Effet des antirétroviraux sur la pathogénèse du VIH : une étude par modélisation mathématique intégrant la cinétique du virus, de l’immunité, du médicament, et le comportement d’adhésion avec leurs variabilités interindividuelles

Les traitements antirétroviraux actuels permettent à beaucoup de patients du VIH de maintenir leurs charges virales à de très faibles niveaux sur plusieurs décennies. Or, malgré ce succès scientifique, de nombreux problèmes persistent, et à ce jour, aucun traitement ne permet de venir à bout du virus. Une prise à vie d’antirétroviraux est donc nécessaire, impliquant ainsi des contraintes posologiques pour le patient, une potentielle atteinte à sa qualité de vie et un fardeau financier pour la société. À ces inconvénients s’ajoute le risque de développer de la résistance aux médicaments. Même si les traitements demeurent efficaces, la persistance du virus peut également causer des dommages aux différents tissus et organes de l’hôte. En se basant sur des connaissances de pointe dans le domaine du VIH, cette thèse aborde ces problématiques par une approche de pharmacologie quantitative des systèmes, appuyée par des données cliniques. L’objectif principal fut d’informer les mécanismes sous-jacents au développement de la résistance et à la persistance du virus in vivo. Nous avons tiré profit d’un maximum d’information sur l’ensemble des composantes impliquées dans la réponse virologique aux médicaments. Les modèles que nous avons développés joignent différentes échelles d’information, allant de l’échelle moléculaire, à virale, puis cellulaire, jusqu’au niveau clinique. Nous avons ensuite évalué la cohérence d’hypothèses de causalité aux phénomènes étudiés en testant la capacité de ces modèles à expliquer et reproduire des données empiriques. En premier lieu, nous avons développé un modèle visant à mieux comprendre l’ampleur du développement de la résistance chez les patients sous plusieurs traitements. Le modèle combine plusieurs composantes, dont la cinétique virale, l’immunité, la pharmacocinétique et pharmacodynamique, l’adhésion au médicament ainsi que leurs variabilités interindividuelles. Les prédictions du modèle in silico concordent avec les observations cliniques d’échec virologique pour les trois traitements considérés et qui font intervenir l’efavirenz, l’emtricitabine, le ténofovir, le darunavir et le ritonavir. Par cette approche intégrative, nous avons remédié à la lacune des modèles précédents qui sous-estimaient grandement le risque de résistance. Nos résultats soulignent le rôle important que joue la faible pénétration des médicaments au niveau des ganglions lymphatiques dans le développement de la résistance. Ce modèle se veut prometteur de son utilité dans la prédiction de réponse virologique en clinique. Nous nous sommes ensuite intéressés au phénomène du déclin en différentes phases, de plus en plus lentes, des charges virales des patients sous traitement antirétroviral. Les causes sous-jacentes à ce phénomène restent encore obscures. Une divergence d’opinions sur le rôle de la faible pénétration tissulaire des médicaments quant à l’existence de ces phases, divise actuellement les efforts de recherche. Afin de mettre la lumière sur cette implication, nous avons ajouté à notre modèle intégratif des taux différents de pénétration tissulaire. Nos résultats indiquent que l’implication seule de la pénétration des médicaments dans l’explication des phases de déclin serait synonyme d’un grand risque de développement de résistance. Ces prédictions contredisent quantitativement la réalité observée (peu de résistance), nous faisant conclure que cette hypothèse ne peut vraisemblablement pas expliquer le phénomène en question. La dernière partie de la thèse se penche sur la capacité de certains patients à maintenir de faibles charges virales après l’interruption d’un traitement prolongé. Nous avons revisité une corrélation rapportée entre la charge virale résiduelle et la durée de maintien post-interruption de charges faibles. L’interprétation de cette corrélation s’avère difficile, puisque la durée en question n’inclut pas seulement le temps de contrôle de la virémie, mais également le temps nécessaire à la charge virale d’atteindre un seuil de tolérance à partir de la charge virale résiduelle. En utilisant un modèle mécanistique et des techniques statistiques avancées, nous avons réussi à estimer la durée attendue de contrôle réel de la charge virale ainsi que la variabilité interindividuelle associée. Contrairement à l’interprétation directe de la corrélation rapportée dans la littérature, notre analyse révèle que la variabilité interindividuelle du temps de contrôle de la virémie n’est pas associée à la charge virale résiduelle. L’approche in silico adoptée dans cette thèse s’inscrit dans l’effort global de ces dernières années visant à minimiser le fardeau humain et le coût financier dans le développement du médicament. L’ensemble de nos résultats de modélisation suggèrent qu’une meilleure pénétration dans les ganglions lymphatiques diminuerait le nombre de cas de résistance chez les patients non-adhérents. Cependant, ils indiquent qu’une telle amélioration aurait peu d’influence sur la vitesse de déclin des charges virales. Aussi, quelle que soit l’influence de la pénétration lymphatique sur la virémie résiduelle, son amélioration n’aurait pas d’impact sur la capacité des patients à contrôler leurs charges virales après avoir cessé les antirétroviraux.Tremendous progress was made in treating people living with HIV. Nowadays, antiretroviral therapy usually allows patients to suppress viral loads for several years, if not decades. Despite this scientific achievement, chronic drug intake is usually necessary as no treatment can completely eradicate the virus. Patients under these conditions may experience constant side effects. Further, patients’ tissues and organs may become damaged over time, as chronic immune activation is observed in most patients despite adequate drug intake and undetectable viremia. The number of treatment options can also become seriously limited over time if patients’ viruses develop and accumulate drug resistance. These issues motivate current scientific efforts. Hopefully, results from these efforts may lead to improvements in patient’s quality of life and lower the financial burden HIV imposes on society. Using the most up-to-date knowledge in the field of HIV, this thesis addresses some of the above-mentioned issues through a quantitative systems pharmacology approach supported by clinical data. Our main objective was to inform the mechanisms underlying the development of resistance and the persistence of the virus in vivo. We used available information on the components involved in the virologic response to drugs. This allowed developing models that bridge multiple scales, going from molecular, to viral, then cellular and finally to the clinical level. By assessing the ensuing models’ ability to explain and reproduce empirical data, we studied the consistency of hypotheses regarding the causality of studied phenomena. First, we developed a model allowing to better understand the extent of drug resistance development in patients undergoing antiretrovial therapy. The model combines several components, including viral kinetics, immunity, pharmacokinetics and pharmacodynamics, drug adherence as well as their interindividual variability. Predictions originating from our in silico model are consistent with clinical observations of virologic failure for the three treatments that were considered consisting of efavirenz, emtricitabine, tenofovir, darunavir and ritonavir. Through this integrative approach, we have remedied previous models that largely underestimated the risk of resistance. Our results highlight the important role played by low lymph node drug penetration in the development of resistance. The model we developed is an added forward step toward the use of in silico methods in the prediction of virologic responses in HIV patients. We then investigated the causes underlying the increasingly slow phases of viral decline observed in patients initiating antiretroviral therapy. Opinions differ as to the role played by low drug penetration in tissues in the existence of these phases, leading to a fragmentation in research efforts. To shed light on this issue, we additionally considered, in our integrative model, different rates of tissue penetration. Our results indicate that, if low drug penetration were the only cause of the decline in phases of the viral load, then the ensuing low drug exposure would put patients at a very high risk of developing drug resistance. Prediction of high risk quantitatively contradicts the observed reality (little to no resistance), leading us to conclude that low penetration is unlikely a fair explanation to the phases of viral decline. The last part of the thesis examines the ability of some patients to maintain low viral loads after interrupting prolonged antiretroviral therapy. We revisited a reported correlation between viral load values at interruption (also called residual viremia) and the duration of time patients maintained low viral loads afterwards. The interpretation of this correlation proved to be challenging since this duration includes both a time of complete control of viremia and a time during which viremia grows to a low-level threshold once control is lost. Using a mechanistic model and advanced statistical techniques, we were able to estimate the expected duration of complete viremia control along with its interindividual variability. Contrary to a direct interpretation of the correlation reported in the literature, our analysis reveals that the time of viremia control is unlikely associated with patients’ residual viremia. In summary, the in silico approach adopted in this thesis is part of an overall effort aiming to minimize patient recruitment and the financial costs involved in drug development. Our models suggest that better drug penetration in lymph nodes would likely lead to a decreased risk of drug resistance in non-adherent patients. However, our results also suggest that such an improvement would have little influence on the rate of decline of viral loads. Further, and regardless of the influence lymphatic tissue drug penetration may have on residual viremia, this improvement would not favour viremia control after antiretroviral discontinuation

Dynamique de colonisation par bactéries résistantes de porcs d'élevage

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal

Utilisation de triades cas-parents dans la régression logique : exploration d'interaction génétique

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Nanoparticle heterogeneity : an emerging structural parameter 2 influencing particle fate in biological media?

Drug nanocarriers’ surface chemistry is often presumed to be uniform. For instance, the polymer surface coverage and distribution of ligands on nanoparticles are described with averaged values obtained from quantification techniques based on particle populations. However, these averaged values may conceal heterogeneities at different levels, either because of the presence of particle sub-populations or because of surface inhomogeneities, such as patchy surfaces on individual particles. The characterization and quantification of chemical surface heterogeneities are tedious tasks, which are rather limited by the currently available instruments and research protocols. However, heterogeneities may contribute to some non-linear effects observed during the nanoformulation optimization process, cause problems related to nanocarrier production scale-up and correlate with unexpected biological outcomes. On the other hand, heterogeneities, while usually unintended and detrimental to nanocarrier performance, may, in some cases, be sought as adjustable properties that provide NPs with unique functionality. In this review, results and processes related to this issue are compiled, and perspectives and possible analytical developments are discussed

Personal Characteristics and Experience of Primary Care Predicting Frequent Use of Emergency Department: A Prospective Cohort Study.

OBJECTIVE:A small number of patients frequently using the emergency department (ED) account for a disproportionate amount of the total ED workload and are considered using this service inappropriately. The aim of this study was to identify prospectively personal characteristics and experience of organizational and relational dimensions of primary care that predict frequent use of ED. METHODS:This study was conducted among parallel cohorts of the general population and primary care patients (N = 1,769). The measures were at baseline (T1), 12 (T2) and 24 months (T3): self-administered questionnaire on current health, health behaviours and primary care experience in the previous year. Use of medical services was confirmed using administrative databases. Mixed effect logistic regression modeling identified characteristics predicting frequent ED utilization. RESULTS:A higher likelihood of frequent ED utilization was predicted by lower socioeconomic status, higher disease burden, lower perceived organizational accessibility, higher number of reported healthcare coordination problems and not having a complete annual check-up, above and beyond adjustment for all independent variables. CONCLUSIONS:Personal characteristics such as low socioeconomic status and high disease burden as well as experience of organizational dimensions of primary care such as low accessibility, high healthcare coordination problems and low comprehensiveness of care are prospectively associated with frequent ED utilization. Interventions developed to prevent inappropriate ED visits, such as case management for example, should tailor low socioeconomic status and patients with high disease burden and should aim to improve experience of primary care regarding accessibility, coordination and comprehensiveness

No Relation between Therapeutic Response to Methylphenidate and its Cardiovascular Side Effects in Children with Attention-Deficit/Hyperactivity Disorder

Objective The aim of this study was to examine the relation between therapeutic response to methylphenidate (MPH) and its associated short term cardiovascular side effects (Systolic Blood Pressure-SBP, Diastolic Blood Pressure-DBP and Heart Rate-HR changes) in children with ADHD, based on the hypothesis that these parameters share common underlying mechanisms. Method A double-blind placebo-controlled crossover clinical trial of children 6 to 12 years old diagnosed with ADHD was done. The children were given one week of 0.5 mg/kg MPH and one week of placebo (divided into two equal doses, given twice every day). On the morning of the third day of each week, Blood Pressure (BP) and HR were recorded immediately before (at time 0) and after (at time 10 and 45 minutes) administration of MPH. Children were grouped into 4 categories according to their therapeutic response (large, moderate, mild or no response) to MPH. A mixed model analysis of variance was performed to determine whether response groups were different with regard to cardiovascular side effects. Results All variables were comparable among the four groups 10 min after treatment with MPH and with placebo. Small but significant (p < 0.001) increases were seen in SBP (3.65 mm of Hg) and DBP (3.99 mm of Hg) 45 minutes after administration of MPH. A small but significant decrease in HR (3.3 beats per minute) was observed 45 min after administration of placebo. No significant differences in SBP, DBP and HR were found between response groups. Conclusions MPH causes a small but significant change in BP at 45 minutes after administration. No changes in HR were observed with MPH at 45 minutes. Responders to MPH treatment do not differ from non-responders in occurrence of BP and HR changes, at least within 45 minutes after administration and with the MPH dosage used in the study

Trauma reactivation under the influence of propranolol: an examination of clinical predictors

In two recent studies conducted by our group, a treatment combining propranolol with a brief reactivation session subsequently reduced posttraumatic stress disorder (PTSD) symptom severity and diagnosis, as well as reducing psychophysiological responses during trauma-related script-driven imagery. One likely explanation for those results is that memory reconsolidation was blocked by propranolol.We explored the influence of various predictors on treatment outcome (i.e., PTSD severity), and whether the treated individuals improved in other important domains of functioning associated with PTSD.Thirty-three patients with longstanding PTSD participated in a 6-week open-label trial consisting of actively recalling one&#x0027;s trauma under the influence of propranolol, once a week.Treated patients reported a better quality of life, less comorbid depressive symptoms, less negative emotions in their daily life and during trauma recollections. Women were also found to improve more than men. Type of trauma (childhood vs. adulthood), time elapsed since trauma, borderline personality traits, depressive symptoms severity, Axis I comorbidity, and age did not influence treatment outcome.These results must await publication of a randomized-controlled trial to further delineate effectiveness with this novel treatment approach.For the abstract or full text in other languages, please see Supplementary files under Reading Toolsonlin

Decay_P2_Phi10_fu40

see SSanche - PLOS One - File descriptions.doc

Decay_P6_Phi13_fu20

see SSanche - PLOS One - File descriptions.doc