQN resistance, TB-related death, quality-adjusted life years, and health system costs. MEASUREMENTS AND MAIN RESULTS: FQN preventive therapy resulted in health system savings, lower incidence of MDR-TB, and lower mortality than no treatment. We found the incidence of MDR-TB with acquired FQN resistance would also be lower with FQN therapy of infected contacts. CONCLUSIONS: In our model, FQN preventive therapy resulted in substantial health system savings and in reduced mortality, incidence of MDR-TB, and incidence of acquired FQN-resistant disease as well as improved quality of life. FQN therapy remained cost saving with improved outcomes even if the effectiveness of therapy in preventing MDR-TB was as low as 10%.

Comparing cost-effectiveness of standardised tuberculosis treatments given varying drug resistance.

There is a growing need to identify appropriate standardised treatment strategies that will adequately treat various forms of drug-resistant tuberculosis (TB) and prevent multidrug-resistant (MDR)-TB. A Markov model estimated treatment-related acquired MDR-TB, mortality, disability-adjusted life years and costs in settings with different prevalence of isoniazid monoresistant TB and MDR-TB. We compared four treatment strategies: 1) the standard World Health Organization recommended treatment strategy; 2) adding ethambutol throughout the 6-month treatment of new cases; 3) using a strengthened standardised retreatment regimen; and 4) using standardised MDR treatment for failures of initial treatment. Treatment-related outcomes were derived from the published literature, and costs from direct surveys. A strengthened retreatment regimen, which could achieve lower failure, relapse and acquired MDR rates in isoniazid monoresistant cases, was predicted to be the most cost-effective strategy in all modelled settings. Empirical MDR treatment of failures of initial treatment was the most costly strategy but resulted in the fewest deaths. Adding ethambutol throughout initial treatment would be most effective in preventing acquired MDR, but would lead to excess cases of blindness. A high priority should be given to improving the standardised retreatment regimen, as this is predicted to produce greater benefits than other recently recommended strategies.