Economic impact of generic antiretrovirals in France for HIV patients' care: a simulation between 2019 and 2023.

BACKGROUND: In a context where the economic burden of HIV is increasing as HIV patients now have a close to normal lifespan, the availability of generic antiretrovirals commonly prescribed in 2017 and the imminence of patent expiration are expected to provide substantial savings in the coming years. This article aims to assess the economic impact of these generic antiretrovirals in France and specifically over a five-year period. METHODS: An agent-based model was developed to simulate patient trajectories and treatment use over a five-year period. By comparing the results of costs for trajectories simulated under different predefined scenarios, a budget impact model can be created and sensitivity analyses performed on several parameters of importance. RESULTS: The potential economic savings from 2019 to 2023 generated by generic antiretrovirals range from €309 million when the penetration rate of generics is set at 10% to €1.5 billion at 70%. These savings range from €984 million to €993 million as the delay between patent and generic marketing authorisation varies from 10 to 15 years, and from €965 million to €993 million as the Negotiated Price per Unit (NPU) of generics at market-entry varies from 40 to 50% of the NPU for patents. DISCUSSION: This economic savings simulation could help decision makers to anticipate resource allocations for further innovation in antiretrovirals therapies as well as prevention, especially by funding the Pre-Exposure Prophylaxis (PrEP) or HIV screening.

Determinants of blood eosinophilia in moderate and severe asthmatic patients during childhood: Evidence from the severe asthma molecular phenotype (SAMP) cohort.

BACKGROUND: Asthma is a heterogeneous disease in which the interaction between genetic and environmental factors plays a major role. The significance of blood eosinophil is unclear. The aim of the study was to determine the significance of blood eosinophil count in moderate-to-severe asthmatic children of preschool age and school age. METHODS: This was a prospective cross-sectional study performed from 2011 to 2015 including children from the severe asthma molecular phenotype (SAMP) cohort at Trousseau Hospital (Paris, France). We included children with severe and moderate asthma, or severe and moderate recurrent wheeze, aged from 1 to 15 years at the time of exploration. RESULTS: We analyzed data from 402 children: 248 of preschool age and 154 of school age. Blood eosinophil count third quartile thresholds were 322 and 600 cells/µL for the preschool- and school-age groups, respectively. In multivariate analysis, a blood eosinophil count over this threshold was associated with elevated total IgE (OR = 5.33, P < .01), multiple hospitalizations for asthma attacks (OR = 4.96, P = .03), and a maternal history of asthma (OR = 4.91, P = .01) in preschool children; and with staphylococcal toxin-specific IgE (OR = 2.75, P = .03) in children of school age. Random forest analysis reinforced these results. CONCLUSION: High blood eosinophil count is linked to both atopic features and control of asthma with different parameters associated with these features depending on age.

Modelling dynamic change of malaria transmission in holoendemic setting (Dielmo, Senegal) using longitudinal measures of antibody prevalence to Plasmodium falciparum crude schizonts extract.

BACKGROUND: Evaluation of local Plasmodium falciparum malaria transmission has been investigated previously using the reversible catalytic model based on prevalence of antibody responses to single antigen to estimate seroconversion rates. High correlations were observed between seroconversion rates and entomological inoculation rates (EIR). However, in this model, the effects of malaria control interventions and clinical episodes on serological measurements were not assessed. This study monitors the use of antibody responses to P. falciparum crude extracts for assessing malaria transmission, compares seroconversion rates estimated from longitudinal data to those derived from cross-sectional surveys and investigates the effects of malaria control interventions on these measures in an area of declining malaria transmission. In addition, the validity of this model was evaluated by comparison with the alternative model. METHODS: Five cross-sectional surveys were carried out at the end of the wet season in Dielmo, a malaria-endemic Senegalese rural area in 2000, 2002, 2008, 2010 and 2012. Antibodies against schizonts crude extract of a local P. falciparum strain adapted to culture (Pf 07/03) were measured by ELISA. Age-specific seroprevalence model was used both for cross-sectional surveys and longitudinal data (combined data of all surveys). RESULTS: A total of 1504 plasma samples obtained through several years follow-up of 350 subjects was used in this study. Seroconversion rates based on P. falciparum schizonts crude extract were estimated for each cross-sectional survey and were found strongly correlated with EIR. High variability between SCRs from cross-sectional and longitudinal surveys was observed. In longitudinal studies, the alternative catalytic reversible model adjusted better with serological data than the catalytic model. Clinical malaria attacks and malaria control interventions were found to have significant effect on seroconversion. DISCUSSION: The results of the study suggested that crude extract was a good serological tool that could be used to assess the level of malaria exposure in areas where malaria transmission is declining. However, additional parameters such as clinical malaria and malaria control interventions must be taken into account for determining serological measurements for more accuracy in transmission assessment.

Childhood allergic asthma is not a single phenotype.

OBJECTIVE: IgE-mediated allergic asthma phenotype appears to be heterogeneous. We set out to define distinct allergic phenotypes by unsupervised cluster analysis. STUDY DESIGN: A total of 18 variables were analyzed: sex and age, eczema and food allergy, asthma duration, asthma severity and control, severe exacerbations, total IgE level, allergic sensitization, fractional exhaled nitric oxide, and functional parameters. Clusters obtained were cross-tabulated with environmental parameters. RESULTS: Four clusters were identified in 125 children (average age 8.9 years): (1) 57 children constituted the "House dust mite Sensitization and Mild Asthma" cluster, 98% of these were monosensitized and had mild asthma (74%); (2) 12 children had "Pollen Sensitization with Severe Exacerbations," 92 % with severe exacerbations and pollen sensitization; (3) 20 children had "Multiple Allergies and Severe Asthma," with 95% having moderate to severe asthma, and a significantly decreased forced expiratory flow rate at 25%-75% of forced vital capacity, 100% had eczema and higher values of IgE (1123 kU/L) and fractional exhaled nitric oxide (67 ppb) (this cluster was associated with molds at home [P = .004]); and (4) 36 children had "Multiple Allergic Sensitizations and Mild Asthma," 97% of these with multiple sensitizations and 100% mild asthma. CONCLUSIONS: The identification of 2 novel severe allergic asthma phenotypes "Pollen Sensitization with Severe Exacerbations"and "Multiple Allergies and Severe Asthma" could lead to specific targeted treatment.

Identification and Economic Evaluation of Differentiated Thyroid Cancer Care Consumption Patterns Using Sequence Analysis.

Objectives: This study aims to assess the impact of care consumption patterns and individual characteristics on the cost of treating differentiated thyroid carcinoma (DTC), in France, with a specific emphasis on socioeconomic position. Methods: The methodology involved a net cost approach utilising cases from the EVATHYR cohort and controls from the French National Health Insurance database. Care consumption patterns were created using Optimal Matching and clustering techniques. The individual characteristics influence on patterns was assessed using multinomial logistic regression. The individual characteristics and patterns influence on care costs was assessed using generalised estimating equations. Results: The findings revealed an average cost of €13,753 per patient during the initial 3 years. Regression models suggested the main predictors of high DTC specific care consumption tended to include having a high risk of cancer recurrence (OR = 4.97), being a woman (OR = 2.00), and experiencing socio-economic deprivation (OR = 1.26), though not reaching statistical significance. Finally, high DTC-specific care consumers also incurred higher general care costs (RR = 1.35). Conclusion: The study underscores the increased costs of managing DTC, shaped by consumption habits and socioeconomic position, emphasising the need for more nuanced DTC management strategies.

Wheeze phenotypes in young children have different courses during the preschool period.

BACKGROUND: Rules for predicting the course of asthma in wheezy infants have low specificity. OBJECTIVE: To determine if the novel phenotypes-mild early viral wheeze (EVW), atopic multiple-trigger wheeze (MTW), and nonatopic uncontrolled wheeze (NAUW)-have different courses during the preschool period. METHODS: Part of the prospectively followed Trousseau Asthma Program cohort was phenotyped using cluster analysis with 12 parameters (sex, asthma severity and control with inhaled corticosteroid [ICS], parental asthma, allergic rhinitis, eczema, food allergy, EVW or MTW, and allergen exposure trigger). Wheezing trajectories were assessed by crossing the original phenotypes with the phenotypes obtained at 5 years. RESULTS: Four clusters were identified at 5 years of age: asymptomatic children (n = 47) with no wheezing (98%), children with mild EVW (n = 40, 87% with EVW, 50% with EVW controlled with low-dose ICS), those with atopic MTW (n = 30, 100% with MTW, only 17% with MTW controlled with low-dose ICS, more significant for pollen asthmatic trigger), and those with atopic severe UW (n = 33, 63% with UW uncontrolled despite high doses of ICS, more significant for allergic rhinitis and dust as asthmatic trigger). Those with mild EVW became asymptomatic or remained with mild EVW. Those with atopic MTW remained with atopic MTW and those with NAUW developed severe UW in most cases. CONCLUSION: These results show that remission is most frequently observed in mild EVW and that no remission is observed in atopic MTW.

Novel severe wheezy young children phenotypes: boys atopic multiple-trigger and girls nonatopic uncontrolled wheeze.

BACKGROUND: Recurrent wheezing during infancy is a heterogeneous disorder that has been associated with early-onset asthma. OBJECTIVE: To identify phenotypes of severe recurrent wheezing and therapeutic approaches. METHODS: We performed cluster analysis with 20 variables of 551 children with active asthma, younger than 36 months old, and enrolled in the Trousseau Asthma Program. RESULTS: We identified 3 independent clusters of children with wheezing. Cluster 1, mild episodic viral wheeze (n= 327), consisted of children with wheezing related only to colds (71%), mild disease (76%), and mainly normal chest x-ray results. Cluster 2, nonatopic uncontrolled wheeze (n = 157), was characterized by moderate to severe disease (91%), uncontrolled wheezing despite high doses of inhaled corticosteroids (55%), parents with asthma, and increased levels of ferritine. Cluster 3, atopic multiple-trigger wheeze (n = 67), included more children with multiple-trigger wheeze (68%) than did clusters 1 or 2; eczema (75%); a positive result from the Phadiatop Infant test (90%); increased levels of IgE, IgA, and IgG; and abnormal results from chest x-rays. In separate analysis, 1 parameter for boys (increased total level of IgE) and 2 parameters for girls (wheezing severity and increased total level of IgE) properly classified 90% of boys and 83% of girls in the appropriate cluster. Significant associations were found between overcrowding, molds and cockroaches at home, and atopic multiple-trigger wheeze and between day-care attendance and nonatopic uncontrolled wheeze in other parts. CONCLUSION: We identified different phenotypes of recurrent wheezing in young children by using cluster analysis with usual variables. These phenotypes require confirmation in longer, follow-up studies.

Agent-based modeling in medical research, virtual baseline generator and change in patients' profile issue.

Simulation studies are promising in medical research in particular to improve drug development. For instance, one can aim to develop In Silico Clinical Trial in order to challenge trial's design parameters in terms of feasibility and probability of success of the trial. Approaches based on agent-based models draw on a particularly useful framework to simulate patients evolution. In this paper, an approach based on agent-based modeling is described and discussed in the context of medical research. An R-vine copula model is used to represent the multivariate distribution of the data. A baseline data cohort can then be simulated and execution models can be developed to simulate the evolution of patients. R-vine copula models are very flexible tools which allow researchers to consider different marginal distributions than the ones observed in the data. It is then possible to perform data augmentation to explore a new population by simulating baseline data which are slightly different than those of the original population. A simulation study illustrates the efficiency of copula modeling to generate data according to specific marginal distributions but also highlights difficulties inherent to data augmentation.

Agent based modeling in health care economics: examples in the field of thyroid cancer.

Although they remain little used in the field of Health Care Economics, Agent Based Models (ABM) are potentially powerful decision-making tools that open up great prospects. The reasons for this lack of popularity are essentially to be found in a methodology that should be further clarified. This article hence aims to illustrate the methodology by means of two applications to medical examples. The first example of ABM illustrates the construction of a Baseline Data Cohort by means of a Virtual Baseline Generator. The aim is to describe the prevalence of thyroid cancer in the French population over the long term according to different scenarios of evolution of this population. The second study considers a setting where the Baseline Data Cohort is an established cohort of (real) patients: the EVATHYR cohort. The aim of the ABM is to describe the long-term costs associated with different scenarios of thyroid cancer management. The results are evaluated using several simulation runs in order to observe the variability of simulations and to derive prediction intervals. The ABM approach is very flexible since several sources of data can be involved and a large variety of simulation models can be calibrated to generate observations according to different evolution scenarios.

Staphylococcal Sensitization: A Correlate of Type 2-High Inflammation in Children With Severe Asthma.

BACKGROUND: Sensitization to Staphylococcus aureus enterotoxin (SE) has been identified to be a risk factor for asthma, but its determinants remain unclear. OBJECTIVE: To determine the significance of SE sensitization in children with moderate to severe asthma. METHODS: This was an observational cross-sectional analysis performed from 2011 to 2015 including children from the prospective Severe Asthma Molecular Phenotype cohort: school-age children with severe and moderate asthma or preschool-age children with severe and moderate recurrent wheeze. We evaluated sensitization to four SEs (Staphylococcus enterotoxin A, Staphylococcus enterotoxin B, Staphylococcus enterotoxin C, and toxic shock staphylococcic toxin). RESULTS: We analyzed data from 377 children: 233 of preschool age and 144 of school age. Among them, 26 (11.2%) and 59 (41.0%) children, respectively, had sensitization to at least one SE. The burden of sensitization was higher in older children in terms of both specific IgE levels and the number of sensitizations. In multivariable analysis, SE sensitization was associated with elevated total IgE in both populations (odds ratio [OR] = 9.35, P = .01; and OR = 8.06, P < .01), and with bronchoalveolar lavage eosinophilia in both preschool and school-age children (OR = 3.95, P = .03; and OR = 4.11, P = .03, respectively). Classification and regression trees showed an association of SE sensitization with age and with total IgE in the entire population, and with total IgE, bronchoalveolar lavage eosinophilia, and blood eosinophilia in school-age children. CONCLUSIONS: Staphylococcal enterotoxin sensitization was correlated with type 2-high inflammation (eosinophilic inflammation and elevated total IgE count) in this population of moderate to severe asthmatic children.

The IL-4 rs2070874 polymorphism may be associated with the severity of recurrent viral-induced wheeze.

BACKGROUND: Childhood recurrent wheezing and consequently asthma corresponds to various phenotypes. Our aim was to link genetic variants of asthma candidate genes to the phenotypes of early onset wheezing. STUDY DESIGN: We included very young consecutive children presenting with recurrent wheezing who had been evaluated for the severity of wheezing, associated atopic comorbidities, and tested for biomarkers of atopy and inflammation. All were genotyped for 16 single nucleotide polymorphisms (SNPs) linked with asthma or atopy. An unsupervised hierarchical bottom-up method was used for clustering the phenotypes and a multinomial logistic regression was performed for each individual SNP. RESULTS: We replicated the three phenotypes previously described Trousseau Asthma Program in 317 children aged 21.5 ± 7.9 months: cluster 1 (nonatopic uncontrolled severe wheeze), n = 207, a severe viral-induced wheeze, cluster 2 (atopic multiple trigger wheeze), n = 61, with multiple allergic comorbidities, and cluster 3 (episodic viral wheeze), n = 49, a mild viral-induced wheeze. The TT-genotype of the IL-4 rs2070874 polymorphism was significantly associated with the nonatopic uncontrolled severe wheeze compared to the episodic viral wheeze (OR 7.9; CI95% [2.5-25.3]; P = 0.001). CONCLUSION: Association between the TT-genotype of IL-4 rs2070874 polymorphism and a severe phenotype of viral-induced wheeze further underlines the role IL-4 plays in the inflammation pathway leading to viral respiratory infections.

Neutrophilic Steroid-Refractory Recurrent Wheeze and Eosinophilic Steroid-Refractory Asthma in Children.

BACKGROUND: Little is known about inflammatory pathways of severe recurrent wheeze in preschool children and severe asthma in children. OBJECTIVES: The aim of the Severe Asthma Molecular Phenotype cohort was to characterize phenotypes of severe recurrent wheeze and severe asthma during childhood in terms of triggers (allergic or not), involved cells (eosinophil or neutrophil), and corticoid responsiveness. METHODS: Children with moderate-to-severe asthma and preschool children with moderate-to-severe recurrent wheeze were enrolled prospectively. They underwent standardized clinical and blood workup, and bronchoalveolar lavage (BAL) evaluation. Cluster analysis was applied to 350 children with 34 variables. RESULTS: Three clusters were identified: cluster 1, Neutrophilic steroid-refractory recurrent wheeze phenotype, with 138 children uncontrolled despite high-dose inhaled corticosteroids (ICS) (92%, P < .001), with more history of pneumonia (31%, P < .001), more gastroesophageal reflux disease (37%, P < .001), and the highest blood neutrophil count (mean 4.524 cells/mm3, P = .05); cluster 2, Severe recurrent wheeze with sensitization to a single aeroallergen (12%, P = .002), with 104 children controlled with high-dose ICS (63%, P < .001); cluster 3, Eosinophilic steroid-refractory asthma phenotype, with 108 children uncontrolled despite high-dose ICS (76%, P < .001) with more allergic rhinitis, atopic dermatitis, and food allergies (82%, 40%, 31%, P < .001, respectively). They also had a higher blood eosinophil count and a higher percentage of BAL eosinophil (506/mm3, 2.6%, P < .001 respectively). CONCLUSIONS: Inflammation pathway of asthma and recurrent wheeze are related to eosinophil cells in older children and neutrophil cells in younger children. These results could improve personalized treatments.

Early-onset atopic dermatitis in children: which are the phenotypes at risk of asthma? Results from the ORCA cohort.

BACKGROUND: Atopic dermatitis (AD) is known to predate asthma and other atopic disorders described under the term "atopic march". However, this classic sequence is not always present and only a few studies have addressed children at risk of developing asthma. The objective of this study is to define early-onset AD phenotypes leading to asthma. METHODS: We performed a cluster analysis with 9 variables of 214 infants with early-onset AD prospectively enrolled in the ORCA cohort and followed each year on the occurrence of asthma until the age of 6. RESULTS: We identified 3 clusters - cluster 1 (n = 94) with low to no sensitization to food (27.7%) or aeroallergens (10.6%) and moderate AD severity (SCORAD 25.29 +/- 14.6) called "AD with low sensitization"; - cluster 2 (n = 84) characterized by a higher AD severity (SCORAD 32.66+/-16.6) and frequent sensitization to food (98.9%) or aeroallergens (26.2%), most likely multiple (96.4% for food allergens), called "AD with multiple sensitizations" - cluster 3 (n = 36) with parental history, moderate AD severity (SCORAD 24.46+/-15.7), moderate rate of sensitization to food allergens (38.9%) (exclusively single) with no sensitization to aeroallergens, called "AD with familial history of asthma". Percentages of children suffering from asthma at the age of 6 were higher in clusters 2 and 3 (36.1% and 33.3% respectively versus 14.9% in cluster 1, p<0.01). CONCLUSION: Two phenotypes in infants with early-onset AD convey a higher risk of developing asthma during childhood: multiple sensitization and familial history of asthma.

Determinants of allergic rhinitis in young children with asthma.

BACKGROUND: In the preschool period, allergic rhinitis (AR) is infrequent and thus under-diagnosed. However, recent works have highlighted the occurrence of AR in toddlers although the causes of AR in this young population remain unknown. The objective of this study was to identify determinants of AR in young children with asthma. METHODS: We carried out a case-control study of 227 children with active asthma and enrolled in the Trousseau Asthma Program. AR and other allergic diseases (asthma, food allergy and eczema) were diagnosed by medical doctors using standardized questionnaires. Parental history of AR and asthma, biological markers of atopy (total IgE, blood eosinophilia, allergic sensitization towards food and aeroallergens) and environmental parameters were also collected. RESULTS: Forty one of the children (18.1%) had AR. By univariate logistic regression analysis, AR was mainly associated with peanut sensitization (OR = 6.75; p = 0.002); food allergy (OR = 4.31; p = 0.026); mold exposure (OR = 3.81 p<0.01) and parental history of AR (OR = 1.42; p = 0.046). Due to the strong link between food allergy and peanut sensitization three models of multivariate logistic regression were performed and confirmed that AR is associated with peanut sensitization but also food allergy and mold exposure. A random forest analysis was also performed to explain AR. The results reinforced the logistic analysis that peanut sensitization and mold exposure were the principal determinants of AR. CONCLUSIONS & CLINICAL RELEVANCE: These results stress the importance of investigating AR in young children with asthma to potentially diagnose a particularly severe allergic asthmatic phenotype. Moreover, these data evoke the hypothesis that peanut could be an aeroallergen.

A semi-Markov model based on generalized Weibull distribution with an illustration for HIV disease.

Multi-state stochastic models are useful tools for studying complex dynamics such as chronic diseases. Semi-Markov models explicitly define distributions of waiting times, giving an extension of continuous time and homogeneous Markov models based implicitly on exponential distributions. This paper develops a parametric model adapted to complex medical processes. (i) We introduced a hazard function of waiting times with a U or inverse U shape. (ii) These distributions were specifically selected for each transition. (iii) The vector of covariates was also selected for each transition. We applied this method to the evolution of HIV infected patients. We used a sample of 1244 patients followed up at the hospital in Nice, France.