Adipose Tissue After Switch to Doravirine

NCT05477407 | Completed DMC

• 1 other identifier: CREPATS 14
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

Integrase-strand-transfer-inhibitors (INSTIs) based regimens have been associated with body weight gain and increase in total body adipose tissue (AT). Whereas there is by now no clear understanding of the mechanisms that induce these changes, we have observed modifications of AT in vitro, in animals models or in vivo in obese patients with raltegravir (RAL) and dolutegravir (DTG) with the presence of increased peri-adipocyte fibrosis and high levels of collagen VI that have been associated with poor metabolic prognoses together with cellular insulin resistance and decreased adiponectin secretion. One major clinical question is whether such AT abnormalities are reversible. Doravirine (DOR), the most recent available Non-Nucleosidic Reverse Transcriptase Inhibitor (NNRTI) drug, has an excellent metabolic profile and as a NNRTI is expected to induce neither changes in fat tissue distribution nor changes in body weight. Tenofovir disoproxil fumarate (TDF) is associated with a protective lipid profile and, unlike tenofovir alafenamide (TAF) which seems to potentiate weight gain in combination with INSTI, has not been associated with weight gain. One major clinical question is whether such AT abnormalities are reversible. Doravirine, the most recent available NNRTI drug, has an excellent metabolic profile and as a NNRTI is expected to induce neither changes in fat tissue distribution nor changes in body weight. Tenofovir DF is associated with a protective lipid profile and, unlike TAF which seems to potentiate weight gain in combination with INSTI, has not been associated with weight gain. We hypothesized that modifications in morphology and function of the adipose tissue in patients with significant weight gain under an INSTI-based regimen could be improved after switching to the triple drug TDF/Emtricitabine/DOR and that fat increase and body weight will be stopped or reversed. This pathogenesis study aimed to evaluate potential changes in adipose tissue after switching from an INSTI-based regimen (Raltegravir or Dolutegravir or Bictegravir) to TDF/Emtricitabine/DOR. Each patient will be evaluated with an adipose tissue biopsy performed before (D0) and after a 48 week switch (W48) from an INSTI-based regimen to the non INSTI-based regimen combining TDF/3TC/Doravirine. With a number of 22 patients at D0, a total of 20 patients with paired adipose tissue biopsies are expected at W48. The antiretroviral therapy with TDF/emtricitabine/Doravirine will be used as routine practice recommends.

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (4)

• Measure the phenotype and alterations in adipose tissue to assess the impact of this weight gain

  Measure the size of adipocytes assessed by Immunohistochemistry experiments Measure the presence of beige adipocytes within the white adipose tissue (Uncoupling protein 1) assessed by Immunohistochemistry experiments Measure the fibrosis (Red Sirius, collagens, fibronectin, Transforming Growth Factor-β, alpha smooth muscle actin) assessed by Immunohistochemistry experiments

  48 weeks

• Measure of markers of white adipose tissue, brown/beige adipose tissue, to assess changes in gene expression

  Measure of markers leptin, adiponectin, transforming growth factor beta and fibroblast growth factor 21 assessed by ReverseTranscriptase-Polymerase Chain Reaction

  48 weeks

• Measure of markers of white adipocytes, brown adipocytes, differentiation lipogenesis, lipolysis enzymes and major players in insulin sensitivity to assess changes in gene expression

  Measure of markers peroxisome proliferator-activated receptor, enhancer binding protein alpha, Cell death activator CIDE-A, Protein domain containing 16, Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, Uncoupling Protein 1, sterol regulatory element binding protein 1C, hormone-sensitive lipase, ATGL and glucose transport protein 4 assessed by ReverseTranscriptase-Polymerase Chain Reaction

  48 weeks

• Measure of components of extra cellular matrix to assess changes in gene expression

  Measure of markers alpha smooth muscle actin, fibronectin, transforming growth factor beta , collagens, connective tissue growth factor, lactate oxidase lipoxygenase assessed by ReverseTranscriptase-Polymerase Chain Reaction

  48 weeks

Study Arms (1)

Pathogenesis study

EXPERIMENTAL

This pathogenesis study aimed to evaluate potential changes in adipose tissue after switching from an INSTI-based regimen (RAL or DTG or BIC) to TDF/FTC/DOR.

Drug: Switch from an INSTI-based regimen to the non INSTI-based regimen combining TDF/3TC/Doravirine

Interventions

Switch from an INSTI-based regimen to the non INSTI-based regimen combining TDF/3TC/Doravirine DRUG

Each patient will be evaluated with an adipose tissue biopsy performed before (D0) and after a 48 week switch (W48) from an INSTI-based regimen to the non INSTI-based regimen combining TDF/3TC/Doravirine (Delstrigo®)

Pathogenesis study

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HIV positive patient \> 18 years
• HIV RNA \< 50 copies/ml in the last 6 months
• on INSTI based regimen (dual or 3-DR) since at least 6 months
• Creatinine clearance \> 60 ml/min
• With a body weight increase defined as:
• % from pre INSTI body weight whatever duration of INSTI duration OR
• % during the first year after INSTI regimen initiation

You may not qualify if:

• Prior hypersensitivity to NNRTI
• Resistance to doravirine in past resistance genotype(s) if available
• Full resistance to tenofovir in past resistance genotype(s) if available
• Diabetes, type 1 or type 2 assessed on by fasting glycemia over 7mmol/L, or non-fasting glycemia over 11 mmol/L or receiving anti-diabetic medications.
• Pregnancy and breast feeding
• Prior bariatric surgery
• Hemostasis disorder or hemophilia
• Oral or injectable anti-diabetics, thyroid hormones, growth hormone, insulin, and corticosteroid therapy lasting more than 5 days.
• Body weight increase (in a context of recent tobacco cessation, introduction of psychotropic drugs, corticosteroids for at least one month, dysthyroidism, anabolic treatment or any hormonal therapy 6 months)
• Current antineoplastic chemotherapy
• Patient with instable housing
• Any acute infection or tumor
• Subjects under judicial protection due to temporarily and slightly diminished mental or physical faculties, or under legal guardianship

Sponsors & Collaborators

• Centre de Recherches et d'Etude sur la Pathologie Tropicale et le Sida: lead

Study Sites (1)

Christine Katlama

Paris, Île-de-France Region, 75013, France

Location

MeSH Terms

Conditions

HIV Infections

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• Christine Katlama, MD

  Pitie Salpetriere Hospital

  PRINCIPAL INVESTIGATOR

• Valerie Pourcher, MD

  Pitie Salpetriere Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: ADDORE is a pilot, open, single arm pathogenesis study to evaluate the impact on adipose tissue (AT) of a switch to TDF/FTC/DOR at week 48 in 20 patients with a body-weight gain under an INSTI-based regimen (RAL or DTG or BIC) Each patient will be evaluated with an adipose tissue biopsy performed just prior (D0) and after week 48 (W48) of switching from an INSTI-based regimen to a non INSTI-based regimen combining TDF/3TC/Doravirine (Delstrigo®).

Study Record Dates

• First Submitted: July 22, 2022
• First Posted: July 28, 2022
• Study Start: October 6, 2022
• Primary Completion: March 15, 2024
• Study Completion: January 1, 2025
• Last Updated: January 10, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)