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Alternative dosing guidelines to improve outcomes in childhood tuberculosis: a mathematical modelling study.

ABSTRACT: BACKGROUND:Malnourished and young children are particularly susceptible to severe forms of tuberculosis and poor treatment response. WHO dosing guidelines for drugs for tuberculosis treatment are based only on weight, which might lead to systematic underdosing and poor outcomes in these children. We aimed to assess and quantify the population effect of WHO guidelines for drug-susceptible tuberculosis in children in the 20 countries with the highest disease burden. METHODS:We used an integrated model that linked country-specific demographic data at the individual level from the 20 countries with the highest disease burden to pharmacokinetic, outcome, and epidemiological models. We estimated tuberculosis treatment outcomes in children younger than 5 years following WHO guidelines (children are dosed by weight bands corresponding to the number of fixed-dose combination tablets [75 mg rifampicin, 50 mg isoniazid, 150 mg pyrazinamide]) and two alternative dosing strategies: one based on a proposed algorithm that uses age, weight, and available formulations, in which underweight children would receive the same drug doses as would normal weight children of the same age; and another based on an individualised algorithm without dose limitations, in which derived doses results in target exposure attainment for the typical child. FINDINGS:We estimated that 57?234 (43%) of 133?302 children younger than 5 years who were treated for tuberculosis in 2017 were underdosed with WHO dosing and only 47% of children would reach the rifampicin exposure target. Underdosing and subtherapeutic exposures were more common among malnourished children than among age-matched healthy children. The proposed dosing approach improved estimated rifampicin target exposure attainment to 62% and equalised outcomes by nutritional status. An estimated third of unfavourable treatment outcomes might be resolved with this dosing strategy, saving the lives of a minimum of 2423 children in these countries annually. With individualised dosing approaches, almost all children could achieve adequate exposure for cure. INTERPRETATION:This work shows that a simple change in dosing procedure to include age and nutritional status, requiring no additional measurements or new drug formulations, is one approach to improve tuberculosis treatment outcomes in children, especially malnourished children who are at high risk of mortality. FUNDING:Eunice Kennedy Shriver National Institute of Child Health and Human Development and UK Medical Research Council.

SUBMITTER: Radtke KK

PROVIDER: S-EPMC7605863 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Alternative dosing guidelines to improve outcomes in childhood tuberculosis: a mathematical modelling study.

Radtke Kendra K KK Dooley Kelly E KE Dodd Peter J PJ Garcia-Prats Anthony J AJ McKenna Lindsay L Hesseling Anneke C AC Savic Radojka M RM

The Lancet. Child & adolescent health 20190716 9

<h4>Background</h4>Malnourished and young children are particularly susceptible to severe forms of tuberculosis and poor treatment response. WHO dosing guidelines for drugs for tuberculosis treatment are based only on weight, which might lead to systematic underdosing and poor outcomes in these children. We aimed to assess and quantify the population effect of WHO guidelines for drug-susceptible tuberculosis in children in the 20 countries with the highest disease burden.<h4>Methods</h4>We used ...[more]

PMID: 31324596

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Project description:BackgroundTuberculosis is recognised as a major cause of morbidity and mortality in children, with most cases in children going undiagnosed and resulting in poor outcomes. Household contact management, which aims to identify children with active tuberculosis and to provide preventive therapy for those with HIV or those younger than 5 years, has long been recommended but has very poor coverage globally. New guidelines include widespread provision of preventive therapy to children with a positive tuberculin skin test (TST) who are older than 5 years.MethodsIn this mathematical modelling study, we provide the first global and national estimates of the impact of moving from zero to full coverage of household contact management (with and without preventive therapy for TST-positive children older than 5 years). We assembled data on tuberculosis notifications, household structure, household contact co-prevalence of tuberculosis disease and infection, the efficacy of preventive therapy, and the natural history of childhood tuberculosis. We used a model to estimate households visited, children screened, and treatment courses given for active and latent tuberculosis. We calculated the numbers of tuberculosis cases, deaths, and life-years lost because of tuberculosis for each intervention scenario and country.FindingsWe estimated that full implementation of household contact management would prevent 159 500 (75% uncertainty interval [UI] 147 000-170 900) cases of tuberculosis and 108 400 (75% UI 98 800-116 700) deaths in children younger than 15 years (representing the loss of 7 305 000 [75% UI 6 663 000-7 874 000] life-years). We estimated that preventing one child death from tuberculosis would require visiting 48 households, screening 77 children, giving 48 preventive therapy courses, and giving two tuberculosis treatments versus no household contact management.InterpretationHousehold contact management could substantially reduce childhood disease and death caused by tuberculosis globally. Funding and research to optimise its implementation should be prioritised.FundingUK Medical Research Council, US National Institutes of Health, Fulbright Commission, Janssen Global Public Health.

Project description:BACKGROUND:Increasing the number of vaccine doses may potentially improve overall efficacy. Decision-makers need information about choosing the most efficient dose schedule to maximise the total health gain of a population when operating under a constrained budget. The objective of this study is to identify the most efficient vaccine dosing schedule within a fixed vaccination budget from a healthcare payer perspective. METHODS:An optimisation model is developed in which maximizing the disease reduction is the functional objective and the constraint is the vaccination budget. The model allows variation in vaccination dosing numbers, in cost difference per dose, in vaccine coverage rate, and in vaccine efficacy. We apply the model using the monovalent rotavirus vaccine as an example. RESULTS:With a fixed budget, a 2-dose schedule for vaccination against rotavirus infection with the monovalent vaccine results in a larger reduction in disease episodes than a 3-dose scheme with the same vaccine under most circumstances. A 3-dose schedule would only be better under certain conditions: a cost reduction of >26% per dose, combined with vaccine efficacy improvement of ?5% and a target coverage rate of 75%. Substantial interaction is observed between cost reduction per dose, vaccine coverage rate, and increased vaccine efficacy. Sensitivity analysis shows that the conditions required for a 3-dose strategy to be better than a 2-dose strategy may seldom occur when the budget is fixed. The model does not consider vaccine herd effect, precise timing for additional doses, or the effect of natural immunity development. CONCLUSIONS:Under budget constraint, optimisation modelling is a helpful tool for a decision-maker selecting the most efficient vaccination dosing schedule. The low dosing scheme could be the optimal option to consider under the many scenarios tested. The model can be applied under many different circumstances of changing dosing schemes with single or multiple vaccines.

Project description:BackgroundTuberculosis in children is increasingly recognised as an important component of the global tuberculosis burden, with an estimated 1 million cases in 2015. Although younger children are vulnerable to severe forms of tuberculosis disease, no age-disaggregated estimates of paediatric tuberculosis mortality exist, and tuberculosis has never been included in official estimates of under-5 child mortality. We aimed to produce a global mortality burden estimate in children using a complementary approach not dependent on vital registration data.MethodsIn this mathematical modelling study, we estimated deaths in children younger than 5 years and those aged 5-14 years for 217 countries and territories using a case-fatality-based approach. We used paediatric tuberculosis notification data and HIV and antiretroviral treatment estimates to disaggregate the WHO paediatric tuberculosis incidence estimates by age, HIV, and treatment status. We then applied systematic review evidence on corresponding case-fatality ratios.FindingsWe estimated that 239 000 (95% uncertainty interval [UI] 194 000-298 000) children younger than 15 years died from tuberculosis worldwide in 2015; 80% (191 000, 95% UI 132 000-257 000) of these deaths were in children younger than 5 years. More than 70% (182 000, 140 000-239 000) of deaths occurred in the WHO southeast Asia and Africa regions. We estimated that 39 000 (17%, 23 000-73 000) paediatric tuberculosis deaths worldwide were in children with HIV infections, with 31 000 (36%, 19 000-59 000) in the WHO Africa region. More than 96% (230 000, 185 000-289 000) of all tuberculosis deaths occurred in children not receiving tuberculosis treatment.InterpretationTuberculosis is a top ten cause of death in children worldwide and a key omission from previous analyses of under-5 mortality. Almost all these deaths occur in children not on tuberculosis treatment, implying substantial scope to reduce this burden.FundingUNITAID, National Institutes of Health, and National Institute for Health Research.

Project description:BackgroundThe current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children.Methods and findingsWe used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies.ConclusionsChildren older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug-drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance.Trial registrationClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542.

Project description:BackgroundFor settings with low tuberculosis incidence, disease elimination is a long-term goal. We investigated pathways to tuberculosis pre-elimination (incidence <1·0 cases per 100 000 people) and elimination (incidence <0·1 cases per 100 000 people) in the USA, where incidence was estimated at 2·9 per 100 000 people in 2023.MethodsUsing a mathematical modelling framework, we simulated how US tuberculosis incidence could be affected by changes in tuberculosis services in the countries of origin for future migrants to the USA, as well as changes in tuberculosis services inside the USA. To do so, we used a linked set of transmission dynamic models, calibrated to demographic and epidemiological data for each setting. We constructed intervention scenarios representing improvements in tuberculosis services internationally and within the USA, individually and in combination, plus a base-case scenario representing continuation of current services. We simulated health and economic outcomes until 2100, using a Bayesian approach to quantify uncertainty in these outcomes.FindingsUnder the base-case scenario, US tuberculosis incidence was projected to decline to 1·8 cases per 100 000 (95% uncertainty interval [UI] 1·5-2·1) in the total population by 2050. Intervention scenarios produced substantial reductions in tuberculosis incidence, with the combination of all domestic and international interventions projected to achieve pre-elimination by 2033 (95% UI 2031-2037). Compared with the base-case scenario, this combination of interventions could avert 101 000 tuberculosis cases (95% UI 84 000-120 000) and 13 300 tuberculosis deaths (95% UI 10 500-16 300) in the USA from 2025 to 2050. Tuberculosis elimination was not projected before 2100.InterpretationStrengthening tuberculosis services domestically, promoting the development of more effective technologies and interventions, and supporting tuberculosis programmes in countries with a high tuberculosis burden are key strategies for accelerating progress towards tuberculosis elimination in the USA.FundingUS Centers for Disease Control and Prevention.

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Alternative dosing guidelines to improve outcomes in childhood tuberculosis: a mathematical modelling study.

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Alternative dosing guidelines to improve outcomes in childhood tuberculosis: a mathematical modelling study.

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