[Interest of a geostatistical approach to analyze the geographical disparities in human papillomavirus vaccine coverage in France]. / Intérêt d'une approche géostatistique pour analyser les disparités géographiques de la couverture vaccinale contre les papillomavirus humains en France.

BACKGROUND: The use of geostatistical methods remains rare in health studies. In order to assess the usefulness of the geostatistical approach in epidemiology, we chose to apply these methods to the vaccination coverage rate (VCR) against human papillomavirus (HPV) in France. Indeed, HPV vaccine coverage remains low in France and geographical disparities are sizable. The objective of this study was to identify the socioecological factors that may explain these geographical variations. METHODS: Sociological, economic and behavioral data for 2016 have been gathered (demographics and public health database, web and social networks) and were correlated with the HPV VCR vaccine coverage over the French territory. Homogeneous geographical areas defined by strong correlations for groups of variables were selected. In each homogeneous area, principal component analysis was performed and a geostatistical approach provided an estimate predicting vaccine coverage at a given scale. RESULTS: HPV VCR spatial variations in France cannot be fully explained by a single model. In urban areas, a low rate of HPV VCR is preferentially associated with unfavorable socioeconomic factors (poverty, unemployment, immigration). In rural areas, HPV VCR is preferentially associated with sociocultural factors (socio-professional categories, education level, interest in alternative medicines the anti-vaccine movement). Two secondary geographical areas were defined: the Île-de-France region and 12 departments in northeastern France. In the Île-de-France region, the association with the economic factors one again appears as in urban areas in general. The northeasteran departments represent a particular case insofar as HPV VCR is relatively high, notwithstanding economic poverty indicators. CONCLUSION: Geostatistical modeling successfully identifies new potential explanations for HPV VCR geographical disparities in France. These results could help to adapt or develop future vaccination programs in specific areas by taking into account the sociological, economic and behavioral characteristics of their populations.

Identifying chronic thromboembolic pulmonary hypertension through the French national hospital discharge database.

Chronic thromboembolic pulmonary hypertension (CTEPH), a rare pulmonary vascular disease, is often misdiagnosed due to nonspecific symptoms. The objective of the study was to develop, refine and validate a case ascertainment algorithm to identify CTEPH patients within the French exhaustive hospital discharge database (PMSI), and to use it to estimate the annual number of hospitalized patients with CTEPH in France in 2015, as a proxy for disease prevalence. As ICD-10 coding specifically for CTEPH was not available at the time of the study, a case ascertainment algorithm was developed in close collaboration with an expert committee, using a two-step process (refinement and validation), based on matched data from PMSI and hospital medical records from 2 centres. The best-performing algorithm (specificity 95%, sensitivity 70%) consisted of ≥1 pulmonary hypertension (PH) diagnosis during 2015 and any of the following criteria over 2009-2015: (i) CTEPH interventional procedure, (ii) admission for PH and pulmonary embolism (PE), (iii) PE followed by hospitalization in competence centre then in reference centre, (iv) history of PE and right heart catheterization. Patients with conditions suggestive of pulmonary arterial hypertension were excluded. A total of 3,138 patients hospitalized for CTEPH was estimated for 2015 (47 cases/million, range 43 to 50 cases/million). Assuming that patients are hospitalized at least once a year, the present study provides an estimate of the minimal prevalence of CTEPH and confirms the heavy burden of this disease.

Two year continuation rates of contraceptive methods in France: a cohort study from the French national health insurance database.

OBJECTIVE: The aim of this study was to evaluate the continuation rates of reimbursed contraceptive methods in French real-world conditions. METHODS: A retrospective cohort study using a representative sample of the national health insurance database, the General Sample of Beneficiaries (Echantillon Généralistes des Bénéficiaires [EGB]), was performed between 2006 and 2012. Selected women were ≥15 years of age and had started a reimbursed contraceptive method between 2009 and 2012 without prior reimbursement for an implant or an intrauterine contraceptive method between 2006 and 2008. The outcome of interest was the continuation rates, defined as the probability of women initiating a contraceptive method and continuing to use the same method over time. Continuation rates were assessed for up to 2 years. Only the first contraceptive method used during the study period was considered in the analysis. Non-parametric Kaplan-Meier survival analysis was used to assess continuation rates. RESULTS: A population of 42,365 women representative of the 4,109,405 French women initiating any reimbursed method between 2009 and 2012 was identified in the EGB: 74.5% of women used oral contraceptives, 12.8% the levonorgestrel-releasing intrauterine system (LNG-IUS), 9.2% the copper intrauterine device (Cu-IUD) and 3.5% the subdermal etonogestrel (ENG) implant. The 2 year continuation rates varied from 9.1% for progestin-only oral contraceptives, 27.6% for first to second generation combined oral contraceptives (COCs) and 33.4% for third generation COCs to 83.6% for the ENG implant, 88.1% for the Cu-IUD and 91.1% for the LNG-IUS. CONCLUSION: This study conducted in real-world conditions showed that long-acting reversible contraceptive (LARC) methods remain rarely used in France despite high continuation rates over 2 years. Increasing the use of LARC methods is therefore a public health priority.

French hospital discharge database (PMSI) and bacterial resistance: Is coding adapted to hospital epidemiology?

OBJECTIVE: A preliminary analysis of data consistency on different types of bacterial resistance by infection site and causative agents was conducted using the French hospital discharge database (French acronym PMSI) to assess the use of the database in a national cartography tool. MATERIAL AND METHODS: Hospital stays in medical, surgical, and obstetrical units were extracted from the 2014 PMSI database using the ICD-10 diagnosis codes. Bacterial infections, causative agents, and resistance corresponding to these stays were also identified. RESULTS: Data from 1258462 patients, corresponding to a total of 1617893 stays, was extracted. Among these stays, 46% were associated with a bacteria code and 7% with a resistance code. Lower respiratory tract infections were the most frequent infections (32% of stays; pneumonia in 95% of cases), followed by genitourinary infections (26%), intra-abdominal infections and diarrhoeas (24%), and skin and soft tissue infections (15%). Inconsistencies were observed between the types of infection and associated bacteria and between bacteria and associated resistance. These inconsistencies are likely due to initial coding errors. CONCLUSION: The cartography of bacterial infections cannot be developed using the data of the current PMSI coding. These results underline the need to improve the coding of PMSI data for its use as a complementary tool of epidemiological surveillance of bacterial infections.

Excess mortality between 2007 and 2014 among patients with Clostridium difficile infection: a French health insurance database analysis.

BACKGROUND: The impact of Clostridium difficile infection (CDI) on mortality is controversial. AIM: To assess excess mortality due to CDI in France. METHOD: Two cohorts of patients with CDI and a cohort of matched controls were extracted from a 1% representative sample of subjects covered by the general health insurance system in France (Echantillon Généraliste de Bénéficiaires database, 660,000 patients). The CDI patients were hospitalized with CDI as a principal diagnosis or an associated diagnosis between 2007 and 2014, but not in 2006. Controls were patients hospitalized between 2007 and 2014 but not hospitalized with CDI between 2006 and 2014. The one-year incidence of deaths between 2007 and 2014 was estimated and compared with that of a propensity score (PS)-matched control group with no CDI (two controls per case). The PS was calculated with the following variables: age; sex; Charlson Comorbidity Index score; duration of stay; year of index stay; and main comorbidities. Cox and Poisson models were used to estimate the increased risk of death while adjusting for PS. Sensitivity analyses (timeframe, diarrhoea, recurrent hospitalization for CDI) were used to explore the robustness of the results. FINDINGS: In total, 482 patients who had been infected with C. difficile were matched with 964 controls. A significantly higher risk of death was observed among the subjects with CDI, with a non-adjusted hazard ratio of 1.65 [95% confidence interval (CI) 1.33-2.04] and an adjusted ratio of 1.58 (95% CI 1.27-1.97). The adjusted relative risk of death was 1.78 (95% CI 1.18-2.70]) at 28 days, 1.52 (95% CI 1.17-1.98) at three months, 1.52 (95% CI 1.20-1.93) at six months and 1.64 (95% CI 1.32-2.03) at 12 months. Sensitivity analyses produced similar results; the hazard ratio ranged from 1.53 to 1.86, and was always statistically significant. CONCLUSION: CDI is responsible for excess mortality after taking age, sex, comorbidities and length of hospital stay into account.

Real-world treatment patterns and clinical outcomes in advanced cutaneous melanoma patients in France.

BACKGROUND: Since 2011, the management of advanced melanoma has radically changed with the availability of new therapies (immunotherapy and BRAF-targeted therapy) and with BRAF testing. OBJECTIVES: Following the introduction of these new therapies, the objectives of this AMEL study were to describe treatment patterns and evaluate overall survival (OS) among unresectable stage III/IV melanoma patients, in a real-life setting in France. METHODS: The AMEL study is a multicentre retrospective record review study. Thirty-three physicians working in 33 unique treatment centres participated in the study. Two hundred and sixty-four patients diagnosed between 1 January 2012 and 31 October 2012 with unresectable stage III/IV melanoma were included in the study. RESULTS: 94.7% of the patients received a first-line antitumour drug treatment, 62.5% a second-line treatment while 26.9% received a third-line treatment with no significant differences between patients with a BRAF mutation (50.4%) and BRAF wild type (47.0%). First-line treatment differs according to the BRAF status: 74.8% of patients with a BRAF mutation received a BRAF inhibitor while 79.3% of the BRAF wild-type patients were treated with conventional chemotherapy. In second line and over, the treatment patterns were more heterogeneous, depending on the BRAF mutation, the treatment received previously, the speed of progression of the disease and the availability of immunotherapy at the time the treatment was initiated. CONCLUSION: Regardless of the BRAF mutation status, the median OS of patients was 16 months (95% CI = 14-18). Compared to a similar study conducted in 2007 (MELODY), a gain of 4 months is observed. The gain seems to be higher for patients with a BRAF mutation (18 months) than for those without a BRAF mutation (14 months). The OS of patients who sequentially received both a BRAF inhibitor and ipilimumab (28 months) highlights the benefit of this treatment sequence.

[Costs of healthcare resource consumption after a myocardial infarction in France: An estimate from a medicoadministrative database (GSB)]. / Coût des consommations de soins après un infarctus du myocarde en France : une estimation à partir de l'échantillon généraliste des bénéficiaires (EGB).

OBJECTIVE: To estimate the costs of healthcare resource consumption in the year preceding and the year following a myocardial infarction (MI). PATIENTS AND METHODS: A historical cohort of patients experiencing an MI in France between 2007 and 2011 was extracted from the échantillon généraliste de bénéficiaires, a 1/97th sample of all beneficiaries of public health insurance in France. RESULTS: A total of 1920 patients experiencing an MI were identified. Two-thirds were men and the mean age was 67 years; 20.6% had diabetes, 37.6% hypercholesterolaemia and 82.4% hypertension. From a societal perspective, the annual costs of medical consumption related to hospitalisations increased from € 4548 before the MI to € 6470 in the following year. Costs of community care rose from € 2932 to € 6208. This increase concerned all components of community healthcare: costs associated with medical transportation increased fourfold, those associated with consultations and laboratory tests tripled, medication costs doubled and costs of paramedical services also increased, but to a lesser extent. It should be noted that the cost of hospitalisation for the index MI (€ 5876) is not included in the above costs. CONCLUSION: From a society perspective, the cost of healthcare resource consumption increased threefold in the year following an MI.

[Cost of systemic lupus erythematosus for adult patients with active and treated disease in France (LUCIE study)]. / Coût du lupus systémique en France des patients adultes avec une maladie active et traitée (étude LUCIE).

PURPOSE: To evaluate in France the annual direct medical cost of adult patients with active systemic lupus erythematosus (SLE) on medication and estimate the cost of a flare. METHODS: A two-year, observational, retrospective, multicenter study, carried out between December 2010 and February 2011. Patients' characteristics, SLE disease activity and severity, rate of flares, healthcare consumption (medications, hospitalisations, etc.) were evaluated. Medical costs were assessed from the national Health Insurance perspective. Cost predictors were estimated using multivariate regression models. RESULTS: Eight centres specialized in SLE management included 93 eligible patients (including 50.5% severe). The mean age was 39.9 (11.9) years and 93.5% were women. At baseline, the mean SLE duration was 9.8 (6.6) years. The mean scores of the SELENA-SLEDAI instrument and the SLICC/ACR index were higher in severe patients (9.8 vs 5.6, and 1.2 vs 0.4 respectively; P<0.001). Over the study period, 51% of patients received the combination containing at least corticosteroids or immunosuppressants. The mean annual direct medical cost of severe patients was €4660 versus €3560 for non-severe patients (non-significant difference). The cost of medications (61.8% of the annual cost) was higher in severe patients (€3214 vs €1856; P<0.05). Immunosuppressants and biologics represented 26.5% and 4.6% of the annual total cost respectively. Patients experienced on average 1.10 (0.59) flares/year, of which 0.50 were severe flare. The occurrence of a new severe flare incremented the annual cost of €1330 (P<0.05). CONCLUSION: Medications represented the major component of the annual direct medical cost. Severe flares increase significantly the cost of SLE care management.

Management of focal epilepsy in adults treated with polytherapy in France: the direct cost of drug resistance (ESPERA study).

PURPOSE: To estimate the direct costs associated with the current management of focal epilepsy in adults treated with a combination of antiepileptic drugs (AEDs) in France and the supplementary costs of drug resistant epilepsy as defined by the International League Against Epilepsy (ILAE) in 2009. METHODS: ESPERA was a multicentre, observational, cross-sectional study conducted in France in 2010. A random sample of neurologists, including specialists in epilepsy, prospectively enrolled adults with focal epilepsy treated with a combination of AEDs. Investigators classified their patients according to the 2009 ILAE criteria for drug resistance and this classification was then reviewed by two experts. All items of healthcare resource use associated with epilepsy over the previous year were documented retrospectively and valued from a societal perspective. RESULTS: Seventy-one neurologists enrolled 405 patients. After experts' review, 70.6% of patients were classified with drug-resistant epilepsy, 22.4% with drug-responsive epilepsy and 7% with undefined epilepsy. The mean annual epilepsy-related direct costs per patient were €4485±€4313 in patients with drug-resistant epilepsy compared to €1926±€1795 in patients with drug-responsive epilepsy. In these two groups, costs of AEDs were estimated at €2603 and €1544, respectively. Patients with drug-resistant epilepsy were more often hospitalised (mean annual cost: €1270 vs. €97) and underwent more additional tests (mean annual cost: €194 vs. €53). CONCLUSION: The direct cost of focal epilepsy in adults on AED combinations was estimated at €3850/patient/year. Drug resistance, as defined by the 2009 ILAE criteria, resulted in significant extra costs which varied with seizure frequency.

[Adult patients treated for focal epilepsy with antiepileptic drugs (AEDs) in combination in France: description according to the 2009 ILAE definition of AED resistance (ESPERA study)]. / Patients adultes traités par une association d'antiépileptiques pour une épilepsie focale en France: description et mode de prise en charge selon les nouveaux critères de définition de la pharmacorésistance (étude ESPERA).

AIMS: To describe the adult population treated with antiepileptic drugs (AEDs) in combination for focal epilepsy according to the definition of AED resistance proposed by the International League Against Epilepsy (ILAE) in 2009 and to evaluate its implementation in current practice. METHODS: ESPERA was a multicenter, observational, cross-sectional study with a clinical data collection covering the past 12 months conducted by neurologists. Classifications according to AED responsiveness established by investigators for each enrolled patient were revised by two experts. RESULTS: Seventy-one neurologists enrolled 405 patients. Their mean age was 42.7 years (sex-ratioM/F 0.98). According to the investigators, 60% of epilepsies were drug-resistant, 37% drug-responsive and 3% had an undefined drug-responsiveness. After revision of experts, 71% of epilepsies were classified as drug resistant, 22% as responsive and 7% as undefined. Among the participating neurologists, 76% have made at least one error in classifying their patients according to the 2009 ILAE definition of AED resistance. Because of epilepsy, 24% of patients (age≤65) were inactive and 42% could not drive (respectively 29 and 49% of patients with AED resistant epilepsy). Half of patients had at least one other chronic condition. Number of prescribed drugs in combination and health care resource utilisation were significantly higher in patients with drug-resistant epilepsies than in patients with drug responsive epilepsies. CONCLUSION: ESPERA study shows that the use of new definition of drug-resistance in everyday practice seems difficult without any additional training and that the social and professional disability is frequent in adults with focal epilepsies treated with polytherapy.

Abacavir (Ziagen(®)) use between 2003 and 2008 in France according to the electronic medical record NADIS(®).

OBJECTIVE: The authors had for objective to describe HIV-infected patients treated with ABC (Ziagen(®), ABC), and the immune, virological, and clinical treatment outcome between 2003 and 2008. PATIENTS AND METHODS: We performed a retrospective analysis of the Dat'AIDS database on patients who were treated with ABC for the first time between 2003 and 2008. RESULTS: Eight hundred and thirty-six patients were included. Before initiation of ABC, 26.3% has stopped the previous treatment because of immuno-virological failure, 30.5% because of adverse events, and 29.8% for other reasons. Thirteen percent were antiretroviral naive. One third of patients were ranked as CDC class C, and more than 2/3 had a viral load<5 log copies/mL or a CD4 count≥200mm(3). ABC was mainly included in a combination containing 2 NRTI and 1 PI (63%), or 1 non-NRTI (16%). Thirty-two percent of patients were still treated with ABC after 2years of treatment and the median of ABC treatment was 11months (IQ 84days-2years). The main causes for stopping ABC were therapeutic simplification (47.4% of patients), intolerance (19.0%), and immuno-virological failure (9.8%). Suspected hypersensitivity reactions were the main cause of discontinuation due to intolerance (27.6%); the rate was 3.8% when ABC had been introduced before the routine use of the screening test HLA-B*5701. The incidence of myocardial infarction was 3.8 per 1000 patient-years; 70.6% of patients received a fixed combination including ABC after discontinuation of ABC as a single agent (Ziagen(®)). CONCLUSION: This retrospective analysis confirmed the effectiveness and the good tolerance of ABC in the therapeutic strategy, between 2003 and 2008.

Impacto económico y en calidad de vida de la epilepsia resistente en España: estudio ESPERA / Quality of life and economic impact of refractory epilepsy in Spain: the ESPERA study

Introducción: El 30% de los pacientes con epilepsia no permanece libre de crisis con los fármacos antiepilépticos (FAE) disponibles actualmente. El objetivo del estudio fue estimar el impacto económico y en calidad de vida de la epilepsia resistente a fármacos (ERF) en España, según la definición de la Liga Internacional contra la Epilepsia (ILAE). Métodos: Estudio observacional retrospectivo (12 meses) que incluyó pacientes adultos con epilepsia focal en tratamiento con, al menos, 2 FAE. Los costes sanitarios directos (€ 2010) se cuantificaron a partir de los recursos sanitarios y de sus costes unitarios. El análisis se realizó desde las perspectivas del Sistema Nacional de Salud (SNS) y la sociedad. El impacto de la ERF en la calidad de vida se valoró mediante los cuestionarios QOLIE 31-P, EQ-5D-3L y NDDIE. Resultados: Se analizaron 263 pacientes (304 seleccionados). El 70,0% tenía ERF y el 20,3% estaban controlados. Bajo la perspectiva del SNS el coste anual por paciente con ERF y por paciente controlado fue de 4.964 y 2.978 €, respectivamente (p<0,01). En relación con los pacientes con ERF, los pacientes controlados presentaron mejores puntuaciones en el QOLIE-31P (70,8 vs 56,4, p<0,0001) y EQ-5D-3L (75,6 vs 64,7, p<0,001), y menor incidencia de depresión mayor según la escala NDDIE (23 vs 8,3%, p<0,05). Conclusiones: En relación con la epilepsia controlada, la ERF se asocia a mayor consumo de recursos y costes, peor calidad de vida y mayor incidencia de depresión mayor, resultando, por tanto, en una considerable carga para el SNS y la sociedad (AU)

Introduction: Despite use of currently available anti-epileptic drugs (AED), 30% of epilepsy patients are not seizure-free. The purpose of this study was to estimate the quality of life and economic impact in Spain of drug-resistant epilepsy (DRE), as defined by the International League Against Epilepsy (ILAE). Methods: Observational retrospective 12-month study conducted in Spain including adults with focal epilepsy treated with at least two AEDs. Direct costs (€ 2010) were calculated based on health care resources used and their official unit costs. Costs were analysed from the perspectives of the Spanish National Health System (SNS) and society. The impact of DRE on patients’ quality of life was examined using the QOLIE 31-P, EQ-5D-3L, and NDDIE questionnaires. Results: We analysed 263 patients out of the 304 recruited. According to ILAE criteria, 70.0% of the patients had drug-resistant epilepsy, while 20.3% achieved seizure freedom. From the viewpoint of the SNS, annual costs for resistant and seizure-free patients were € 4964 and € 2978 respectively (P<.01). Compared to resistant patients, seizure-free patients showed better scores on QOLIE-31P (70.8 vs 56.4, P<.0001) and EQ-5D-3L (75.6 vs 64.7, P<.001). Seizure-free patients showed a lower incidence of major depression compared to resistant patients according to the NDDIE scale (23 vs 8.3%, P<.05). Conclusions: Results suggest that DRE is associated with increased use of healthcare resources and consequently with higher costs, poorer quality of life and higher incidence of major depression compared to seizure-free patients, thus representing a considerable burden to the SNS and society (AU)

Quality of life and economic impact of refractory epilepsy in Spain: the ESPERA study.

INTRODUCTION: Despite use of currently available anti-epileptic drugs (AED), 30% of epilepsy patients are not seizure-free. The purpose of this study was to estimate the quality of life and economic impact in Spain of drug-resistant epilepsy (DRE), as defined by the International League Against Epilepsy (ILAE). METHODS: Observational retrospective 12-month study conducted in Spain including adults with focal epilepsy treated with at least two AEDs. Direct costs (€ 2010) were calculated based on health care resources used and their official unit costs. Costs were analysed from the perspectives of the Spanish National Health System (SNS) and society. The impact of DRE on patients' quality of life was examined using the QOLIE 31-P, EQ-5D-3L, and NDDIE questionnaires. RESULTS: We analysed 263 patients out of the 304 recruited. According to ILAE criteria, 70.0% of the patients had drug-resistant epilepsy, while 20.3% achieved seizure freedom. From the viewpoint of the SNS, annual costs for resistant and seizure-free patients were € 4964 and € 2978 respectively (P<.01). Compared to resistant patients, seizure-free patients showed better scores on QOLIE-31P (70.8 vs 56.4, P<.0001) and EQ-5D-3L (75.6 vs 64.7, P<.001). Seizure-free patients showed a lower incidence of major depression compared to resistant patients according to the NDDIE scale (23 vs 8.3%, P<.05). CONCLUSIONS: Results suggest that DRE is associated with increased use of healthcare resources and consequently with higher costs, poorer quality of life and higher incidence of major depression compared to seizure-free patients, thus representing a considerable burden to the SNS and society.

[Management of immune thrombocytopenia in France before the era of thrombopoietin receptor agonists]. / Prise en charge du purpura thrombopénique immunologique en France avant la mise à disposition des agonistes du récepteur à la thrombopoïétine.

PURPOSE: Adult immune thrombocytopenia (ITP) is an auto-immune disease with most often a chronic course for which a consensual therapeutic strategy is missing. The objective of this study was to describe treatment practices in adult ITP in France before the era of thrombopoietin receptor (TpoR) agonists. METHODS: A retrospective observational study was conducted in eight hospitals in France. All eligible patients were at least 18 years of age and were seen for a chronic ITP between January 2004 and March 2006 in one of the participating centers. Data were collected retrospectively from clinical charts. ITP treatment from disease onset was analyzed for every patient according to the time of diagnosis. RESULTS: The study included 122 patients (73% of women) with a mean age of 52.6 years. Patients in whom ITP had been diagnosed less than 4 years earlier (n=71) received on average 2.9 treatment lines. Corticosteroids possibly combined with intravenous immunoglobulins were most often used as a first-line. From the second line, up to 12 different regimens were identified. As a third line, rituximab and splenectomy were the most common therapeutic procedures. The number of splenectomy tended to decrease over time. CONCLUSION: This analysis reflects the great heterogeneity into the management of chronic ITP. Whether such heterogeneity has declined after national guidelines have been produced remains to be assessed as well as the place of the newly develop TpoR agonists.