Gut Microbiota, PGx and INSTIs Response

Gut Microbiota, Pharmacogenetics and Integrase Strand Transfer Inhibitors Response

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.

Study Overview

• Status: Recruiting
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Dolutegravir; Drug: Dolutegravir; Drug: Dolutegravir; Drug: Bictegravir; 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 Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

• Study Contact: Name: Leïla Belkhir, MD, PhD; Phone Number: 003227642198; Email: leila.belkhir@uclouvain.be

Study Locations

• Belgium
  • Brussels, Belgium
    • Recruiting
    • Cliniques Universitaires Saint-Luc
    • Contact: Julien De Greef, MD; Phone Number: 003227642198; Email: julien.degreef@uclouvain.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Subjects will be recruited among regularly HIV-infected patients regularly followed at the Centre de Prise en charge VIH of Cliniques universitaires Saint-Luc - UCLouvain

Description

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)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort	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.; 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.; 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
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.; 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
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; Dolutegravir treated patients will be included and samples (blood for pharmacokinetic, pharmacogenetic et metabolite profiling, stools for microbiota profiling) drawn at follow-up.; 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.; 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 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; Dolutegravir treated patients will be included and samples (blood for pharmacokinetic, pharmacogenetic et metabolite profiling, stools for microbiota profiling) drawn at follow-up.; 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.; 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; Bictegravir treated patients will be included and samples (blood for pharmacokinetic, pharmacogenetic and metabolite profiling, stools for microbiota profiling) drawn at follow-up.; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dolutegravir and bictegravir through concentration	Measurement of drug through concentration for groups A, B, D and E	24 hours post last dose
Dolutegravir and bictegravir intracellular concentration	Measurement of drug intracellular concentration for groups A, B, D and E	24 hours post last dose
Viral replication	Viral replication measured for groups A, B, D and E	At second clinical visit occuring at least 6 months after the initiation of DTG/BIC, no longer than 12 months after inclusion
Microbiota profile under treatment	Determination microbiota profile for groups A, B, C, D and E	At second clinical visit occuring at least 6 months after the initiation of DTG/BIC, no longer than 12 months after inclusion
Change of microbiota profile	Change from baseline microbiota profile at 6 month after treatment initiation, for groups D and E	Baseline and at 6 months
Change in weight	Overall weight change between treatment initiation through study completion	Through study completion, an average of 1 year
Psychometric evaluation (Symptom-checklist-90-R)	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.	At second clinical visit occuring at least 6 months after the initiation of DTG/BIC, no longer than 12 months after inclusion
Change of psychometric evaluation (Symptom-checklist-90-R)	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.	Baseline and at 6 months
Psychometric evaluation (Pittsburgh Sleep Quality Index)	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.	At second clinical visit occuring at least 6 months after the initiation of DTG/BIC, no longer than 12 months after inclusion
Change of psychometric evaluation (Pittsburgh Sleep Quality Index)	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.	Baseline and at 6 months
Psychometric evaluation (Pichot's fatigue scale)	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.	At second clinical visit occuring at least 6 months after the initiation of DTG/BIC, no longer than 12 months after inclusion
Change of psychometric evaluation (Pichot's fatigue scale)	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.	Baseline and at 6 months
Psychometric evaluation (Hospital Anxiety and Depression Scale)	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.	At second clinical visit occuring at least 6 months after the initiation of DTG/BIC, no longer than 12 months after inclusion
Change of psychometric evaluation (Hospital Anxiety and Depression Scale)	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.	Baseline and at 6 months

Collaborators and Investigators

• Sponsor: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
• Investigators: Principal Investigator: Leïla Belkhir, MD, PhD, Cliniques universitaires Saint-Luc; UCLouvain/IREC/LTAP

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2021
• Primary Completion (Anticipated): June 30, 2023
• Study Completion (Anticipated): June 30, 2023

Study Registration Dates

• First Submitted: March 8, 2021
• First Submitted That Met QC Criteria: March 16, 2021
• First Posted (Actual): March 18, 2021

Study Record Updates

• Last Update Posted (Actual): January 18, 2023
• Last Update Submitted That Met QC Criteria: January 16, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: hiv; dolutegravir; integrase strand transfer inhibitors; bictegravir
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Dolutegravir
• Other Study ID Numbers: INSTI

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No