Gut Microbiota, PGx and INSTIs Response

Sponsor

Cliniques universitaires Saint-Luc- Université Catholique de Louvain (Other)

Overall Status

Recruiting

CT.gov ID

NCT04805944

Collaborator

(none)

200

Enrollment

Location

27.8

Anticipated Duration (Months)

7.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an interventional phase IV trial enrolling HIV-infected patients treated by dolutegravir or bictegravir-based combined antiretroviral therapy, and patients with a planned shift to a dolutegravir or bictegravir-based combined antiretroviral therapy, that aims at understanding the individual response to dolutegravir and bictegravir, in terms of efficacy and toxicity.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: Dolutegravir Drug: Bictegravir Drug: Dolutegravir Drug: Dolutegravir Drug: Bictegravir

Detailed Description

The main objective of our research project is to better define the inter-individual variability in terms of clinical and biological response towards Integrase Strand Transfer Inhibitors, an important ARV drug class used in the treatment of HIV infection. We aim at identifying predictors of drug efficacy and toxicity, which are eagerly awaited by clinicians as INSTIs are now prescribed worldwide and concerns about previously unidentified side effects are emerging.

The specific objectives of the project are:

To study the impact of genetic polymorphisms in selected pharmacogenes (including genes coding for biotransformation enzymes and transport proteins) on INSTIs PK parameters and biomarkers relevant for TDM, such as trough (C0) and intracellular (IC) concentrations.
To determine whether genetic polymorphisms in selected pharmacogenes might affect INSTIs efficacy, as assessed by the measurement of the viral load.
To address the important question of the pathophysiological mechanisms lying behind the two main side effects of INSTIs, namely neuropsychiatric adverse events and abnormal weight gain.
To describe how INSTIs affect the gut microbiome of treated patients, and to determine in turn how and by which pathways the gut microbiome might influence the clinical response (i.e. efficacy and toxicity) to INSTIs.

Study Design

Study Type:

Observational

Anticipated Enrollment :

200 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Gut Microbiota, Pharmacogenetics and Integrase Strand Transfer Inhibitors Response

Actual Study Start Date :

Mar 5, 2021

Anticipated Primary Completion Date :

Jun 30, 2023

Anticipated Study Completion Date :

Jun 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
DTG treated (A) 80 HIV-infected adults treated with dolutegravir (as a component of their usual provider-prescribed antiretroviral regimen)	Drug: Dolutegravir Dolutegravir treated patients will be included and samples (blood for pharmacokinetic, pharmacogenetic et metabolite profiling, stools for microbiota profiling) drawn at follow-up.
BIC treated (B) 30 HIV-infected adults treated with bictegravir (as a component of their usual provider-prescribed antiretroviral regimen)	Drug: Bictegravir Bictegravir treated patients will be included and samples (blood for pharmacokinetic, pharmacogenetic and metabolite profiling, stools for microbiota profiling) drawn at follow-up.
DTG discontinued due to neuropsychiatric adverse event (C) 50 HIV-infected adults having stopped dolutegravir due to neuropsychiatric adverse effects (insomnia, depression, anxiety)	Drug: Dolutegravir Patient having discontinued dolutegravir will be included and samples (blood for pharmacogenetic and metabolite profiling, stools for microbiota profiling) drawn at follow-up.
Shifting to DTG (D) 20 virally controlled and immunologically functional HIV-infected adults shifting (as per standard care) from another ARV class to an antiretroviral regimen containing dolutegravir	Drug: Dolutegravir Patients starting dolutegravir will be included and sampled both before (blood for pharmacogenetic and metabolite profiling, stools for microbiota profiling) and after (blood for pharmacokinetic and metabolite profiling, stools for microbiota profiling) the start of dolutegravir
Shifting to BIC (E) 20 virally controlled and immunologically functional HIV-infected adults shifting (as per standard care) from another ARV class to an antiretroviral regimen containing bictegravir	Drug: Bictegravir Patients starting bictegravir will be included and sampled both before (blood for pharmacogenetic and metabolite profiling, stools for microbiota profiling) and after (blood for pharmacokinetic and metabolite profiling, stools for microbiota profiling) the start of bictegravir

Outcome Measures

Primary Outcome Measures

Dolutegravir and bictegravir through concentration [24 hours post last dose]
Measurement of drug through concentration for groups A, B, D and E
Dolutegravir and bictegravir intracellular concentration [24 hours post last dose]
Measurement of drug intracellular concentration for groups A, B, D and E
Viral replication [At second clinical visit occuring at least 6 months after the initiation of DTG/BIC, no longer than 12 months after inclusion]
Viral replication measured for groups A, B, D and E
Microbiota profile under treatment [At second clinical visit occuring at least 6 months after the initiation of DTG/BIC, no longer than 12 months after inclusion]
Determination microbiota profile for groups A, B, C, D and E
Change of microbiota profile [Baseline and at 6 months]
Change from baseline microbiota profile at 6 month after treatment initiation, for groups D and E
Change in weight [Through study completion, an average of 1 year]
Overall weight change between treatment initiation through study completion
Psychometric evaluation (Symptom-checklist-90-R) [At second clinical visit occuring at least 6 months after the initiation of DTG/BIC, no longer than 12 months after inclusion]
Psychometric evaluation through Symptom-checklist-90-R questionnaire, for groups A and B. The mean scores of each of the 10 subscales of Symptom-checklist-90-R will be calculated. A global severity index is computed as the average score of all 90 items. A higher score indicates a worse outcome.
Change of psychometric evaluation (Symptom-checklist-90-R) [Baseline and at 6 months]
Change from baseline Symptom-checklist-90-R at 6 month after treatment initiation, for groups D and E. The mean scores of each of the 10 subscales of Symptom-checklist-90-R will be calculated. A global severity index is computed as the average score of all 90 items. A higher score indicates a worse outcome.
Psychometric evaluation (Pittsburgh Sleep Quality Index) [At second clinical visit occuring at least 6 months after the initiation of DTG/BIC, no longer than 12 months after inclusion]
Psychometric evaluation through Pittsburgh Sleep Quality Index questionnaire, for groups A and B. Pittsburgh Sleep Quality Index scores answers from 0 to 21. A higher score means a worse outcome.
Change of psychometric evaluation (Pittsburgh Sleep Quality Index) [Baseline and at 6 months]
Change from baseline Pittsburgh Sleep Quality Index at 6 month after treatment initiation, for groups D and E. Pittsburgh Sleep Quality Index scores answers from 0 to 21. A higher score means a worse outcome.
Psychometric evaluation (Pichot's fatigue scale) [At second clinical visit occuring at least 6 months after the initiation of DTG/BIC, no longer than 12 months after inclusion]
Psychometric evaluation through Pichot's fatigue scale questionnaire, for groups A and B. Pichot's fatigue scale scores answers between 0 and 32. A higher score means a worse outcome.
Change of psychometric evaluation (Pichot's fatigue scale) [Baseline and at 6 months]
Change from baseline Pichot's fatigue scale at 6 month after treatment initiation, for groups D and E. Pichot's fatigue scale scores answers between 0 and 32. A higher score means a worse outcome.
Psychometric evaluation (Hospital Anxiety and Depression Scale) [At second clinical visit occuring at least 6 months after the initiation of DTG/BIC, no longer than 12 months after inclusion]
Psychometric evaluation through Hospital Anxiety and Depression Scale questionnaire, for groups A and B. Hospital Anxiety and Depression Scale scores answers between 0 and 21 for its two compoinents, anxiety and depression. A higher score means a worse outcome.
Change of psychometric evaluation (Hospital Anxiety and Depression Scale) [Baseline and at 6 months]
Change from baseline Hospital Anxiety and Depression Scale at 6 month after treatment initiation, for groups D and E. Hospital Anxiety and Depression Scale scores answers between 0 and 21 for its two compoinents, anxiety and depression. A higher score means a worse outcome.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion will be proposed to:

HIV infected adult patient regularly followed at Centre de reference HIV of CUSL and currently treated by 50mg OD of DTG (n=80) or 50mg OD of BIC (n=30).
Virally controlled immunologically functional HIV infected adult patient regularly followed at Centre de reference HIV of CUSL and shifting from another ARV class to a treatment containing 50mg OD of DTG (n=20) or 50mg OD of BIC (n=20).
HIV infected adult patient retrospectively identified as having stopped standard dosage of DTG (ie. 50mg OD) due to NPAE (insomnia, depression, anxiety) (n=50). Identification will be based on the interrogation of our prospective clinical database.

Exclusion Criteria:

Pregnancy at the time of inclusion or expected pregnancy within 12 months, for patients treated by DTG or BIC during the study
Liver failure (Child-Pugh A, B or C)