Profils patients associés à la non conformité des décisions aux recommandations de prise en charge thérapeutique des cancers du sein : utilisation de l'analyse de concepts formels

International audienceLes systèmes d'aide à la décision médicale permettent d'améliorer le suivi des recommandations de pratique clinique. OncoDoc2 est un tel système s’appuyant sur des recommandations de prise en charge du cancer du sein. Malgré son utilisation en routine lors de réunions de concertation pluridisciplinaire de sénologie, des décisions non conformes aux recommandations subsistent. L'objectif est d'utiliser l'analyse de concepts formels afin de caractériser les profils patients associés aux deux modalités de la conformité. Deux étapes de pré-traitement permettant de simplifier les données à analyser sont proposées : une réduction d'attributs par suppression de ceux non statistiquement associés à la non conformité, et un gommage sélectif de valeurs. Parmi les décisions recueillies sur 3 ans à l'hôpital Tenon, 198 concernent la reprise chirurgicale et ont été analysées. Les profils patients associés à la non conformité retrouvés sont ceux pour lesquels il n'existe pas de preuve scientifique des recommandations. Mots-clés

Use of neuraminidase inhibitors in primary health care during pandemic and seasonal influenza between 2009 and 2013: Outpatient influenza antiviral treatment

International audienceBACKGROUND:In a context of controversy about influenza antiviral treatments, this study assessed primary health-care physicians' prescription of neuraminidase inhibitors (NIs) in France during pandemic and seasonal influenza between 2009 and 2013.METHODS:This observational study, using data recorded in three national databases, estimated the rate of NI prescription among influenza-like illness (ILI) patients seen in GP and paediatrician consultations, and determined factors associated with this prescription according to a multivariate analysis. NI delivery by pharmacists was also evaluated.RESULTS:Rates of NI prescription were estimated to be 61.1% among ILI patients with a severe influenza risk factor seen in GP consultation during the A(H1N1)pdm2009 pandemic versus an average rate of 25.9% during the three following seasonal influenza epidemics. Factors associated with NI prescription were a chronic disease in patients under 65 years (OR 14.85; 95% CI 13.00, 16.97) and in those aged 65 and older (OR 7.54; 5.86, 9.70), an age ≥65 years in patients without chronic disease (OR 1.35; 1.04, 1.74), a pregnancy (OR 10.63; 7.67, 15.76), obesity (OR 4.67; 3.50, 6.22) and a consultation during the pandemic A(H1N1)pdm2009 (OR 3.19; 2.93, 3.48). The number of antiviral treatments delivered by pharmacists during the A(H1N1)pdm2009 pandemic was 835 per 100,000 inhabitants, and an average of 275 per 100,000 inhabitants during the three following seasonal influenza epidemics.CONCLUSIONS:Although physicians seem to follow the recommended indications for NIs in primary health-care practice, this study confirms the low rate of NI prescription to ILI patients with a severe influenza risk factor, especially during seasonal epidemics

Assessing Zika Virus Transmission Within Households During an Outbreak in Martinique, 2015-2016.

Since 2015, Zika virus (ZIKV) has caused large epidemics in the Americas. Households are natural targets for control interventions, but quantification of the contribution of household transmission to overall spread is needed to guide policy. We developed a modeling framework to evaluate this contribution and key epidemic features of the ZIKV epidemic in Martinique in 2015-2016 from the joint analysis of a household transmission study (n = 68 households), a study among symptomatic pregnant women (n = 281), and seroprevalence surveys of blood donors (n = 457). We estimated that the probability of mosquito-mediated within-household transmission (from an infected member to a susceptible one) was 21% (95% credible interval (CrI): 5, 51), and the overall probability of infection from outside the household (i.e., in the community) was 39% (95% CrI: 27, 50). Overall, 50% (95% CrI: 43, 58) of the population was infected, with 22% (95% CrI: 5, 46) of infections acquired in households and 40% (95% CrI: 23, 56) being asymptomatic. The probability of presenting with Zika-like symptoms due to another cause was 16% (95% CrI: 10, 23). This study characterized the contribution of household transmission in ZIKV epidemics, demonstrating the benefits of integrating multiple data sets to gain more insight into epidemic dynamics

Using Pharmacokinetic and Viral Kinetic Modeling To Estimate the Antiviral Effectiveness of Telaprevir, Boceprevir, and Pegylated Interferon during Triple Therapy in Treatment-Experienced Hepatitis C Virus-Infected Cirrhotic Patients.: Effectiveness of triple therapy in cirrhotic patients

International audienceTriple therapy combining a protease inhibitor (PI) (telaprevir or boceprevir), pegylated interferon (PEG-IFN), and ribavirin (RBV) has dramatically increased the chance of eradicating hepatitis C virus (HCV). However, the efficacy of this treatment remains suboptimal in cirrhotic treatment-experienced patients. Here, we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug. Fifteen HCV genotype 1-infected patients with compensated cirrhosis, who were nonresponders to prior PEG-IFN/RBV therapy, were enrolled in a nonrandomized study. HCV RNA and concentrations of PIs, PEG-IFN, and RBV were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetic/viral kinetic model. The two PIs achieved similar levels of molar concentrations (P = 0.5), but there was a significant difference in the 50% effective concentrations (EC50) (P = 0.008), leading to greater effectiveness for telaprevir than for boceprevir in blocking viral production (99.8% versus 99.0%, respectively, P = 0.002). In all patients, the antiviral effectiveness of PEG-IFN was modest (43.4%), and there was no significant contribution of RBV exposure to the total antiviral effectiveness. The second phase of viral decline, which is attributed to the loss rate of infected cells, was slow (0.19 day(-1)) and was higher in patients who subsequently eradicated HCV (P = 0.03). The two PIs achieved high levels of antiviral effectiveness. However, the suboptimal antiviral effectiveness of PEG-IFN/RBV and the low loss of infected cells suggest that a longer treatment duration might be needed in cirrhotic treatment-experienced patients and that a future IFN-free regimen may be particularly beneficial in these patients

Clinical trial simulation to evaluate power to compare the antiviral effectiveness of two hepatitis C protease inhibitors using nonlinear mixed effect models: a viral kinetic approach.

International audienceBACKGROUND: Models of hepatitis C virus (HCV) kinetics are increasingly used to estimate and to compare in vivo drug's antiviral effectiveness of new potent anti-HCV agents. Viral kinetic parameters can be estimated using non-linear mixed effect models (NLMEM). Here we aimed to evaluate the performance of this approach to precisely estimate the parameters and to evaluate the type I errors and the power of the Wald test to compare the antiviral effectiveness between two treatment groups when data are sparse and/or a large proportion of viral load (VL) are below the limit of detection (BLD). METHODS: We performed a clinical trial simulation assuming two treatment groups with different levels of antiviral effectiveness. We evaluated the precision and the accuracy of parameter estimates obtained on 500 replication of this trial using the stochastic approximation expectation-approximation algorithm which appropriately handles BLD data. Next we evaluated the type I error and the power of the Wald test to assess a difference of antiviral effectiveness between the two groups. Standard error of the parameters and Wald test property were evaluated according to the number of patients, the number of samples per patient and the expected difference in antiviral effectiveness. RESULTS: NLMEM provided precise and accurate estimates for both the fixed effects and the inter-individual variance parameters even with sparse data and large proportion of BLD data. However Wald test with small number of patients and lack of information due to BLD resulted in an inflation of the type I error as compared to the results obtained when no limit of detection of VL was considered. The corrected power of the test was very high and largely outperformed what can be obtained with empirical comparison of the mean VL decline using Wilcoxon test. CONCLUSION: This simulation study shows the benefit of viral kinetic models analyzed with NLMEM over empirical approaches used in most clinical studies. When designing a viral kinetic study, our results indicate that the enrollment of a large number of patients is to be preferred to small population sample with frequent assessments of VL

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Utilisation des modèles dynamiques pour l'évaluation des traitements de l'hépatite C

Since 2011, the introduction of triple therapies combining a protease inhibitor (PI), telaprevir or boceprevir, with the pegylated-interferon and the ribavirin (Peg-IFN/RBV) marked a milestone for anti hepatitis C virus (HCV) therapy. However, the response to treatment in cirrhotic patients remains unclear and poses serious safety problems. Viral kinetic models, analyzed by nonlinear mixed effect models (NLMEM), are a powerful tool for understanding the response to treatment.We have demonstrated, by means of clinical trial simulation, the power of the Wald test within NLMEM to detect a HCV drug’s antiviral effectiveness difference. This approach, even for a small number of samples, provided consistently higher power to the standard approach based on a non parametric Wilcoxon test on the viral load decay. However, we have highlighted an inflation of the type I error with the Wald test when the number of patients is low and have proposed a permutation correction.We applied this approach to estimate the antiviral effectiveness of the triple therapies in cirrhotic patients and non-responders to a prior therapy (ANRS MODCUPIC). We have shown that over 99% of the viral replication was blocked by PI, with a significantly superior effectiveness of telaprevir compared to boceprevir and suboptimal effectiveness of Peg-IFN/RBV.Finally, by modeling the kinetics of blood parameters, we demonstrated that the concentrations of Peg-IFN and RBV are associated with, respectively, anemia and thrombocytopenia which are frequently observed in these patients.L’introduction depuis 2011 des trithérapies associant un inhibiteur de protéase (IP), telaprevir ou boceprevir, à l’interféron pégylé et la ribavirine (Peg-IFN/RBV), constitue un tournant majeur dans la lutte contre le virus de l’hépatite C (VHC). Cependant la réponse au traitement chez les patients cirrhotiques reste mal connue et pose de sérieux problèmes de tolérance. Les modèles de cinétique virale, analysés par modèles non-linéaires à effets mixtes (MNLEM), constituent un outil puissant pour la compréhension de la réponse au traitement.Nous avons démontré par simulation la puissance du test de Wald dans le cadre des MNLEM pour détecter une différence d’efficacité antivirale entre deux traitements. Cette approche, même pour un nombre réduit de prélèvements, s’est révélée systématiquement supérieure à l’approche standard reposant sur un test de Wilcoxon sur le déclin de charge virale. Cependant nous avons mis en évidence une inflation de l’erreur de type I de ce test lorsque le nombre de patients est faible et avons proposé une correction par permutation.Nous avons appliqué cette approche pour estimer l’efficacité antivirale des trithérapies chez des patients cirrhotiques en échec thérapeutique (ANRS MODCUPIC). Nous avons démontré que plus de 99% de la réplication virale était bloqué par les IP, avec une efficacité significativement supérieure du telaprevir par rapport au boceprevir, et une efficacité sous-optimale de Peg-IFN/RBV.Enfin, en modélisant la cinétique des paramètres sanguins, nous avons démontré que les concentrations de Peg-IFN et de RBV sont directement associées, respectivement, à l’anémie et la thrombopénie fréquemment observées chez ces patients

Evaluation by simulation of clinical trial designs for evaluation of treatment during a viral haemorrhagic fever outbreak

International audienceBackground: Viral haemorrhagic fevers are characterized by irregular outbreaks with high mortality rate. Difficulties arise when implementing therapeutic trials in this context. The outbreak duration is hard to predict and can be short compared to delays of trial launch and number of subject needed (NSN) recruitment. Our objectives were to compare, using clinical trial simulation, different trial designs for experimental treatment evaluation in various outbreak scenarios.Methods: Four type of designs were compared: fixed or group-sequential, each being single- or two-arm. The primary outcome was 14-day survival rate. For single-arm designs, results were compared to a pre-trial historical survival rate pH. Treatments efficacy was evaluated by one-sided tests of proportion (fixed designs) and Whitehead triangular tests (group-sequential designs) with type-I-error = 0.025. Both survival rates in the control arm pC and survival rate differences Δ (including 0) varied. Three specific cases were considered: "standard" (fixed pC, reaching NSN for fixed designs and maximum sample size NMax for group-sequential designs); "changing with time" (increased pC over time); "stopping of recruitment" (epidemic ends). We calculated the proportion of simulated trials showing treatment efficacy, with K = 93,639 simulated trials to get a type-I-error PI95% of [0.024;0.026].Results: Under H0 (Δ = 0), for the "standard" case, the type-I-error was maintained regardless of trial designs. For "changing with time" case, when pC > pH, type-I-error was inflated, and when pC < pH it decreased. Wrong conclusions were more often observed for single-arm designs due to an increase of Δ over time. Under H1 (Δ = + 0.2), for the "standard" case, the power was similar between single- and two-arm designs when pC = pH. For "stopping of recruitment" case, single-arm performed better than two-arm designs, and fixed designs reported higher power than group-sequential designs. A web R-Shiny application was developed.Conclusions: At an outbreak beginning, group-sequential two-arm trials should be preferred, as the infected cases number increases allowing to conduct a strong randomized control trial. Group-sequential designs allow early termination of trials in cases of harmful experimental treatment. After the epidemic peak, fixed single-arm design should be preferred, as the cases number decreases but this assumes a high level of confidence on the pre-trial historical survival rate

Mesurer les contacts entre soignants et patients au moyen de capteurs électroniques : le cas de la tuberculose

Doi : 10.1016/j.respe.2011.02.055National audienc