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Background: Despite improvements in treatment success rates for tuberculosis (TB), current six-month regimen duration remains a challenge for many National TB Programmes, health systems, and patients. There is increasing investment in the development of shortened regimens with a number of candidates in phase 3 trials. Methods: We developed an individual-based decision analytic model to assess the cost-effectiveness of a hypothetical four-month regimen for first-line treatment of TB, assuming non-inferiority to current regimens of six-month duration. The model was populated using extensive, empirically-collected data to estimate the economic impact on both health systems and patients of regimen shortening for first-line TB treatment in South Africa, Brazil, Bangladesh, and Tanzania. We explicitly considered 'real world' constraints such as sub-optimal guideline adherence. Results: From a societal perspective, a shortened regimen, priced at USD1 per day, could be a cost-saving option in South Africa, Brazil, and Tanzania, but would not be cost-effective in Bangladesh when compared to one gross domestic product (GDP) per capita. Incorporating 'real world' constraints reduces cost-effectiveness. Patient-incurred costs could be reduced in all settings. From a health service perspective, increased drug costs need to be balanced against decreased delivery costs. The new regimen would remain a cost-effective option, when compared to each countries' GDP per capita, even if new drugs cost up to USD7.5 and USD53.8 per day in South Africa and Brazil; this threshold was above USD1 in Tanzania and under USD1 in Bangladesh. Conclusion: Reducing the duration of first-line TB treatment has the potential for substantial economic gains from a patient perspective. The potential economic gains for health services may also be important, but will be context-specific and dependent on the appropriate pricing of any new regimen. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) remains disproportionately concentrated among the poor, yet known determinants of TB reactivation may fail to explain observed disparities in disease rates according to wealth. Reviewing data on TB disparities in India and the wealth distribution of known TB risk factors, we describe how social mixing patterns could be contributing to TB disparities. Wealth-assortative mixing, whereby individuals are more likely to be in contact with others from similar socio-economic backgrounds, amplifies smaller differences in risk of TB, resulting in large population-level disparities. As disparities and assortativeness increase, TB becomes more difficult to control, an effect that is obscured by looking at population averages of epidemiological parameters, such as case detection rates. We illustrate how TB control efforts may benefit from preferential targeting toward the poor. In India, an equivalent-scale intervention could have a substantially greater impact if targeted at those living below the poverty line than with a population-wide strategy. In addition to potential efficiencies in targeting higher-risk populations, TB control efforts would lead to a greater reduction in secondary TB cases per primary case diagnosed if they were preferentially targeted at the poor. We highlight the need to collect programmatic data on TB disparities and explicitly incorporate equity considerations into TB control plans. [ABSTRACT FROM AUTHOR]

Background: Effective strategies are needed to facilitate the prompt diagnosis and treatment of tuberculosis in countries with a high burden of the disease.Methods: We conducted a cluster-randomized trial in which Ugandan community health centers were assigned to a multicomponent diagnostic strategy (on-site molecular testing for tuberculosis, guided restructuring of clinic workflows, and monthly feedback of quality metrics) or routine care (on-site sputum-smear microscopy and referral-based molecular testing). The primary outcome was the number of adults treated for confirmed tuberculosis within 14 days after presenting to the health center for evaluation during the 16-month intervention period. Secondary outcomes included completion of tuberculosis testing, same-day diagnosis, and same-day treatment. Outcomes were also assessed on the basis of proportions.Results: A total of 20 health centers underwent randomization, with 10 assigned to each group. Of 10,644 eligible adults (median age, 40 years) whose data were evaluated, 60.1% were women and 43.8% had human immunodeficiency virus infection. The intervention strategy led to a greater number of patients being treated for confirmed tuberculosis within 14 days after presentation (342 patients across 10 intervention health centers vs. 220 across 10 control health centers; adjusted rate ratio, 1.56; 95% confidence interval [CI], 1.21 to 2.01). More patients at intervention centers than at control centers completed tuberculosis testing (adjusted rate ratio, 1.85; 95% CI, 1.21 to 2.82), received a same-day diagnosis (adjusted rate ratio, 1.89; 95% CI, 1.39 to 2.56), and received same-day treatment for confirmed tuberculosis (adjusted rate ratio, 2.38; 95% CI, 1.57 to 3.61). Among 706 patients with confirmed tuberculosis, a higher proportion in the intervention group than in the control group were treated on the same day (adjusted rate ratio, 2.29; 95% CI, 1.23 to 4.25) or within 14 days after presentation (adjusted rate ratio, 1.22; 95% CI, 1.06 to 1.40).Conclusions: A multicomponent diagnostic strategy that included on-site molecular testing plus implementation supports to address barriers to delivery of high-quality tuberculosis evaluation services led to greater numbers of patients being tested, receiving a diagnosis, and being treated for confirmed tuberculosis. (Funded by the National Heart, Lung, and Blood Institute; XPEL-TB ClinicalTrials.gov number, NCT03044158.). [ABSTRACT FROM AUTHOR]

Competing Interests: Conflicts of interest: none declared.

Background: Household contact investigation (HCI) is an effective and widely used approach to identify persons with tuberculosis (TB) disease and infection, globally. Despite widespread recommendations for the use of HCI, there remains poor understanding of the impact on and value of contact investigation for participants. Further, how HCI as a practice impacts psychosocial factors, including stigma and possible unintended disclosure of illness among persons with TB, their families, and communities, is largely unknown., Methods: This exploratory qualitative study nested within a randomized trial (ClinicalTrials.gov: NCT04520113, 17 August 2020) was conducted in South Africa to understand the impacts of HCI on index patients living with TB and their household contact persons in two rural districts in the Limpopo province (Vhembe and Capricorn) and Soshanguve, a peri-urban township in Gauteng province. People with TB and household members of people with TB were recruited to participate in in-depth interviews and focus group discussions using semi-structured guides. We explored individual, interpersonal, and community-level perceptions of potential impacts of household contact investigation to elucidate their perceptions of HCI. Thematic analysis identified key themes., Results: Twenty-four individual interviews and six focus group discussions (n=39 participants) were conducted. Participants viewed HCI as an effective approach to finding TB cases, helpful in educating households about TB symptoms and reducing barriers to health-related services. At the interpersonal level, HCI aided people with TB in safely disclosing their TB status to family members and facilitated family and social support for accountability. The introduction of HIV testing during HCI was reported by some participants as making household members slightly uncomfortable, decreasing interest in household members being tested for TB. HCI negatively impacted community-level TB and HIV-related stigma due to healthcare worker visibility at home., Conclusion: Our data suggests varying impacts of HCI on people with TB, their families and interpersonal relationships, and communities, highlighting the importance of considering approaches that address concerns about community stigma and HIV testing to enhance acceptance of HCI., Competing Interests: Competing interests The authors declare that they have no competing interests.

Background: Both 1 month of daily (1HP) and 3 months of weekly (3HP) isoniazid-rifapentine are recommended as short-course regimens for TB prevention among people living with HIV (PLHIV). We aimed to assess acceptability and preferences for 1HP vs. 3HP among PLHIV., Methods: In a cross-sectional survey among PLHIV at an HIV clinic in Kampala, Uganda, participants were randomly assigned to a hypothetical scenario of receiving 1HP or 3HP. Participants rated their level of perceived intention and confidence to complete treatment using a 0-10 Likert scale, and chose between 1HP and 3HP., Results: Among 429 respondents (median age: 43 years, 71% female, median time on ART: 10 years), intention and confidence were rated high for both regimens. Intention to complete treatment was rated at least 7/10 by 92% (189/206 randomized to 1HP) and 93% (207/223 randomized to 3HP). Respectively 86% (178/206) and 93% (208/223) expressed high confidence to complete treatment. Overall, 81% (348/429) preferred 3HP over 1HP., Conclusions: Both 1HP and 3HP were highly acceptable regimens, with 3HP preferred by most PLHIV. Weekly, rather than daily, dosing appears preferable to shorter duration of treatment, which should inform scale-up and further development of short-course regimens for TB prevention., (© 2024 The Authors.)

BACKGROUND: TB-related stigma hampers access to diagnosis and treatment, making it important to understand the demographic and clinical characteristics associated with perceived TB stigma. TB stigma has not been studied in household contacts before, yet they comprise an important population for epidemic control, with high risk of infection. METHOD: A cross-sectional study was conducted among people with TB and household contacts in South Africa using a 12-item perceived TB stigma scale (score range: 0-36). Demographic and clinical characteristic data were collected using a close-ended questionnaire. A linear mixed-effects regression model was used to explore perceived TB stigma levels and its associated characteristics. RESULTS: The sample included 143 people with TB and 135 household contacts. The mean perceived TB stigma score among people with TB was 22.1 (95% CI 21.1-23.1) and 22.2 (95% CI 21.1-23.3) among household contacts. Being in the same household explained 24.3% variability in stigma perception. Residence in the urban study site (Soshanguve) and a positive HIV diagnosis were associated with higher perceived TB stigma score. CONCLUSIONS: People with TB and household contacts have similarly high prevalence of perceived TB stigma. Positive HIV status and urban location were associated with higher prevalence of perceived TB stigma.

BACKGROUND: Twelve weeks of weekly isoniazid and rifapentine (3HP) prevents TB disease among people with HIV (PWH), but the costs to people of taking TB preventive treatment is not well described. METHODS: We surveyed PWH who initiated 3HP at a large urban HIV/AIDS clinic in Kampala, Uganda, as part of a larger trial. We estimated the cost of one 3HP visit from the patient perspective, including both out-of-pocket costs and estimated lost wages. Costs were reported in 2021 Ugandan shillings (UGX) and US dollars (USD; USD1 = UGX3,587) RESULTS: The survey included 1,655 PWH. The median participant cost of one clinic visit was UGX19,200 (USD5.36), or 38.5% of the median weekly income. Per visit, the cost of transportation was the largest component (median: UGX10,000/USD2.79), followed by lost income (median: UGX4,200/USD1.16) and food (median: UGX2,000/USD0.56). Men reported greater income loss than women (median: UGX6,400/USD1.79 vs. UGX3,300/USD0.93), and participants who lived further than a 30-minute drive to the clinic had higher transportation costs than others (median: UGX14,000/USD3.90 vs. UGX8,000/USD2.23). CONCLUSION: Patient-level costs to receive 3HP accounted for over one-third of weekly income. Patient-centered approaches to averting or defraying these costs are needed.

BACKGROUND: Population-based active case-finding (ACF) identifies people with TB in communities but can be costly. METHODS: We conducted an empiric costing study within a door-to-door household ACF campaign in an urban community in Uganda, where all adults, regardless of symptoms, were screened by sputum Xpert Ultra testing. We used a combination of direct observation and self-reported logs to estimate staffing requirements. Study budgets were reviewed to collect costs of overheads, equipment, and consumables. Our primary outcome was the cost per person diagnosed with TB. RESULTS: Over a 28-week period, three teams of two people collected sputum from 11,341 adults, of whom 48 (0.4%) tested positive for TB. Screening 1,000 adults required 258 person-hours of effort at a cost of US$35,000, 70% of which was for GeneXpert cartridges. The estimated cost per person screened was $36 (95% uncertainty range [95% UR] 34–38), and the cost per person diagnosed with Xpert-positive TB was $8,400 (95% UR 8,000–8,900). The prevalence of TB in the underlying community was the primary modifiable determinant of the cost per person diagnosed. CONCLUSION: Door-to-door screening can be feasibly performed at scale, but will require effective triage and identification of high-prevalence populations to be affordable and cost-effective.

Objectives: Disease transmission models are used in impact assessment and economic evaluations of infectious disease prevention and treatment strategies, prominently so in the COVID-19 response. These models rarely consider dimensions of equity relating to the differential health burden between individuals and groups. We describe concepts and approaches which are useful when considering equity in the priority setting process, and outline the technical choices concerning model structure, outputs, and data requirements needed to use transmission models in analyses of health equity., Methods: We reviewed the literature on equity concepts and approaches to their application in economic evaluation and undertook a technical consultation on how equity can be incorporated in priority setting for infectious disease control. The technical consultation brought together health economists with an interest in equity-informative economic evaluation, ethicists specialising in public health, mathematical modellers from various disease backgrounds, and representatives of global health funding and technical assistance organisations, to formulate key areas of consensus and recommendations., Results: We provide a series of recommendations for applying the Reference Case for Economic Evaluation in Global Health to infectious disease interventions, comprising guidance on 1) the specification of equity concepts; 2) choice of evaluation framework; 3) model structure; and 4) data needs. We present available conceptual and analytical choices, for example how correlation between different equity- and disease-relevant strata should be considered dependent on available data, and outline how assumptions and data limitations can be reported transparently by noting key factors for consideration., Conclusions: Current developments in economic evaluations in global health provide a wide range of methodologies to incorporate equity into economic evaluations. Those employing infectious disease models need to use these frameworks more in priority setting to accurately represent health inequities. We provide guidance on the technical approaches to support this goal and ultimately, to achieve more equitable health policies., Competing Interests: Declarations of interest none., (Copyright © 2022. Published by Elsevier B.V.)

SETTING: Human mobility contributes to the spread of infectious diseases. South Africa has a long history of internal labor migration and a high burden of TB. METHODS: People newly diagnosed with TB in the Vhembe and Waterberg Districts of Limpopo answered a questionnaire regarding geographic movement over the past year. Participants were classified as 'highly mobile' (spending more than 30 nights at a residence other than their primary residence in the past year, or being ≥250 km from their primary residence at the time of the interview) or 'less mobile'. We explored associations between sociodemographic characteristics and high mobility, and between mobility and time to presentation at a clinic. RESULTS: Of the 717 participants included, 185 (25.7%) were classified as 'highly mobile'. Factors associated with high mobility included living with someone outside of Limpopo Province, HIV-positive status (men only), and current smoking (men only). Highly mobile individuals had similar care-seeking behavior as less mobile individuals (adjusted time ratio 0.9, 95% CI 0.6-1.2, P = 0.304) CONCLUSION: Highly mobile people with TB in Limpopo Province were more likely to live with people from outside the province, smoke, and have HIV. These patients had similar delays in seeking care as less mobile individuals.

Active case-finding (ACF) is an important component of the End TB Strategy. However, ACF is resource-intensive, and the economics of ACF are not well-understood. Data on the costs of ACF are limited, with little consistency in the units and methods used to estimate and report costs. Mathematical models to forecast the long-term effects of ACF require empirical measurements of the yield, timing and costs of case detection. Pragmatic trials offer an opportunity to assess the cost-effectiveness of ACF interventions within a 'real-world´ context. However, such analyses generally require early introduction of economic evaluations to enable prospective data collection on resource requirements. Closing the global case-detection gap will require substantial additional resources, including continued investment in innovative technologies. Research is essential to the optimal implementation, cost-effectiveness, and affordability of ACF in high-burden settings. To assess the value of ACF, we must prioritize the collection of high-quality data regarding costs and effectiveness, and link those data to analytical models that are adapted to local settings.

INTRODUCTION: Patients being treated for TB may suffer reductions in health-related quality of life (HRQoL). This study aims to assess the extent of such reductions and the trajectory of HRQoL over the course of treatment in rural Malawi. METHODS: We collected patient demographic and socioeconomic status, TB-related characteristics, and HRQoL data (i.e., EQ-5D and a visual analogue scale VAS) from adults (age ≥18 years) being treated for TB in 12 primary health centers and one hospital in rural Thyolo District, Malawi, from 2014 to 2016. Associations between HRQoL and patient characteristics were estimated using multivariable linear regression. RESULTS: Inpatients ( n = 197) consistently showed lower median HRQoL scores and suffered more severe health impairments during hospitalization than outpatients ( n = 156) (EQ5D and VAS: 0.79, 55 vs. 0.84, 70). Longer treatment duration was associated with higher HRQoL among outpatients (EQ5D: 0.034 increase per 2 months, 95%CI 0.012-0.057). We found no substantial associations between patients´ demographic and socioeconomic characteristics and HRQoL in this setting. CONCLUSION: HRQoL scores among patients receiving treatment for TB in rural Malawi differ by clinical setting and duration of treatment, with greater impairment among inpatients and those early in their treatment course.

BACKGROUND: There has been slow uptake of isoniazid preventive therapy (IPT) among people living with HIV (PLWH). METHODS: We surveyed adults recently diagnosed with HIV in 14 South African primary health clinics. Based on the literature and qualitative interviews, sixteen potential barriers and facilitators related to preventive therapy among PLWH were selected. Best-worst scaling (BWS) was used to quantify the relative importance of the attributes. BWS scores were calculated based on the frequency of participants' selecting each attribute as the best or worst among six options (across multiple choice sets) and rescaled from 0 (always selected as worst) to 100 (always selected as best) and compared by currently receiving IPT or not. RESULTS: Among 342 patients surveyed, 33% ( n = 114) were currently taking IPT. Having the same standard of life as someone without HIV was most highly prioritized (BWS score = 67.3, SE = 0.6), followed by trust in healthcare providers (score, 66.3 ± 0.6). Poor standard of care in public clinics (score, 30.6 ± 0.6) and side effects of medications (score, 33.7 ± 0.6) were least prioritized. BWS scores differed by IPT status for few attributes, but overall ranking was similar (spearman's rho = 0.9). CONCLUSION: Perceived benefits of preventive therapy were high among PLWH. IPT prescription by healthcare providers should be encouraged to enhance IPT uptake among PLWH.

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.

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., Competing Interests: Conflicts of interest: none declared., (© 2019 The Union.)

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.

Objective: To estimate the incremental cost-effectiveness of universal vs. test-directed treatment of latent tuberculous infection (LTBI) among human immunodeficiency virus (HIV) positive pregnant women in South Africa., Methods: We compared tuberculin skin test (TST) directed isoniazid preventive therapy (IPT) (TST placement with delivery of IPT to women with positive results) against QuantiFERON ® -TB Gold In-Tube (QGIT) directed IPT and universal IPT using decision analysis. Costs were measured empirically in six primary care public health clinics in Matlosana, South Africa. The primary outcome was the incremental cost-effectiveness ratio, expressed in 2016 US$ per disability-adjusted life-year (DALY) averted., Results: We estimated that 29.2 of every 1000 pregnant women would develop TB over the course of 1 year in the absence of IPT. TST-directed IPT reduced this number to 24.5 vs. 22.6 with QGIT-directed IPT and 21.0 with universal IPT. Universal IPT was estimated to cost $640/DALY averted (95% uncertainty range $44-$3146) relative to TST-directed IPT and was less costly and more effective (i.e., dominant) than QGIT-directed IPT. Cost-effectiveness was most sensitive to the probability of developing TB and LTBI prevalence., Conclusion: Providing IPT to all eligible women can be a cost-effective strategy to prevent TB among HIV-positive pregnant women in South Africa.

Setting: To reduce the risk of tuberculosis (TB) among individuals with human immunodeficiency virus (HIV) infection, the World Health Organization recommends at least 6 months of isoniazid preventive therapy (IPT). Completion of IPT remains a major challenge in resource-limited settings., Objective: To evaluate predictors of IPT completion in individuals newly diagnosed with HIV., Design: Predictors of IPT completion among adults newly diagnosed with HIV in rural Malawi were evaluated using a multilevel logistic regression model., Results: Of 974 participants who screened negative for active TB and were started on IPT, 732 (75%) completed treatment. Only one IPT-eligible individual refused treatment. Participants who were aged <25 years (compared with those aged 45 years, adjusted OR [aOR] 0.33, 95%CI 0.18-0.60) and male (compared to non-pregnant females, aOR 0.57, 95%CI 0.37-0.88) had lower odds of IPT completion., Conclusion: IPT provision at the time of initial HIV diagnosis was highly acceptable in rural Malawi; three quarters of those who initiated IPT successfully completed therapy. We observed lower odds of completion among males and among female participants aged <25 years. Additional efforts may be needed to ensure IPT completion among males and young females who have recently been diagnosed with HIV.

Setting: Ten primary health clinics in rural Thyolo District, Malawi., Objective: Tuberculosis (TB) is a common initial presentation of human immunodeficiency virus (HIV) infection. We investigated the time from TB symptom onset to HIV diagnosis to describe TB health-seeking behaviour in adults newly diagnosed with HIV., Design: We asked adults (18 years) about the presence and duration of TB symptoms at the time of receiving a new HIV diagnosis. Associations with delayed health seeking (defined as >30 and >90 days from the onset of TB symptoms) were evaluated using multivariable logistic regression., Results: TB symptoms were reported by 416 of 1265 participants (33%), of whom 36% (150/416) had been symptomatic for >30 days before HIV testing. Most participants (260/416, 63%) were below the poverty line (US$0.41 per household member per day). Patients who first sought care from informal providers had an increased odds of delay of >30 days (adjusted odds ratio [aOR] 1.6, 95%CI 0.9-2.8) or 90 days (aOR 2.0, 95%CI 1.1-3.8)., Conclusions: Delayed health seeking for TB-related symptoms was common. Poverty was ubiquitous, but had no clear relationship to diagnostic delay. HIV-positive individuals who first sought care from informal providers were more likely to experience diagnostic delays for TB symptoms.

Introduction: Despite the close link between tuberculosis (TB) and poverty, most mathematical models of TB have not addressed underlying social and structural determinants., Objective: To review studies employing mathematical modelling to evaluate the epidemiological impact of the structural determinants of TB., Methods: We systematically searched PubMed and personal libraries to identify eligible articles. We extracted data on the modelling techniques employed, research question, types of structural determinants modelled and setting., Results: From 232 records identified, we included eight articles published between 2008 and 2015; six employed population-based dynamic TB transmission models and two non-dynamic analytic models. Seven studies focused on proximal TB determinants (four on nutritional status, one on wealth, one on indoor air pollution, and one examined overcrowding, socio-economic and nutritional status), and one focused on macro-economic influences., Conclusions: Few modelling studies have attempted to evaluate structural determinants of TB, resulting in key knowledge gaps. Despite the challenges of modelling such a complex system, models must broaden their scope to remain useful for policy making. Given the intersectoral nature of the interrelations between structural determinants and TB outcomes, this work will require multidisciplinary collaborations. A useful starting point would be to focus on developing relatively simple models that can strengthen our knowledge regarding the potential effect of the structural determinants on TB outcomes.

Objective: To assess the feasibility of a streamlined strategy for improving tuberculosis (TB) diagnostic evaluation and treatment initiation among patients with presumed TB., Design: Single-arm interventional pilot study at five primary care health centers of a streamlined, SIngle-saMPLE (SIMPLE) TB diagnostic evaluation strategy: 1) examination of two smear results from a single spot sputum specimen using light-emitting diode fluorescence microscopy, and 2) daily transportation of smear-negative sputum samples to Xpert® MTB/RIF testing sites., Results: Of 1212 adults who underwent sputum testing for TB, 99.6% had two smears examined from the spot sputum specimen. Sputum was transported for Xpert testing within 1 clinic day for 83% (907/1091) of the smear-negative patients. Of 157 (13%) patients with bacteriologically positive TB, 116 (74%) were identified using sputum smear microscopy and 41 (26%) using Xpert testing of smear-negative samples. Anti-tuberculosis treatment was initiated in 142 (90%) patients with bacteriologically positive TB, with a median time to treatment of 1 day for smear-positive patients and 6 days for smear-negative, Xpert-positive patients., Conclusion: The SIMPLE TB strategy led to successful incorporation of Xpert testing and rapid treatment initiation in the majority of patients with bacteriologically confirmed TB in a resource-limited setting.

Setting: The diagnosis and treatment of tuberculosis (TB) in India are characterized by heavy private-sector involvement. Delays in treatment remain poorly characterized among patients seeking care in the Indian private sector., Objective: To assess delays in TB diagnosis and treatment initiation among patients diagnosed in the private sector, and pathways to care in an urban setting., Design: Cross-sectional survey of 289 consecutive patients diagnosed with TB in the private sector and referred for anti-tuberculosis treatment through a public-private mix program in Chennai from January 2014 to February 2015., Results: Among 212 patients with pulmonary TB, 90% first contacted a formal private provider, and 78% were diagnosed by the first or second provider seen after a median of three visits per provider. Median total delay was 51 days (mean 68). Consulting an informal (rather than formally trained) provider first was associated with significant increases in total delay (absolute increase 22.8 days, 95%CI 6.2-39.5) and in the risk of prolonged delay >90 days (aRR 2.4, 95%CI 1.3-4.4)., Conclusion: Even among patients seeking care in the formal (vs. informal) private sector in Chennai, diagnostic delays are substantial. Novel strategies are required to engage private providers, who often serve as the first point of contact.

User-friendly models (UFMs) allow local decision makers to explore relationships and apply results from more detailed models of such outcomes as cost-effectiveness. When developing UFMs, modelers must decide which simplifications may be appropriate, enabling the UFM to retain accuracy while reducing complexity. We use the example of cost-effectiveness analysis (CEA) for novel shortened anti-tuberculosis treatment regimens across four settings to demonstrate how UFMs can allow decision makers to adapt published results to their local context. We simplified a complex model to produce a UFM that provides similar results, the ability to modify key parameter values, and receive customized results in seconds.

Tuberculosis (TB) remains disproportionately concentrated among the poor, yet known determinants of TB reactivation may fail to explain observed disparities in disease rates according to wealth. Reviewing data on TB disparities in India and the wealth distribution of known TB risk factors, we describe how social mixing patterns could be contributing to TB disparities. Wealth-assortative mixing, whereby individuals are more likely to be in contact with others from similar socio-economic backgrounds, amplifies smaller differences in risk of TB, resulting in large population-level disparities. As disparities and assortativeness increase, TB becomes more difficult to control, an effect that is obscured by looking at population averages of epidemiological parameters, such as case detection rates. We illustrate how TB control efforts may benefit from preferential targeting toward the poor. In India, an equivalent-scale intervention could have a substantially greater impact if targeted at those living below the poverty line than with a population-wide strategy. In addition to potential efficiencies in targeting higher-risk populations, TB control efforts would lead to a greater reduction in secondary TB cases per primary case diagnosed if they were preferentially targeted at the poor. We highlight the need to collect programmatic data on TB disparities and explicitly incorporate equity considerations into TB control plans.

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

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

Background: Drug susceptibility testing (DST) against second-line tuberculosis drugs (SLDs) is essential for improving outcomes among multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) cases., Objective: To evaluate the potential cost-effectiveness of rapid DST for SLDs., Design: We constructed a decision analysis model of Xpert MTB/RIF-based TB diagnosis in East and South-East Asia to compare culture-based DST vs. a hypothetical rapid SLD DST system for specimens resistant to rifampin. Our primary outcomes were the effectiveness and incremental cost-effectiveness of a rapid SLD DST assay relative to culture-based DST., Results: For rapid SLD DST to be more effective than culture-based DST, treating individuals with pre-XDR/XDR-TB with a standardized MDR-TB regimen while awaiting culture-based DST must incur at least 30% excess XDR-TB mortality (100% = treatment with first-line drugs); rapid SLD DST should attain an aggregate sensitivity and specificity for all pre-XDR/XDR mutations of 88% and 96%, respectively. The unit cost of the rapid SLD DST assay must approach that of culture to achieve common thresholds for cost-effectiveness in low-income countries., Conclusion: Rapid SLD DST has the potential to be cost-effective, but must meet stringent criteria for accuracy and costs, and requires that standardized second-line treatment for pre-XDR/XDR-TB incur substantial excess mortality before the return of culture results.

Existing approaches to tuberculosis (TB) control have been no more than partially successful in areas with high human immunodeficiency virus (HIV) prevalence. In the context of increasingly constrained resources, mathematical modelling can augment understanding and support policy for implementing those strategies that are most likely to bring public health and economic benefits. In this paper, we present an overview of past and recent contributions of TB modelling in this key area, and suggest a way forward through a modelling research agenda that supports a more effective response to the TB-HIV epidemic, based on expert discussions at a meeting convened by the TB Modelling and Analysis Consortium. The research agenda identified high-priority areas for future modelling efforts, including 1) the difficult diagnosis and high mortality of TB-HIV; 2) the high risk of disease progression; 3) TB health systems in high HIV prevalence settings; 4) uncertainty in the natural progression of TB-HIV; and 5) combined interventions for TB-HIV. Efficient and rapid progress towards completion of this modelling agenda will require co-ordination between the modelling community and key stakeholders, including advocates, health policy makers, donors and national or regional finance officials. A continuing dialogue will ensure that new results are effectively communicated and new policy-relevant questions are addressed swiftly.

Setting: Programmatic management of drug-resistant tuberculosis at Persahabatan Hospital, Jakarta, Indonesia., Objective: To evaluate the association between body mass index (BMI) and sputum culture conversion during treatment for multidrug-resistant tuberculosis (MDR-TB)., Design: We conducted a retrospective cohort study of 212 MDR-TB patients. MDR-TB was confirmed using culture in liquid medium and line-probe assay. Patients were treated with a standardised regimen unless they were resistant to any of the drugs tested. Study outcomes were time to culture conversion (primary) and probability of conversion within 4 months (secondary). Data were analysed using Kaplan-Meier curves, discrete time-survival analysis and Poisson regression., Results: Compared to patients with normal weight (BMI ≥18.5 kg/m(2)), severely underweight patients (BMI <16 kg/m(2)) had longer time to initial conversion (adjusted hazard ratio [aHR] 0.55, 95%CI 0.37-0.84) and a lower probability of sputum culture conversion within 4 months (adjusted relative risk 0.67, 95%CI 0.54-0.83). Other predictors for longer sputum culture conversion were female sex (aHR 0.55, 95%CI 0.39-0.78), resistance to injectables (aHR 0.59, 95%CI 0.42-0.83) and high baseline smear grade (aHR 0.33, 95%CI 0.18-0.60)., Conclusion: Severe underweight was associated with longer time to initial sputum culture conversion among MDR-TB patients.

Infectious disease models are important tools for understanding epidemiology and supporting policy decisions for disease control. In the case of tuberculosis (TB), such models have informed our understanding and control strategies for over 40 years, but the primary assumptions of these models--and their most urgent data needs--remain obscure to many TB researchers and control officers. The structure and parameter values of TB models are informed by observational studies and experiments, but the evidence base in support of these models remains incomplete. Speaking from the perspective of infectious disease modelers addressing the broader TB research and control communities, we describe the basic structure common to most TB models and present a 'wish list' that would improve the evidence foundation upon which these models are built. As a comprehensive TB research agenda is formulated, we argue that the data needs of infectious disease models--our primary long-term decision-making tools--should figure prominently.

As active screening strategies for tuberculosis (TB) continue to rise globally, it has become increasingly important to consider the methodological challenges in designing and implementing these strategies. The key challenges associated with TB screening can be summarized in terms of four continua or spectra, namely those of 1) TB disease and diagnostic yield, 2) TB risk and resource availability, 3) TB screening strategies, and 4) outcomes and impact measurements of screening programs. In this review, we provide a discussion of these challenges to help guide development of TB screening strategies that will be effective in a given epidemiological setting.

Objective: To evaluate the cost-effectiveness of novel first-line treatment regimens for tuberculosis (TB)., Design: Using decision analysis, we projected the costs and effectiveness, from the health care perspective, of treating a patient cohort in the public sector for active TB without known or suspected resistance to first-line drugs. We compared standard (6-month) treatment to hypothetical regimens of equal efficacy, higher cost and shorter duration., Results: For every 100 TB patients treated, replacing standard treatment with shorter-course regimens would avert an estimated 2-4 failures/relapses, 0.2-0.4 deaths and 8-14 disability-adjusted life years (DALYs), or 6-11% of all DALYs suffered. We identified three primary determinants of cost-effectiveness: drug price, continuation phase treatment delivery costs and deaths averted through fewer relapses. In a high treatment cost scenario (similar to Brazil), averted delivery costs outweighed higher drug costs, making novel regimens cost-saving. In a low treatment cost scenario (similar to the Philippines), a 4-month regimen with a drug price of $1/day cost $66 per patient, or $840 per DALY averted, and became cost-saving if the drug price dropped below $0.37/day., Conclusion: Although they avert a small proportion of total DALYs, novel, shorter-course first-line regimens for TB are likely to be cost-effective or cost-saving in most settings.

Setting: In-patient hospitals in South Africa and Uganda., Objective: To evaluate the cost-effectiveness of a lateral-flow urine lipoarabinomannan (LAM) test when added to existing strategies for tuberculosis (TB) diagnosis in human immunodeficiency virus infected adults (CD4(+) T-cell counts < 100 cells/l) with symptoms of active TB., Design: Decision-analytic cost-utility model, with the primary outcome being the incremental cost-effectiveness ratio, expressed in 2010 US dollars per disability-adjusted life year (DALY) averted from the perspective of a public sector TB control program., Results and Conclusion: For every 1000 patients tested, adding lateral-flow urine LAM generated 80 incremental appropriate anti-tuberculosis treatments and averted 224 DALYs. Estimated cost utility was US$353 per DALY averted (95% uncertainty range $192$1161) in South Africa and $86 per DALY averted (95% uncertainty range $49$239) in Uganda, reflecting the lower treatment costs in Uganda. Cost utility was most sensitive to assay specificity, cost of anti-tuberculosis treatment, life expectancy after TB cure and cohort TB prevalence, but did not rise above $1500 per DALY averted in South Africa under any one-way sensitivity analysis. The probability of acceptability was >99.8% at a per-DALY willingness-to-pay threshold equal to the per capita gross domestic product in South Africa ($7275) and Uganda ($509).

We measured quality of life (QOL) among individuals receiving treatment for human immunodeficiency virus (HIV; n = 45), active tuberculosis (TB; n = 44) and both TB and HIV (n = 9) in Rio de Janeiro, Brazil. Active treated TB was associated with lower physical health (absolute decrease of 0.95 standard deviation in summary score), but not mental health, among people being treated for HIV. Visual analogue scale scores were similar across all three populations, and corresponded closely to standard disability weights used in the literature. Among patients receiving treatment, those with HIV, active TB and both conditions together appear to have similar QOL.