Gut Microbiota, PGx and INSTIs Response

Study Overview
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Brief Summary
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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
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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.

Official Title
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Gut Microbiota, Pharmacogenetics and Integrase Strand Transfer Inhibitors Response

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Dolutegravir
* Drug: Bictegravir
* Drug: Dolutegravir
* Drug: Dolutegravir
* Drug: Bictegravir


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| DTG treated (A)<br>80 HIV-infected adults treated with dolutegravir (as a component of their usual provider-prescribed antiretroviral regimen) | Drug: Dolutegravir<br>* Dolutegravir treated patients will be included and samples (blood for pharmacokinetic, pharmacogenetic et metabolite profiling, stools for microbiota profiling) drawn at follow-up.<br>|
| BIC treated (B)<br>30 HIV-infected adults treated with bictegravir (as a component of their usual provider-prescribed antiretroviral regimen) | Drug: Bictegravir<br>* Bictegravir treated patients will be included and samples (blood for pharmacokinetic, pharmacogenetic and metabolite profiling, stools for microbiota profiling) drawn at follow-up.<br>|
| DTG discontinued due to neuropsychiatric adverse event (C)<br>50 HIV-infected adults having stopped dolutegravir due to neuropsychiatric adverse effects (insomnia, depression, anxiety) | Drug: Dolutegravir<br>* Patient having discontinued dolutegravir will be included and samples (blood for pharmacogenetic and metabolite profiling, stools for microbiota profiling) drawn at follow-up.<br>|
| Shifting to DTG (D)<br>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<br>* 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<br>|
| Shifting to BIC (E)<br>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<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hiv, integrase strand transfer inhibitors, dolutegravir, bictegravir