Global burden of drug-resistant tuberculosis in children: a mathematical modelling study

Background: After infection with Mycobacterium tuberculosis, children are at an increased risk of progression to tuberculosis disease; a condition that can be challenging to diagnose. New estimation approaches for children have highlighted the gap between incidence and notifications of M tuberculosis, and suggest there are more cases of isoniazid-resistant and multidrug-resistant (MDR) disease than are identified. No work has yet quantified the burden of drug-resistant infection, or accounted for other types of drug resistance or sampling uncertainty. Methods: We combined a mathematical model of tuberculosis in children with an analysis of drug-resistance patterns to produce country-level, regional, and global estimates of drug-resistant infection and disease. We determined drug resistance using data from the Global Project on Antituberculosis Drug Resistance Surveillance at WHO, from surveys and surveillance reported between 1988 and 2014. We combined 1000 sampled proportions for each country from a Bayesian approach with 10 000 sampled country estimates of tuberculosis disease incidence and M tuberculosis infection prevalence. We estimated the proportions of tuberculosis cases at a country level with isoniazid monoresistance, rifampicin monoresistance, multidrug resistance (MDR), fluoroquinolone-resistant multidrug resistance, second-line injectable-resistant multidrug resistance, and extensive multidrug resistance with resistance to both a fluoroquinolone and a second-line injectable (XDR). Findings: We estimated that 850 000 children developed tuberculosis in 2014; 58 000 with isoniazid-monoresistant tuberculosis, 25 000 with MDR tuberculosis, and 1200 with XDR tuberculosis. We estimate 67 million children are infected with M tuberculosis; 5 million with isoniazid monoresistance, 2 million with MDR, and 100 000 with XDR. Africa and southeast Asia have the highest numbers of children with tuberculosis, but the WHO Eastern Mediterranean region, European region, and Western Pacific region also contribute substantially to the burden of drug-resistant tuberculosis because of their much higher proportions of resistance. Interpretation: Far more drug-resistant tuberculosis occurs in children than is diagnosed, and there is a large pool of drug-resistant infection. This finding has implications for approaches to empirical treatment and preventive therapy in some regions of the world

CD4 count and tuberculosis risk in HIV-positive adults not on ART: a systematic review and meta-analysis

Background: CD4 cell count in adults with human immunodeficiency virus (HIV) infection (PLHIV) not receiving antiretroviral therapy (ART) influences tuberculosis (TB) risk. Despite widespread use in models informing resource allocation, this relationship has not been systematically reviewed. Methods: We systematically searched MEDLINE, Aidsinfo, Cochrane review database and Google Scholar for reports in English describing TB incidence stratified by updated CD4 cell count in cohorts of HIV-positive adults (age ≥15 years) not on ART (PROSPERO protocol no: CRD42016048888). Among inclusion criteria were: reporting precision for TB incidence, repeated CD4 measurements, and TB incidence reported for those not on ART or monotherapy. Study quality was assessed via the Newcastle-Ottawa tool for cohort studies. A Bayesian hierarchical model was fitted to estimate the pooled factor increase in TB incidence with respect to CD4 cell count decrement. Results: A total of 1,555 distinct records were identified from which 164 full text articles were obtained. Common reasons for exclusion of full texts were: no valid TB incidence, no repeat CD4 measurements, and not reporting TB incidence by ART status. The seven studies included reported on 1,206 TB cases among 41,271 individuals, with a typical median follow-up of four years. Studies were generally rated as moderate or high quality. Our meta-analysis estimated a 1.43 (95% credible interval: 1.16-1.88)-fold increase in TB incidence per 100 cells per mm3 decrease in CD4 cell count. Discussion: Our analysis confirms previous estimates of exponential increase in TB incidence with declining CD4 cell count in adults, emphasizing the importance of early ART initiation to reduce TB risk in PLHIV

The potential impact of BCG vaccine supply shortages on global paediatric tuberculosis mortality.

BACKGROUND: The Bacillus Calmette-Guérin (BCG) vaccine is provided to over 100 million neonates annually to protect against childhood tuberculosis (TB). Recent BCG manufacturing interruptions highlight global supply risks. We estimated the potential impact of BCG shortfalls on global paediatric (<15 years) TB mortality. METHODS: A static mathematical model was employed to estimate the number of paediatric TB deaths avoided by usual levels of BCG coverage, and potential additional TB deaths in the first 15 years of life due to 1-year BCG supply shortfalls of 6.3 % (as occurred in 2015) to 27.6 % (as anticipated without mitigating action in 2015) assuming no catch-up campaigns. RESULTS: BCG coverage without shortfalls, estimated at 90 % globally, was estimated to avoid 117,132 (95 % uncertainty range (UR): 5049-306,911) TB deaths globally per birth cohort in the first 15 years of life. An estimated 11,713 (UR: 505-30,691) additional TB deaths would occur in the first 15 years of life per 10 % (26 million dose) annual supply shortfall. A 16.5 million dose (6.3 %) shortfall as reported at the close of 2015, reflecting 84 % global coverage, was estimated as associated with 7433 (95 % UR: 320-19,477) excess TB deaths in the affected cohort in the first 15 years. A possible 24,914 (UR: 1074-65,278) additional deaths were avoided due to prompt shortfall reduction measures in 2015. CONCLUSIONS: BCG shortages could greatly increase paediatric TB mortality. Although rapid action in 2015 minimised BCG shortfalls, avoiding a large number of potential additional deaths, the possible public health impact of even relatively small shortfalls highlights the critical importance of ensuring secure future manufacturing capacity and global BCG supply continuity

Operational research to support equitable non-communicable disease policy in low-income and middle-income countries in the sustainable development era : a scoping review

Introduction Non-communicable diseases (NCDs) represent a growing health burden in low-income and middle-income countries (LMICs). Operational research (OR) has been used globally to support the design of effective and efficient public policies. Equity is emphasised in the Sustainable Development Goal (SDG) framework introduced in 2015 and can be analysed within OR studies. Methods We systematically searched MEDLINE, Embase, Scopus and Web of Science for studies published between 2015 and 2018 at the intersection of five domains (OR, LMICs, NCDs, health and decision-making and/or policy-making). We categorised the type of policy intervention and described any concern for equity, which we defined as either analysis of differential impact by subgroups or, policy focus on disadvantaged groups or promoting universal health coverage (UHC). Results A total of 149 papers met the inclusion criteria. The papers covered a number of policy types and a broad range of NCDs, although not in proportion to their relative disease burden. A concern for equity was demonstrated by 88 of the 149 papers (59%), with 8 (5%) demonstrating differential impact, 47 (32%) targeting disadvantaged groups, and 68 (46%) promoting UHC. Conclusion Overall, OR for NCD health policy in the SDG era is being applied to a diverse set of interventions and conditions across LMICs and researchers appear to be concerned with equity. However, the current focus of published research does not fully reflect population needs and the analysis of differential impact within populations is rare

Improving cycle corrections in discrete time Markov models : a Gaussian quadrature approach

Introduction: Discrete-time Markov models are widely used within health economic modelling. Analyses usually associate costs and health outcomes with health states and calculate totals for each decision option over some timeframe. Frequently, a correction method (e.g. half-cycle correction) is applied to unadjusted model outputs to yield an approximation to an assumed underlying continuous-time Markov model. In this study, we introduce a novel approximation method based on Gaussian Quadrature (GQ). Methods: We exploited analytical results for time-homogeneous Markov chains to derive a new GQ-based approximation, which is applied to an unadjusted discrete-time model output. The GQ method approximates a continuous-time Markov model result by approximating a correction matrix, formulated as an integral, using a weighted sum of integrand values at specified points. GQ approximations can be made arbitrarily accurate by increasing order of the approximation. We compared the first five orders of GQ approximation with four existing cycle correction methods (half-cycle correction, trapezoidal and Simpson 1/3 and 3/8 rules) across 100,000 randomly generated input parameter-sets. Results: We show that first-order GQ method is identical to half-cycle correction method, which is itself equivalent to trapezoidal method. The second-order GQ is identical to Simpson 1/3 method. The third, fourth and fifth order GQ methods are novel in this context and provide increasingly accurate approximations to the output of the continuous-time model. In our simulation study, fifth-order GQ method outperformed other existing methods in over 99.8% of simulations. Of the existing methods, Simpson 1/3 rule performed the best. Conclusion: Our novel GQ-based approximation outperforms other cycle correction methods for time-homogeneous models. The method is easy to implement, and R code and an Excel workbook are provided as supplementary materials

Estimating long-term tuberculosis reactivation rates in Australian migrants

BACKGROUND: The risk of progression to tuberculosis (TB) disease is greatest soon after infection, yet disease may occur many years or decades later. However, rates of TB reactivation long after infection remain poorly quantified. Australia is a low-TB incidence setting and most cases occur among migrants. We explored how TB rates in Australian migrants varied with time from migration, age and gender. METHODS: We combined TB notifications in census years 2006, 2011 and 2016 with time and country-specific estimates oflatent TB prevalence in migrant cohorts to quantifypost-migration reactivation rates. RESULTS: During the census years 3,246 TB cases occurred among an estimated 2,084,000 migrants with latent-TB. There were consistent trends in post-migration reactivation rates, which appeared to be dependent on both time from migration and age. Rates were lower in cohorts with increasing time until at least twenty years from migration, and on this background there also appeared to be increasing rates during youth (15-24 years of age), and in those aged 70 years and above. Within five years of migration, annual reactivation rates were approximately 400 per 100,000 (uncertainty interval [UI]: 320-480), dropping to 170 (UI: 130-220) and 110 (UI: 70-160) from five-to-ten and ten-to-twenty, then sustaining at 60-70 per 100,000 up to sixty years from migration. Rates varied depending on age at migration. CONCLUSIONS: Post-migration reactivation rates appeared to show dependency on both time from migration and age. This approach to quantifying reactivation risk will enable evaluation of the potential impact of TB control and elimination strategies

Forecasting the impact of population ageing on tuberculosis incidence

Background Tuberculosis (TB) disease reactivates from distant latent infection or recent (re)infection. Progression risks increase with age. Across the World Health Organisation Western Pacific region, many populations are ageing and have the highest per capita TB incidence rates in older age groups. However, methods for analysing age-specific TB incidence and forecasting epidemic trends while accounting for demographic change remain limited. Methods We applied the Lee-Carter models, which were originally developed for mortality modelling, to model the temporal trends in age-specific TB incidence data from 2005 to 2018 in Taiwan. Females and males were modelled separately. We combined our demographic forecasts, and age-specific TB incidence forecasts to project TB incidence until 2035. We compared TB incidence projections with demography fixed in 2018 to projections accounting for demographic change. Results Our models quantified increasing incidence rates with age and declining temporal trends. By 2035, the forecast suggests that the TB incidence rate in Taiwan will decrease by 54% (95% Prediction Interval (PI): 45%-59%) compared to 2015, while most age-specific incidence rates will reduce by more than 60%. In 2035, adults aged 65 and above will make up 78% of incident TB cases. Forecast TB incidence in 2035 accounting for demographic change will be 39% (95% PI: 36%-42%) higher than without population ageing. Conclusions Age-specific incidence forecasts coupled with demographic forecasts can inform the impact of population ageing on TB epidemics. The TB control programme in Taiwan should develop plans specific to older age groups and their care needs

Patient pathways of tuberculosis care-seeking and treatment: an individual-level analysis of National Health Insurance data in Taiwan

Introduction Patients with tuberculosis (TB) often experience difficulties in accessing diagnosis and treatment. Patient pathway analysis identifies mismatches between TB patient care-seeking patterns and service coverage, but to date, studies have only employed cross-sectional aggregate data. Methods We developed an algorithmic approach to analyse and interpret patient-level routine data on healthcare use and to construct patients’ pathways from initial care-seeking to treatment outcome. We applied this to patients with TB in a simple random sample of one million patients’ records in the Taiwan National Health Insurance database. We analysed heterogeneity in pathway patterns, delays, service coverage and patient flows between different health system levels. Results We constructed 7255 pathways for 6258 patients. Patients most commonly initially sought care at the primary clinic level, where the capacity for diagnosing TB patients was 12%, before eventually initiating treatment at higher levels. Patient pathways are extremely heterogeneous prior to diagnosis, with the 10% most complex pathways accounting for 48% of all clinical encounters, and 55% of those pathways yet to initiate treatment after a year. Extended consideration of alternative diagnoses was more common for patients aged 65 years or older and for patients with chronic lung disease. Conclusion Our study demonstrates that longitudinal analysis of routine individual-level healthcare data can be used to generate a detailed picture of TB care-seeking pathways. This allows an understanding of several temporal aspects of care pathways, including lead times to care and the variability in patient pathways