Gut Microbiota, PGx and INSTIs Response

NCT ID: NCT04805944

Last Updated: 2024-05-10

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 180 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2021-03-10
• Study Completion Date: 2023-12-31

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.

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.

Conditions

HIV Infections

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

DTG treated (A)

80 HIV-infected adults treated with dolutegravir (as a component of their usual provider-prescribed antiretroviral regimen)

Dolutegravir

Intervention Type: DRUG

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)

Bictegravir

Intervention Type: DRUG

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)

Dolutegravir

Intervention Type: DRUG

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

Dolutegravir

Intervention Type: DRUG

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

Bictegravir

Intervention Type: DRUG

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

Interventions

Dolutegravir

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

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: 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

Intervention Type: 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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Leïla Belkhir, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Cliniques universitaires Saint-Luc; UCLouvain/IREC/LTAP

Locations

Cliniques universitaires Saint-Luc

Brussels, , Belgium

Countries

Belgium

References

De Greef J, Nguyen KN, Van Hul M, Puel A, Yombi JC, Vandercam B, Vincent A, Elens L, Belkhir L, Haufroid V, Cani PD. Associations between weight gain, integrase inhibitors antiretroviral agents, and gut microbiome in people living with HIV: a cross-sectional study. Sci Rep. 2025 Jul 2;15(1):22603. doi: 10.1038/s41598-025-06500-0.

Reference Type: DERIVED

PMID: 40592975 (View on PubMed)

Other Identifiers

INSTI

Identifier Type: -

Identifier Source: org_study_id