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Novel Long Acting Injectable Antiretrovirals: Real-Life Monitoring in the Swiss HIV Cohort Study

English title Novel Long Acting Injectable Antiretrovirals: Real-Life Monitoring in the Swiss HIV Cohort Study
Applicant Decosterd Laurent Arthur
Number 192449
Funding scheme Project funding (special)
Research institution Département des laboratoires CHUV
Institution of higher education University of Lausanne - LA
Main discipline Clinical Pharmacology
Start/End 01.11.2020 - 31.10.2023
Approved amount 643'365.00
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Keywords (12)

Large nested project; SHCS; Therapeutic Drug Monitoring; Pharmacogenetics; Antiretroviral drugs; Population pharmacokinetics; Clinical pharmacokinetics; Long Acting Injectable anti-HIV drugs; Liquid chromatography-tandem mass spectrometry; Model-based simulation; Drug-drug interactions; Swiss HIV Cohort Study

Lay Summary (French)

Lead
Les formulations injectables à action prolongée (Long Acting Injectables, LAI) de médicaments antirétroviraux (ART) vont permettre de s’affranchir du problème de l’adhérence au traitement par voie orale de l’infection HIV. Jusqu'à présent, cette approche par LAI-ART a été testée chez des patients sélectionnés pour les études cliniques, qui reflètent mal la situation complexe des patients dans la vie réelle, susceptibles d’être traités pour des pathologies chroniques (hypertension, problèmes cardiovasculaires, diabète…) ou des morbidités coïncidentes (tuberculose, épilepsie, cancer...) avec un risque important d’interactions médicamenteuses.
Lay summary
Nous allons ainsi conduire une étude observationnelle de ces traitements LAI-ART dans le cadre de la Swiss HIV Cohort Study (SHCS). Ce projet implique la récolte d'échantillons sanguins des patients recevant des LAI-ART lors des visites de routine, ou lors de problèmes d’interactions médicamenteuses, ou d’affections intercurrentes. Les concentrations des médicaments LAI-ART seront mesurées par spectrométrie de masse. L’évolution des concentrations sanguines au cours du temps (pharmacocinétique, PK) chez les patients sera étudiée par des approches de PK de population, complétées par des travaux de modélisation et de simulation, qui étudieront notamment l’impact potentiel des co-médications. Enfin, nous allons comparer les prédictions PK déduites par le modèle et les concentrations réelles de LAI-ART mesurées chez les patients. Cette validation clinique indiquera si une intervention basée sur le TDM pourrait améliorer l'exposition plasmatique aux antiviraux chez les patients sous LAI-ART, et éventuellement de permettre à l'avenir de raccourcir ou d'étendre le temps entre deux injections chez les patients présentant des concentrations minimales plus faibles, respectivement plus élevées.
Ces efforts de recherche s’inscrivent dans le mouvement de la médecine de précision et devraient améliorer la prescription des LAI-ART en terme d’efficacité, de tolérance, de sécurité à long terme et des interactions potentielles.
 
Direct link to Lay Summary Last update: 27.07.2020

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
188504 Use of physiologically based pharmacokinetic modelling to simulate dosing requirements of long-acting intramuscular antiretroviral drugs in special populations and to manage drug-drug interactions 01.04.2020 Project funding (special)
165956 Modélisation, Simulation et Validation clinique des Interactions Médicamenteuses dans la Swiss HIV Cohort Study 01.09.2016 Project funding (special)
165956 Modélisation, Simulation et Validation clinique des Interactions Médicamenteuses dans la Swiss HIV Cohort Study 01.09.2016 Project funding (special)

Abstract

At present, current antiretrovirals (ART) regimens have for the most part, achieved optimal antiretroviral efficacy and tolerability, transforming HIV infection from a deadly disease into a manageable chronic condition. Yet, besides therapeutic effectiveness and drug tolerability, long-term adherence to therapy became a key issue, as for most treatments to be taken indefinitely. A promising approach to overcome the adherence challenge is the development of long-acting injectable (LAI) formulations, following an approach successfully applied for more than 30 years e.g. to antipsychotics and hormonal contraceptives. LAI-ART raises a considerable interest from the patients and the medical community. Ensuring month-long effective plasma concentrations, it might overcome obstacles in adherence and thus prevent drug resistance. It may also improve patients’ privacy and reduce social stigmas associated with the daily intake of anti-HIV treatments. The first two-drug LAI formulation of cabotegravir plus rilpivirine reaches the final phase of its clinical development, while potent newer agents with long half-lives (e.g. islatravir) are coming around the corner. Still, these novel LAI approaches have been so far tested within the stringent frame of clinical trials in carefully selected patients, who poorly reflect the complex situation of real-life patients. These trials already show an important pharmacokinetic variability of cabotegravir and rilpivirine injected intramuscularly as LAI. This variability may further increase in underweight or obese patients, in case of alteration of hepatic or renal functions, with drug-dug interactions (DDIs) involving treatments for chronic conditions (hypertension, cardiovascular problems, diabetes…) or coincident morbidities (tuberculosis, HCV infection, epilepsy, cancer...) and finally, should it occur, during pregnancy. In such instances, we have at present very few, if any, information of the pharmacokinetic profile of those novel LAI-ART and resulting impact on HIV infection management. The Swiss HIV Cohort Study (SHCS) framework is ideally suited for addressing prospectively such issues during the nation-wide implementation of LAI-ART. Building up on our mass spectrometry facilities, population pharmacokinetic-pharmacodynamic modeling expertise and established network, we intend to launch a prospective observational study of the implementation of LAI-ART in SHCS. Specifically, we propose in the present request for grant renewal:1.A large-scale, longitudinal observational study of SHCS patients initiating LAI-ART, implying the systematic capture of TDM (Therapeutic Drug Monitoring) samples along with relevant clinical information (date/time of last administration and blood sampling) and co-medication record: i) at LAI-ART initiation, ii) at SHCS cohort visits while on stable LAI-ART therapy, and iii) for any concern in case of drug interactions or intercurrent conditions; 2.Multiplex mass spectrometry analyses of LAI antiviral drugs, and also newer oral ART drugs and relevant comedication in TDM samples; 3.Population pharmacokinetic modeling and simulation of the exposure of LAI-ART agents and relevant comedication in pharmacogenotyped SHCS patients;4.Finally, translation of this knowledge into a prospective observational study comparing the inferred PK-models predictions, and actual LAI-ART trough concentrations (Cmin) in SHCS patients. This clinical validation will indicate whether a TDM-based intervention might improve antivirals plasma exposure in patients on LAI-ART, and possibly in the future may allow to shorten or extend dosing intervals in patients exhibiting lower, respectively higher trough concentrations. It will bring together the elements required to elaborate a rational TDM strategy, predict its potential clinical benefit and design a formal trial to confirm it. In the growing movement of precision medicine, such research efforts are expected to improve the prescription of ARTs not only with regard to antiretroviral efficacy but also according to tolerability, long-term safety and potential DDIs, possibly modulated by patients’ pharmacogenetics traits. The major strength of this proposal is to address an integrated monitoring strategy for LAI-ART, readily applicable to the management of persons living with HIV.
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