Prise en charge du VIH au stade de la primo-infection

In France, since 2013, HIV treatment has been recommended for all HIV-infected patients independently of their CD4 count. However, when to start anti-retroviral (ARV) treatment is still an issue. This thesis aims to explore the therapeutic management of HIV at the stage of PHI in different aspects: 1) we explored how physicians in France have applied the evolving guidelines for ART initiation since 1996 2) the impact of a transient ARV treatment at PHI on immuno-virological response during 2nd treatment and 3) identification of new biomarkers prognostic of HIV progression.Most of the work presented in this thesis is based on data from the ongoing ANRS PRIMO cohort that enrolled more than 1 500 HIV infected patients enrolled at PHI since June 1996 in 94 French hospitals. All patients were antiretroviral therapy naive at baseline.The first part of the thesis analyzes the implementation of the recommendations of ARV treatment initiation between 1996 and 2010 by physicians in France, in two distinct situations: in the chronic HIV-1 infection and during primary HIV-1 infection. We have shown that the recommendations of ARV treatment initiation were widely followed. Nevertheless, there was inertia in guidelines application when changes in the recommendations took place. The time to treatment when CD4 cell counts reach the threshold to treat can be improved. 96% of the patients initiated ART when they had a CD4 cell count below the threshold to treat at entry, while treatment was less timely initiated when the CD4 threshold was reached during active follow-up (78%, p 5), a lower education level and poor living conditions.The impact of ARV interruption after a first treatment initiated at PHI on the CD4 count restoration after resumption was explored by modeling the evolution of CD4 cells with linear mixed effects models with random intercept and slope. Patients who initiated ARV treatment during the chronic phase had a better immune response than patients who initiated a second course treatment after a transient ART at PHI: at 36 months, the gains in √CD4 cells / mm3 and CD4 percentage were significantly higher. However, this difference was clinically modest and further research on treatment interruptions seeking to induce post-treatment controllers is still an issue but only in research settings and under close medical surveillance. After an overview of the complex mechanisms of activation / inflammation of the immune system during primary infection we sought to identify new predictive biomarkers of disease progression. The level of sCD14 (marker of monocyte/macrophage activation and an indirect marker of microbial translocation) at the time of PHI was identified as predictive marker of CD4 decline and of risk of cardio-vascular mortality. In conclusion, although considerable progress has been made in the management of HIV, further studies are needed to optimize and adapt the treatment to the patient profile in the early stages of HIV infection.Depuis 2013, le traitement « universel » est recommandé en France. Le moment de l’initiation thérapeutique est une question qui reste cependant d’actualité pour les patients se présentant en primo-infection. Cette thèse s’attache à étudier la prise en charge thérapeutique du VIH au stade de la primo-infection (PIV) sous différents angles :1) le suivi par les cliniciens des recommandations d’initiation des traitements antirétroviraux depuis 1996 en fonction de l’évolution de ces recommandations; 2) l’impact d’un traitement ARV transitoire en PIV sur la réponse immuno-virologique lors de la reprise du traitement et 3) l’identification de nouveaux biomarqueurs comme facteurs pronostiques de progression de l’infection VIH. La majorité des travaux présentés dans cette thèse repose sur les données de la cohorte ANRS PRIMO qui comporte environ 1 500 patients infectés par le VIH inclus en PIV entre juin 1996 et décembre 2013, dans 94 hôpitaux français. Tous les patients étaient naïfs de traitement antirétroviral à l'inclusion.La première partie de la thèse analyse la mise en œuvre des recommandations d’initiation du traitement ARV entre 1996 et 2010 par les médecins en France, dans deux situations distinctes : au stade chronique et lors de la primo-infection par le VIH-1. Nous avons montré que les recommandations d’initiation du traitement ARV étaient largement suivies. Néanmoins, il existe un effet d’inertie dans leurs applications lors des changements de recommandation. Il reste à améliorer le délai de mise sous traitement lorsque le taux de CD4 atteint le seuil recommandé. Au stade chronique, le traitement était plus fréquemment initié chez les patients présentant un critère d’initiation dès le diagnostic d’infection par le VIH (96%), que chez les patients qui atteignaient un critère d’initiation au cours du suivi (78%, p5), un plus faible niveau d’éducation et des conditions de vie précaires.L’impact de l’interruption d’un traitement antirétroviral initié en PIV sur la restauration des CD4 après reprise du traitement a été exploré en modélisant l’évolution des CD4 avec des modèles linéaires à effets mixtes avec intercept et pente aléatoires. Les patients qui avaient initié un traitement ARV pendant la phase chronique avaient une meilleure réponse immunologique que les patients reprenant un 2ème traitement après un traitement transitoire en PIV : à 36 mois, les gains en √CD4 cellules/mm3 et en pourcentage de CD4 étaient significativement plus élevés. Cependant, il s’agissait de différences modestes en termes cliniques, qui ne conduisent pas à recommander d’arrêter la recherche clinique sur les arrêts de traitement cherchant à induire des contrôleurs post traitement. Après un état des lieux des mécanismes complexes d’activation/inflammation du système immunitaire pendant la primo-infection nous avons cherché à identifier de nouveaux biomarqueurs prédictifs de l’évolution de l’infection. Le taux de sCD14 (marqueur d’activation monocyte/macrophage et marqueur indirect de translocation microbienne) au moment de la PIV a été identifié comme marqueur potentiel de prédiction du déclin des CD4 et du risque de mortalité d’origine cardio-vasculaire. En conclusion, bien que des progrès considérables aient été réalisés dans la prise en charge du VIH, d'autres études sont nécessaires pour optimiser et adapter le traitement au profil du patient dès les premiers stades de l’infection VIH

Role of Epidural Analgesia within an ERAS Program after Laparoscopic Colorectal Surgery: A Review and Meta-Analysis of Randomised Controlled Studies

Introduction. Epidural analgesia has been a cornerstone of any ERAS program for open colorectal surgery. With the improvements in anesthetic and analgesic techniques as well as the introduction of the laparoscopy for colorectal resection, the role of epidural analgesia has been questioned. The aim of the review was to assess through a meta-analysis the impact of epidural analgesia compared to other analgesic techniques for colorectal laparoscopic surgery within an ERAS program. Methods. Literature research was performed on PubMed, Embase, and the Cochrane Library. All randomised clinical trials that reported data on hospital stay, postoperative complications, and readmissions rates within an ERAS program with and without an epidural analgesia after a colorectal laparoscopic resection were included. Results. Five randomised clinical trials were selected and a total of 168 patients submitted to epidural analgesia were compared to 163 patients treated by an alternative analgesic technique. Pooled data show a longer hospital stay in the epidural group with a mean difference of 1.07 (95% CI 0.06–2.08) without any significant differences in postoperative complications and readmissions rates. Conclusion. Epidural analgesia does not seem to offer any additional clinical benefits to patients undergoing laparoscopic colorectal surgery within an ERAS program

Prognostic Accuracy of Sepsis-3 Criteria for In-Hospital Mortality Among Patients With Suspected Infection Presenting to the Emergency Department.

An international task force recently redefined the concept of sepsis. This task force recommended the use of the quick Sequential Organ Failure Assessment (qSOFA) score instead of systemic inflammatory response syndrome (SIRS) criteria to identify patients at high risk of mortality. However, these new criteria have not been prospectively validated in some settings, and their added value in the emergency department remains unknown. To prospectively validate qSOFA as a mortality predictor and compare the performances of the new sepsis criteria to the previous ones. International prospective cohort study, conducted in France, Spain, Belgium, and Switzerland between May and June 2016. In the 30 participating emergency departments, for a 4-week period, consecutive patients who visited the emergency departments with suspected infection were included. All variables from previous and new definitions of sepsis were collected. Patients were followed up until hospital discharge or death. Measurement of qSOFA, SOFA, and SIRS. In-hospital mortality. Of 1088 patients screened, 879 were included in the analysis. Median age was 67 years (interquartile range, 47-81 years), 414 (47%) were women, and 379 (43%) had respiratory tract infection. Overall in-hospital mortality was 8%: 3% for patients with a qSOFA score lower than 2 vs 24% for those with qSOFA score of 2 or higher (absolute difference, 21%; 95% CI, 15%-26%). The qSOFA performed better than both SIRS and severe sepsis in predicting in-hospital mortality, with an area under the receiver operating curve (AUROC) of 0.80 (95% CI, 0.74-0.85) vs 0.65 (95% CI, 0.59-0.70) for both SIRS and severe sepsis (P < .001; incremental AUROC, 0.15; 95% CI, 0.09-0.22). The hazard ratio of qSOFA score for death was 6.2 (95% CI, 3.8-10.3) vs 3.5 (95% CI, 2.2-5.5) for severe sepsis. Among patients presenting to the emergency department with suspected infection, the use of qSOFA resulted in greater prognostic accuracy for in-hospital mortality than did either SIRS or severe sepsis. These findings provide support for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria in the emergency department setting. clinicaltrials.gov Identifier: NCT02738164

Care and Treatment of HIV-Infected Patients During Primary HIV-Infection

Depuis 2013, le traitement « universel » est recommandé en France. Le moment de l’initiation thérapeutique est une question qui reste cependant d’actualité pour les patients se présentant en primo-infection. Cette thèse s’attache à étudier la prise en charge thérapeutique du VIH au stade de la primo-infection (PIV) sous différents angles :1) le suivi par les cliniciens des recommandations d’initiation des traitements antirétroviraux depuis 1996 en fonction de l’évolution de ces recommandations; 2) l’impact d’un traitement ARV transitoire en PIV sur la réponse immuno-virologique lors de la reprise du traitement et 3) l’identification de nouveaux biomarqueurs comme facteurs pronostiques de progression de l’infection VIH. La majorité des travaux présentés dans cette thèse repose sur les données de la cohorte ANRS PRIMO qui comporte environ 1 500 patients infectés par le VIH inclus en PIV entre juin 1996 et décembre 2013, dans 94 hôpitaux français. Tous les patients étaient naïfs de traitement antirétroviral à l'inclusion.La première partie de la thèse analyse la mise en œuvre des recommandations d’initiation du traitement ARV entre 1996 et 2010 par les médecins en France, dans deux situations distinctes : au stade chronique et lors de la primo-infection par le VIH-1. Nous avons montré que les recommandations d’initiation du traitement ARV étaient largement suivies. Néanmoins, il existe un effet d’inertie dans leurs applications lors des changements de recommandation. Il reste à améliorer le délai de mise sous traitement lorsque le taux de CD4 atteint le seuil recommandé. Au stade chronique, le traitement était plus fréquemment initié chez les patients présentant un critère d’initiation dès le diagnostic d’infection par le VIH (96%), que chez les patients qui atteignaient un critère d’initiation au cours du suivi (78%, p5), un plus faible niveau d’éducation et des conditions de vie précaires.L’impact de l’interruption d’un traitement antirétroviral initié en PIV sur la restauration des CD4 après reprise du traitement a été exploré en modélisant l’évolution des CD4 avec des modèles linéaires à effets mixtes avec intercept et pente aléatoires. Les patients qui avaient initié un traitement ARV pendant la phase chronique avaient une meilleure réponse immunologique que les patients reprenant un 2ème traitement après un traitement transitoire en PIV : à 36 mois, les gains en √CD4 cellules/mm3 et en pourcentage de CD4 étaient significativement plus élevés. Cependant, il s’agissait de différences modestes en termes cliniques, qui ne conduisent pas à recommander d’arrêter la recherche clinique sur les arrêts de traitement cherchant à induire des contrôleurs post traitement. Après un état des lieux des mécanismes complexes d’activation/inflammation du système immunitaire pendant la primo-infection nous avons cherché à identifier de nouveaux biomarqueurs prédictifs de l’évolution de l’infection. Le taux de sCD14 (marqueur d’activation monocyte/macrophage et marqueur indirect de translocation microbienne) au moment de la PIV a été identifié comme marqueur potentiel de prédiction du déclin des CD4 et du risque de mortalité d’origine cardio-vasculaire. En conclusion, bien que des progrès considérables aient été réalisés dans la prise en charge du VIH, d'autres études sont nécessaires pour optimiser et adapter le traitement au profil du patient dès les premiers stades de l’infection VIH.In France, since 2013, HIV treatment has been recommended for all HIV-infected patients independently of their CD4 count. However, when to start anti-retroviral (ARV) treatment is still an issue. This thesis aims to explore the therapeutic management of HIV at the stage of PHI in different aspects: 1) we explored how physicians in France have applied the evolving guidelines for ART initiation since 1996 2) the impact of a transient ARV treatment at PHI on immuno-virological response during 2nd treatment and 3) identification of new biomarkers prognostic of HIV progression.Most of the work presented in this thesis is based on data from the ongoing ANRS PRIMO cohort that enrolled more than 1 500 HIV infected patients enrolled at PHI since June 1996 in 94 French hospitals. All patients were antiretroviral therapy naive at baseline.The first part of the thesis analyzes the implementation of the recommendations of ARV treatment initiation between 1996 and 2010 by physicians in France, in two distinct situations: in the chronic HIV-1 infection and during primary HIV-1 infection. We have shown that the recommendations of ARV treatment initiation were widely followed. Nevertheless, there was inertia in guidelines application when changes in the recommendations took place. The time to treatment when CD4 cell counts reach the threshold to treat can be improved. 96% of the patients initiated ART when they had a CD4 cell count below the threshold to treat at entry, while treatment was less timely initiated when the CD4 threshold was reached during active follow-up (78%, p 5), a lower education level and poor living conditions.The impact of ARV interruption after a first treatment initiated at PHI on the CD4 count restoration after resumption was explored by modeling the evolution of CD4 cells with linear mixed effects models with random intercept and slope. Patients who initiated ARV treatment during the chronic phase had a better immune response than patients who initiated a second course treatment after a transient ART at PHI: at 36 months, the gains in √CD4 cells / mm3 and CD4 percentage were significantly higher. However, this difference was clinically modest and further research on treatment interruptions seeking to induce post-treatment controllers is still an issue but only in research settings and under close medical surveillance. After an overview of the complex mechanisms of activation / inflammation of the immune system during primary infection we sought to identify new predictive biomarkers of disease progression. The level of sCD14 (marker of monocyte/macrophage activation and an indirect marker of microbial translocation) at the time of PHI was identified as predictive marker of CD4 decline and of risk of cardio-vascular mortality. In conclusion, although considerable progress has been made in the management of HIV, further studies are needed to optimize and adapt the treatment to the patient profile in the early stages of HIV infection

Causalité dans les études observationnelles (bibliographie et application dans une étude de patients co-infectés par le VIH et le VHC)

PARIS7-Xavier Bichat (751182101) / SudocSudocFranceF

Role of Epidural Analgesia within an ERAS Program after Laparoscopic Colorectal Surgery: A Review and Meta-Analysis of Randomised Controlled Studies

Introduction. Epidural analgesia has been a cornerstone of any ERAS program for open colorectal surgery. With the improvements in anesthetic and analgesic techniques as well as the introduction of the laparoscopy for colorectal resection, the role of epidural analgesia has been questioned. The aim of the review was to assess through a meta-analysis the impact of epidural analgesia compared to other analgesic techniques for colorectal laparoscopic surgery within an ERAS program. Methods. Literature research was performed on PubMed, Embase, and the Cochrane Library. All randomised clinical trials that reported data on hospital stay, postoperative complications, and readmissions rates within an ERAS program with and without an epidural analgesia after a colorectal laparoscopic resection were included. Results. Five randomised clinical trials were selected and a total of 168 patients submitted to epidural analgesia were compared to 163 patients treated by an alternative analgesic technique. Pooled data show a longer hospital stay in the epidural group with a mean difference of 1.07 (95% CI 0.06–2.08) without any significant differences in postoperative complications and readmissions rates. Conclusion. Epidural analgesia does not seem to offer any additional clinical benefits to patients undergoing laparoscopic colorectal surgery within an ERAS program

Effect of emergency physician burnout on patient waiting times

International audienceBurnout is common in emergency physicians. This syndrome may negatively affect patient care and alter work productivity. We seek to assess whether burnout of emergency physicians impacts waiting times in the emergency department. Prospective study in an academic ED. All patients who visited the main ED for a 4-month period in 2016 were included. Target waiting times are assigned by triage nurse to patients on arrival depending on their severity. The primary endpoint was an exceeded target waiting time for ED patients. All emergency physicians were surveyed by a psychologist to assess their level of burnout using the Maslach Burnout Inventory. We defined the level of burnout of the day in the ED as the mean burnout level of the physicians working that day (8:30 to the 8:30 the next day). A logistic regression model was performed to assess whether burnout level of the day was independently associated with prolonged waiting times, along with previously reported predictors. Target waiting time was exceeded in 7524 patients (59%). Twenty-six emergency physicians were surveyed. Median burnout score was 35 [Interquartile (24–49)]. A burnout level of the day higher than 35 was independently associated with an exceeded target waiting time (adjusted odds ratio 1.54, 95% confidence interval 1.39–1.70), together with previously reported predictors (i.e., day of the week, time of the day, trauma, age and daily census). Burnout of emergency physicians was independently associated with a prolonged waiting time for patients visiting the ED

Does transient cART started during primary HIV infection undermine the long-term immunologic and virologic response on cART resumption?

International audienceWe explored the impact of transient cART started during the primary HIV-infection (PHI) on the long-term immunologic and virologic response on cART resumption, by comparison with treatment initiation during the chronic phase of HIV infection (CHI). We analyzed data on 1450 patients enrolled during PHI in the ANRS PRIMO cohort between 1996 and 2013. "Treatment resumption" was defined as at least 3 months of resumed treatment following interruption of at least 1 month of treatment initiated during PHI. "Treatment initiation during CHI" was defined as cART initiated ≥6 months after PHI. The virologic response to resumed treatment and to treatment initiated during CHI was analyzed with survival models. The CD4 cell count dynamics was modeled with piecewise linear mixed models. 136 patients who resumed cART for a median (IQR) of 32 (18-51) months were compared with 377 patients who started cART during CHI for a median of 45 (22-57) months. Most patients (97%) achieved HIV-RNA <50 cp/mL after similar times in the two groups. The CD4 cell count rose similarly in the two groups during the first 12 months. However, after 12 months, patients who started cART during CHI had a better immunological response than those who resumed cART (p = 0.01); therefore, at 36 months, the gains in √CD4 cells/mm(3) and CD4% were significantly greater in patients who started treatment during CHI. These results suggest that interruption of cART started during PHI has a significant, albeit modest negative impact on CD4 cell recovery on cART resumption