Pharmacokinetics and Optimal Dosing of Levofloxacin in Children for Drug-Resistant Tuberculosis: An Individual Patient Data Meta-Analysis.

BACKGROUND: Each year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children. METHODS: Levofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)-recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses. RESULTS: Data from 242 children (2.8 years [0.2-16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16-33 mg/kg for dispersible tablets or 16-50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax. CONCLUSIONS: Revised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses.

Scale-Up of Rifapentine and Isoniazid for Tuberculosis Prevention Among Household Contacts in 2 Urban Centers: An Effectiveness Assessment.

BACKGROUND: Scaling up a shorter preventive regimen such as weekly isoniazid and rifapentine (3HP) for 3 months is a priority for tuberculosis (TB) preventive treatment (TPT). However, there are limited data on 3HP acceptability and completion from high-burden-TB countries. METHODS: We scaled up 3HP from 2018 to 2021 in 2 cities in Pakistan. Eligible participants were household contacts of persons diagnosed with TB disease. Participants were prescribed 3HP after ruling out TB disease. Treatment was self-administered. We analyzed the proportion who completed 3HP. RESULTS: In Karachi, we verbally screened 22 054 household contacts of all ages. Of these, 83% were clinically evaluated and 3% were diagnosed with TB. Of household contacts without TB disease, 59% initiated the 3HP regimen, of which 69% completed treatment. In Peshawar, we verbally screened 6389 household contacts of all ages. We evaluated 95% of household contacts, of whom 2% were diagnosed with TB disease. Among those without TB disease, 65% initiated 3HP, of which 93% completed. Factors associated with higher 3HP completion included residence in Peshawar (risk ratio [RR], 1.35 [95% confidence interval {CI}: 1.32-1.37]), index patient being a male (RR, 1.03 [95% CI: 1.01-1.05]), and index patient with extrapulmonary TB compared to bacteriologically positive pulmonary TB (RR, 1.10 [95% CI: 1.06-1.14]). The age of the index patient was inversely associated with completion. CONCLUSIONS: We observed a high level of acceptance and completion of 3HP in programs implemented in 2 cities in Pakistan, with differences observed across the cities. These findings suggest that 3HP can be effectively scaled up in urban settings to improve the reach and impact of TPT.

Tuberculosis care models for children and adolescents: a scoping review.

Objective: To map which tuberculosis care models are best suited for children and adolescents. Methods: We conducted a scoping review to assess the impact of decentralized, integrated and family-centred care on child and adolescent tuberculosis-related outcomes, describe approaches for these care models and identify key knowledge gaps. We searched seven literature databases on 5 February 2021 (updated 16 February 2022), searched the references of 18 published reviews and requested data from ongoing studies. We included studies from countries with a high tuberculosis burden that used a care model of interest and reported tuberculosis diagnostic, treatment or prevention outcomes for an age group < 20 years old. Findings: We identified 28 studies with a comparator group for the impact assessment and added 19 non-comparative studies to a qualitative analysis of care delivery approaches. Approaches included strengthening capacity in primary-level facilities, providing services in communities, screening for tuberculosis in other health services, co-locating tuberculosis and human immunodeficiency virus treatment, offering a choice of treatment location and providing social or economic support. Strengthening both decentralized diagnostic services and community linkages led to one-to-sevenfold increases in case detection across nine studies and improved prevention outcomes. We identified only five comparative studies on integrated or family-centred care, but 11 non-comparative studies reported successful treatment outcomes for at least 71% of children and adolescents. Conclusion: Strengthening decentralized services in facilities and communities can improve tuberculosis outcomes for children and adolescents. Further research is needed to identify optimal integrated and family-centred care approaches.

Risk Factors for Adverse Events in Household Contacts Prescribed Preventive Treatment for Drug-resistant Tuberculosis Exposure.

BACKGROUND: Completion of tuberculosis (TB) preventive treatment is important to optimize efficacy; treatment-related adverse events (AEs) sometimes result in discontinuation. This study describes the occurrence of AEs and their risk factors during a 6-month, 2-drug, fluoroquinolone-based preventive treatment for household contacts of patients with drug-resistant TB in Karachi, Pakistan. METHODS: The primary outcome was development of any clinical AE during preventive treatment. Adverse events were categorized using the AE grading tables of the National Institutes of Health. Time-to-event analysis with Kaplan-Meier curves and Cox proportional hazards models accounting for recurrence were used to analyze associated risk factors. RESULTS: Of the 172 household contacts on preventive treatment, 36 (21%) developed 64 AEs during 813 months of treatment. The incidence of AEs over 6 months of treatment was 7.9 per 100 person-months; 16 per 100 person-months with a fluoroquinolone and ethionamide, and 4.4 per 100 person-months with a fluoroquinolone and ethambutol. There were 53 (83%) grade 1 and 11 grade 2 AEs, with no grade 3 or 4 AEs. In multivariable analysis, the risk of AEs was higher in contacts prescribed ethionamide as compared to ethambutol adjusting for age, sex, and body mass index (adjusted hazard ratio, 2.1 [95% confidence interval {CI}, 1.2-3.6]). Overall, there was no notable difference in treatment completion among the contacts who experienced an AE and those who did not (crude odds ratio, 1.1 [95% CI, .52-2.5]). CONCLUSIONS: A fluoroquinolone-based preventive treatment regimen for drug-resistant TB exposure is well tolerated. Regimens with ethionamide are more likely to result in AEs.

Cost of Delivering 12-Dose Isoniazid and Rifapentine Versus 6 Months of Isoniazid for Tuberculosis Infection in a High-Burden Setting.

BACKGROUND: Successful delivery and completion of tuberculosis preventive treatment are necessary for tuberculosis elimination. Shorter preventive treatment regimens currently have higher medication costs, but patients spend less time in care and are more likely to complete treatment. It is unknown how economic costs of successful delivery differ between longer and shorter regimens in high-tuberculosis-burden settings. METHODS: We developed survey instruments to collect costs from program and patient sources, considering costs incurred from when household contacts first entered the health system. We compared the cost per completed course of preventive treatment with either 6 months of daily isoniazid (6H) or 3 months of weekly isoniazid and rifapentine (3HP), delivered by the Indus Health Network tuberculosis program in Karachi, Pakistan, between October 2016 and February 2018. RESULTS: During this period, 459 individuals initiated 6H and 643 initiated 3HP; 39% and 61% completed treatment, respectively. Considering costs to both the program and care recipients, the cost per completed course was 394 US dollars (USD) for 6H and 333 USD for 3HP. Using a new 2020 price for rifapentine reduced the cost per completed course of 3HP to 290 USD. Under varying assumptions about drug prices and costs incurred by care recipients, the cost per completed course was lower for 3HP in all scenarios, and the largest cost drivers were the salaries of clinical staff. CONCLUSIONS: In a high-burden setting, the cost of successful delivery of 3HP was lower than that of 6H, driven by higher completion.

Isoniazid or rifampicin preventive therapy with and without screening for subclinical TB: a modeling analysis.

BACKGROUND: Short-course, rifamycin-based regimens could facilitate scale-up of tuberculosis preventive therapy (TPT), but it is unclear how stringently tuberculosis (TB) disease should be ruled out before TPT use. METHODS: We developed a state-transition model of a TPT intervention among two TPT-eligible cohorts: adults newly diagnosed with HIV in South Africa (PWH) and TB household contacts in Pakistan (HHCs). We modeled two TPT regimens-4 months of rifampicin [4R] or 6 months of isoniazid [6H]-comparing each to a reference of no intervention. Before initiating TPT, TB disease was excluded either through symptom-only screening or with additional radiographic screening that could detect subclinical TB but might limit access to the TPT intervention. TPT's potential curative effects on both latent and subclinical TB were modeled, as were both acquisitions of resistance and prevention of drug-resistant disease. Although all eligible individuals received the screening and/or TPT interventions, the modeled TB outcomes comprised only those with latent or subclinical TB that would have progressed to symptomatic disease if untreated. RESULTS: When prescribed after only symptom-based TB screening (such that individuals with subclinical TB were included among TPT recipients), 4R averted 45 active (i.e., symptomatic) TB cases (95% uncertainty range 24-79 cases or 40-89% of progressions to active TB) per 1000 PWH [17 (9-29, 43-94%) per 1000 HHCs]; 6H averted 37 (19-66, 52-73%) active TB cases among PWH [13 (7-23, 53-75%) among HHCs]. With this symptom-only screening, for each net rifampicin resistance case added by 4R, 12 (3-102) active TB cases were averted among PWH (37 [9-580] among HHCs); isoniazid-resistant TB was also reduced. Similarly, 6H after symptom-only screening increased isoniazid resistance while reducing overall and rifampicin-resistant active TB. Screening for subclinical TB before TPT eliminated this net increase in resistance to the TPT drug; however, if the screening requirement reduced TPT access by more than 10% (the estimated threshold for 4R among HHCs) to 30% (for 6H among PWH), it was likely to reduce the intervention's overall TB prevention impact. CONCLUSIONS: All modeled TPT strategies prevent TB relative to no intervention, and differences between TPT regimens or between screening approaches are small relative to uncertainty in the outcomes of any given strategy. If most TPT-eligible individuals can be screened for subclinical TB, then pairing such screening with rifamycin-based TPT maximizes active TB prevention and does not increase rifampicin resistance. Where subclinical TB cannot be routinely excluded without substantially reducing TPT access, the choice of TPT regimen requires weighing 4R's efficacy advantages (as well as its greater safety and shorter duration that we did not directly model) against the consequences of rifampicin resistance in a small fraction of recipients.

Sub-district level correlation between tuberculosis notifications and socio-demographic factors in Dhaka City corporation, Bangladesh.

We developed a novel method to align two data sources (TB notifications and the Demographic Health Survey, DHS) captured at different geographic scales. We used this method to identify sociodemographic indicators - specifically population density - that were ecologically correlated with elevated TB notification rates across wards (~100 000 people) in Dhaka, Bangladesh. We found population density was the variable most closely correlated with ward-level TB notification rates (Spearman's rank correlation 0.45). Our approach can be useful, as publicly available data (e.g. DHS data) could help identify factors that are ecologically associated with disease burden when more granular data (e.g. ward-level TB notifications) are not available. Use of this approach might help in designing spatially targeted interventions for TB and other diseases in settings of weak existing data on disease burden at the subdistrict level.

Quantifying geographic heterogeneity in TB incidence and the potential impact of geographically targeted interventions in South and North City Corporations of Dhaka, Bangladesh: a model-based study.

In rapidly growing and high-burden urban centres, identifying tuberculosis (TB) transmission hotspots and understanding the potential impact of interventions can inform future control and prevention strategies. Using data on local demography, TB reports and patient reporting patterns in Dhaka South City Corporation (DSCC) and Dhaka North City Corporation (DNCC), Bangladesh, between 2010 and 2017, we developed maps of TB reporting rates across wards in DSCC and DNCC and identified wards with high rates of reported TB (i.e. 'hotspots') in DSCC and DNCC. We developed ward-level transmission models and estimated the potential epidemiological impact of three TB interventions: active case finding (ACF), mass preventive therapy (PT) and a combination of ACF and PT, implemented either citywide or targeted to high-incidence hotspots. There was substantial geographic heterogeneity in the estimated TB incidence in both DSCC and DNCC: incidence in the highest-incidence wards was over ten times higher than in the lowest-incidence wards in each city corporation. ACF, PT and combined ACF plus PT delivered to 10% of the population reduced TB incidence by a projected 7%-9%, 13%-15% and 19%-23% over five years, respectively. Targeting TB hotspots increased the projected reduction in TB incidence achieved by each intervention 1.4- to 1.8-fold. The geographical pattern of TB notifications suggests high levels of ongoing TB transmission in DSCC and DNCC, with substantial heterogeneity at the ward level. Interventions that reduce transmission are likely to be highly effective and incorporating notification data at the local level can further improve intervention efficiency.

Tuberculosis Preventive Therapy for Individuals Exposed to Drug-resistant Tuberculosis: Feasibility and Safety of a Community-based Delivery of Fluoroquinolone-containing Preventive Regimen.

BACKGROUND: Observational studies have demonstrated the effectiveness of a fluoroquinolone-based regimen to treat individuals presumed to be infected with drug-resistant tuberculosis (DR-TB). We sought to assess the feasibility of this approach in an urban setting in South Asia. METHODS: From February 2016 until March 2017, all household contacts of DR-TB patients enrolled at the Indus Hospital were screened for TB symptoms at home. Children aged 0-17 years, symptomatic adults, and those with an immunocompromising condition (human immunodeficiency virus, diabetes, or malnutrition) were evaluated for TB disease. Contacts diagnosed with TB disease were started on treatment. Contacts without TB disease aged <5 years, contacts aged between 5 and 17 years with either a positive tuberculin skin test or an immunocompromising condition, or contacts aged ≥18 years with an immunocompromising condition were offered 6 months of treatment with a fluoroquinolone. RESULTS: One hundred households with 800 contacts were enrolled: 353 (44.1%) individuals aged ≤17 years with a median age of 19 years (interquartile range, 10-32); 423 (52.9%) were males. In total, 737 (92.1%) individuals were screened, of which 8 were already on treatment for TB (1.1%); another 3 (0.4%) contacts were diagnosed with TB disease and started on treatment. Of 215 eligible for infection treatment, 172 (80.0%) contacts initiated and 121 (70.3%) completed treatment. No TB disease or significant adverse events were observed during 12 months of follow-up. CONCLUSIONS: Fluoroquinolone-based treatment for contacts with presumed DR-TB infection is feasible and well tolerated in a high TB burden setting.

Pharmacokinetics of Levofloxacin in Children Treated for Exposure to Drug-Resistant Tuberculosis.

Levofloxacin is used to treat and prevent drug-resistant tuberculosis in children. We assessed levofloxacin serum drug concentrations in 24 children aged 2 to 10 years who received levofloxacin-based tuberculosis preventive therapy in Karachi, Pakistan. Only 9 children (37.5%) achieved adequate drug exposure. Target serum drug concentration was met in 4 (26.7%) of 15 children dosed consistently with World Health Organization recommendations and 4 (80.0%) of 5 who received higher-than-recommended doses. Levofloxacin dosing recommendations may require reevaluation.

Correction to: The cost-effectiveness of incentive-based active case finding for tuberculosis (TB) control in the private sector Karachi, Pakistan.

In the original publication of this article [1], an author's name needs to be revised from Jacob Creswel to Jacob Creswell.

The cost-effectiveness of incentive-based active case finding for tuberculosis (TB) control in the private sector Karachi, Pakistan.

BACKGROUND: In Asia, over 50% of patients with symptoms of tuberculosis (TB) access health care from private providers. These patients are usually not notified to the National TB Control Programs, which contributes to low notification rates in many countries. METHODS: From January 1, 2011 to December 31, 2012, Karachi's Indus Hospital - a private sector partner to the National TB Programme - engaged 80 private family clinics in its catchment area in active case finding using health worker incentives to increase notification of TB disease. The costs incurred were estimated from the perspective of patients, health facility and the program providing TB services. A Markov decision tree model was developed to calculate the cost-effectiveness of the active case finding as compared to case detection through the routine passive TB centers. Pakistan has a large private health sector, which can be mobilized for TB screening using an incentivized active case finding strategy. Currently, TB screening is largely performed in specialist public TB centers through passive case finding. Active and passive case finding strategies are assumed to operate independently from each other. RESULTS: The incentive-based active case finding program costed USD 223 per patient treated. In contrast, the center based non-incentive arm was 23.4% cheaper, costing USD 171 per patient treated. Cost-effectiveness analysis showed that the incentive-based active case finding program was more effective and less expensive per DALY averted when compared to the baseline passive case finding as it averts an additional 0.01966 DALYs and saved 15.74 US$ per patient treated. CONCLUSION: Both screening strategies appear to be cost-effective in an urban Pakistan context. Incentive driven active case findings of TB in the private sector costs less and averts more DALYs per health seeker than passive case finding, when both alternatives are compared to a common baseline situation of no screening.

Operationalization of bi-directional screening for tuberculosis and diabetes in private sector healthcare clinics in Karachi, Pakistan.

BACKGROUND: Many countries are facing overlapping epidemics of tuberculosis (TB) and diabetes mellitus (DM). Diabetes increases the overall risk of developing Tuberculosis (TB) and contributes to adverse treatment outcomes. Active screening for both diseases can reduce TB transmission and prevent the development of complications of DM. We investigated bi-directional TB-DM screening in Karachi, Pakistan, a country that ranks fifth among high TB burden countries, and has the seventh highest country burden for DM. METHODS: Between February to November 2014, community-based screeners identified presumptive TB and DM through verbal screening at private health clinics. Individuals with presumptive TB were referred for a chest X-ray and Xpert MTB/RIF. Presumptive DM cases had random blood glucose (RBS) tested. All individuals with bacteriologically positive TB were referred for diabetes testing (RBS). All pre-diabetics and diabetics were referred for a chest X-ray and Xpert MTB/RIF test. The primary outcomes of this study were uptake of TB and DM testing. RESULTS: A total of 450,385 individuals were screened, of whom 18,109 had presumptive DM and 90,137 had presumptive TB. 14,550 of these individuals were presumptive for both DM and TB. The uptake of DM testing among those with presumptive diabetes was 26.1% while the uptake of TB testing among presumptive TB cases was 5.9%. Despite efforts to promote bi-directional screening of TB and DM, the uptake of TB testing among pre-diabetes and diabetes cases was only 4.7%, while the uptake of DM testing among MTB positive cases was 21.8%. CONCLUSION: While a high yield for TB was identified among pre-diabetics and diabetics along with a high yield of DM among individuals diagnosed with TB, there was a low uptake of TB testing amongst presumptive TB patients who were recorded as pre-diabetic or diabetic. Bi-directional screening for TB and DM which includes the integration of TB diagnostics, DM screening and TB-DM treatment within existing health care programs will need to address the operational challenges identified before implementing this as a strategy in public health programs.

Health-related quality of life among pulmonary tuberculosis patients in Pakistan.

PURPOSE: Health-related quality of life (HRQoL) of pulmonary TB patients has not been assessed in Pakistan. We assessed self-reported HRQoL of pulmonary TB patients in Karachi, Pakistan utilizing the EQ-5D and EQ-VAS prior to, during, and after completion of TB treatment. METHODS: We enrolled 226 pulmonary TB patients in a longitudinal cohort study. Health-utility scores were estimated by the EQ-5D five dimensions and the EQ-Visual Analogue Scale (VAS) at baseline (month 0) and each monthly follow-up visit until treatment completion at month 6. Repeated-measures ANOVA was used to investigate effect of time into treatment on EQ-5D and EQ-VAS scores. RESULTS: EQ-5D health utility and EQ-VAS scores increase with treatment progression. For the enrolled TB patients, the mean EQ-5D utility scores more than doubled from 0.43 to 0.88, p < .001, effect size η2 = 0.40 from treatment initiation to treatment completion. CONCLUSION: Perceived HRQoL of TB patients improves with treatment progression. This can inform targeted treatment plans as well as TB policy and funding for high-burden countries.

Treatment outcomes of patients with multidrug-resistant and extensively drug-resistant tuberculosis according to drug susceptibility testing to first- and second-line drugs: an individual patient data meta-analysis.

BACKGROUND: Individualized treatment for multidrug-resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis depends upon reliable and valid drug susceptibility testing (DST) for pyrazinamide, ethambutol, and second-line tuberculosis drugs. However, the reliability of these tests is uncertain, due to unresolved methodological issues. We estimated the association of DST results for pyrazinamide, ethambutol, and second-line drugs with treatment outcomes in patients with MDR tuberculosis and XDR tuberculosis. METHODS: We conducted an analysis of individual patient data assembled from 31 previously published cohort studies of patients with MDR and XDR tuberculosis. We used data on patients' clinical characteristics including DST results, treatment received, outcomes, and laboratory methods in each center. RESULTS: DST methods and treatment regimens used in different centers varied considerably. Among 8955 analyzed patients, in vitro susceptibility to individual drugs was consistently and significantly associated with higher odds of treatment success (compared with resistance to the drug), if that drug was used in the treatment regimen. Various adjusted and sensitivity analyses suggest that this was not explained by confounding. The adjusted odds of treatment success for ethambutol, pyrazinamide, and the group 4 drugs ranged from 1.7 to 2.3, whereas for second-line injectables and fluoroquinolones, odds ranged from 2.4 to 4.6. CONCLUSIONS: DST for ethambutol, pyrazinamide, and second-line tuberculosis drugs appears to provide clinically useful information to guide selection of treatment regimens for MDR and XDR tuberculosis.

Cost-effectiveness of the Ponseti method for treatment of clubfoot in Pakistan.

BACKGROUND: Clubfoot is disabling, with an incidence of 0.9/1,000 live births to 7/1,000 live births. It affects mobility, productivity, and quality of life. Patients are treated surgically or non-surgically using the Ponseti method. We estimated the cost per patient treated with both methods and the cost-effectiveness of these methods in Pakistan. METHODS: Parents of patients treated, either surgically or with the Ponseti method, at the Indus Hospital's free program for clubfoot were interviewed between February and May 2012. We measured the direct and indirect household expenditures for pre-diagnosis, incomplete treatment, and current treatment until the first brace for Ponseti method and the first corrective surgery for surgically treated patients. Hospital expenditure was measured by existing accounts. RESULTS: Average per-patient cost was $349 for the Ponseti method and $810 for patients treated surgically. Of these, the Indus hospital costs were $170 the for Ponseti method and $452 for surgically treated patients. The direct household expenditure was $154 and $314 for the Ponseti and surgical methods, respectively. The majority of the costs were incurred pre-diagnosis and after inadequate treatment, with the largest proportion spent on transportation, material, and fee for service. The Ponseti method is shown to be the dominant method of treatment, with an incremental cost-effectiveness ratio of $1,225. CONCLUSIONS: The Ponseti method is clearly the treatment of choice in resource-constrained settings like Pakistan. Household costs for clubfoot treatment are substantial, even in programs offering free diagnostics and treatments and may be a barrier to service utilization for the poorest patients.

Two Clinical Prediction Tools to Inform Rapid Tuberculosis Treatment Decision-making in Children.

Background: In the absence of bacteriologic confirmation to diagnose tuberculosis (TB) in children, it is suggested that treatment should be initiated when sufficient clinical evidence of disease is available. However, it is unclear what clinical evidence is sufficient to make this decision. To identify children who would benefit from rapid initiation of TB treatment, we developed 2 clinical prediction tools. Methods: We conducted a secondary analysis of a prospective intensified TB patient-finding intervention conducted in Pakistan in 2014-2016. TB disease was determined through either bacteriologic confirmation or a clinical diagnosis. We derived 2 tools: 1 uses classification and regression tree (CART) analysis to develop decision trees, while the second uses multivariable logistic regression to calculate a risk score. Results: Of the 5162 and 5074 children included in the CART and prediction score, respectively, 1417 (27.5%) and 1365 (26.9%) were eligible for TB treatment. CART identified abnormal chest radiographs and family history of TB as the most important predictors (area under the receiver operating characteristic curve [AUC], 0.949). The final prediction score model included age group (0-4, 5-9, 10-14), weight <5th percentile, cough, fever, weight loss, chest radiograph suggestive of TB disease, and family history of TB; the identified best cutoff score was 9 (AUC, 0.985%). Conclusions: Use of clinical evidence was sufficient to accurately identify children who would benefit from treatment initiation. Our tools performed well compared with existing algorithms, though these results need to be externally validated before operationalization.

Uptake and Completion of Tuberculosis Preventive Treatment Using 12-Dose, Weekly Isoniazid-Rifapentine Regimen in Bangladesh: A Community-Based Implementation Study.

BACKGROUND: The United Nations high-level meeting (UNHLM) pledged to enroll 30 million in tuberculosis preventive treatment (TPT) by 2022, necessitating TPT expansion to all at tuberculosis (TB) risk. We assessed the uptake and completion of a 12-dose, weekly isoniazid-rifapentine (3HP) TPT regimen. METHODS: Between February 2018 and March 2019 in Dhaka, community-based TPT using 3HP targeted household contacts of 883 confirmed drug-sensitive pulmonary TB patients. Adhering to World Health Organization guidelines, contacts underwent active TB screening before TPT initiation. RESULTS: Of 3193 contacts who were advised health facility visits for screening, 67% (n = 2149) complied. Among these, 1804 (84%) received chest X-rays. Active TB was diagnosed in 39 (2%) contacts; they commenced TB treatment. Over 97% of 1216 contacts began TPT, with completion rates higher among females, those with more education and income, non-slum residents, and those without 3HP-related adverse events. Adverse events, mainly mild, occurred in 5% of participants. CONCLUSIONS: The 3HP regimen, with its short duration, self-administered option, and minimal side effects, achieved satisfactory completion rates. A community-focused TPT approach is feasible, scalable nationally, and aligns with UNHLM targets.

Economic analysis of different throughput scenarios and implementation strategies of computer-aided detection software as a screening and triage test for pulmonary TB.

BACKGROUND: Artificial Intelligence (AI) systems have demonstrated potential in detecting tuberculosis (TB) associated abnormalities from chest X-ray (CXR) images. Thus, they might provide a solution to radiologist shortages in high TB burden countries. However, the cost of implementing computer-aided detection (CAD) software has thus far been understudied. In this study, we performed a costing analysis of CAD software when used as a screening or triage test for pulmonary TB, estimated the incremental cost compared to a radiologist reading of different throughput scenarios, and predicted the cost for the national scale-up plan in Pakistan. METHODS: For the study, we focused on CAD software reviewed by the World Health Organization (CAD4TB, Lunit INSIGHT CXR, qXR) or listed in the Global Drug Facility diagnostics catalogue (CAD4TB, InferRead). Costing information was obtained from the CAD software developers. CAD4TB and InferRead use a perpetual license pricing model, while Lunit and qXR are priced per license for restricted number of scans. A major implementer in Pakistan provided costing information for human resource and software training. The per-screen cost was estimated for each CAD software and for radiologist for 1) active case finding, and 2) facility based CXR testing scenarios with throughputs ranging from 50,000-100,000 scans. Moreover, we estimated the scale-up cost for CAD or radiologist CXR reading in Pakistan based on the National Strategic Plan, considering that to reach 80% diagnostic coverage, 50% of TB patients would need to be found through facility-based triage and 30% through active case finding (ACF). RESULTS: The per-screen cost for CAD4TB (0.25 USD- 2.33 USD) and InferRead (0.19 USD- 2.78 USD) was lower than that of a radiologist (0.70 USD- 0.93 USD) for high throughput scenarios studied. In comparison, the per-screen cost for Lunit (0.94 USD- 1.69 USD) and qXR (0.95 USD-1.9 USD) were only comparable with that of the radiologists in the highest throughput scenario in ACF. To achieve 80 percent diagnostic coverage at scale in Pakistan, the projected additional cost of deploying CAD software to complement the current infrastructure over a four-year period were estimated at 2.65-19.23 million USD, whereas Human readers, would cost an additional 23.97 million USD. CONCLUSIONS: Our findings suggest that using CAD software could enable large-scale screening programs in high TB-burden countries and be less costly than radiologist. To achieve minimum cost, the target number of screens in a specific screening strategy should be carefully considered when selecting CAD software, along with the offered pricing structure and other aspects such as performance and operational features. Integrating CAD software in implementation strategies for case finding could be an economical way to attain the intended programmatic goals.