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Contribution of Dolutegravir to Obesity and Cardiovascular Disease

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ClinicalTrials.gov Identifier: NCT04340388
Recruitment Status : Not yet recruiting
First Posted : April 9, 2020
Last Update Posted : April 9, 2020
Sponsor:
Information provided by (Responsible Party):
Jonell Poe, Augusta University

Brief Summary:
The goal of the study is to combine a collaborative and translational approach to evaluate the effect antiretroviral regimen switch to a dolutegravir containing regimen compared to continued treatment with a non- dolutegravir based regimen on on lipid and metabolic profiles, renal function, body composition, vascular function and diet.

Condition or disease Intervention/treatment Phase
HIV-1-infection Antiviral Drug Adverse Reaction Vascular Diseases Cardiovascular Abnormalities Abnormality of Adipose Tissue Body Weight Changes Body Fat Disorder HIV-Associated Lipodystrophy Syndrome Drug: Dolutegravir 50 MG Drug: Antiretroviral/Anti HIV Phase 4

Detailed Description:

Over the last decades, the use of combined antiretroviral therapy has led to profound suppression of HIV-1 replication and increased the survival of persons living with HIV (PLWH) to close to that of the general population. As a consequence, the spectrum of diseases related to HIV has shifted from opportunistic AIDS-related diseases towards long-term-age-related complications. Individuals living with HIV are now exhibiting accelerated development of obesity, metabolic derangements and cardiovascular disease (CVD). Recent compelling clinical evidence has documented a drastic shift in anthropometric profiles among persons living with HIV. In addition, several reports present dolutegravir, a second-generation integrase inhibitor currently highly prescribed for its high antiviral efficiency, as the potential cause of unpredicted weight gain. A critical gap in the investigators' knowledge is a lack of understanding of the etiopathology of the contribution of dolutegravir on weight gain and the consequential impact on obesity and cardiovascular disease in persons living with HIV on combined antiretroviral therapy. As overweight and obesity are among the leading risk factors for cardiovascular disease in persons living with HIV, it is critical to directly investigate whether dolutegravir increases fat mass in persons living with HIV and whether body weight gains-associated with dolutegravir based regimen contribute to the increased prevalence of CVD in this population of people.

This application seeks to investigate alterations in body fat and cardiometabolic risk markers associated with dolutegravir. The investigators propose that in patients with undetectable plasma HIV RNA, there is a direct correlation of weight gain and dolutegravir after antiretroviral regimen switch. They also contend that dolutegravir associated weight gain induces a phenotypic metabolic shift which alters the vascular endothelium and potentiates CVD risk. If the investigators are correct in their hypotheses, modifications in the clinical practice of treatment and prevention strategies for CVD in people living with HIV may be warranted.

Herein the investigators propose a novel translational study which will concomitantly investigate in human patients and animal models of HIV:

  1. whether dolutegravir based regimen increases body weight
  2. the mechanisms whereby dolutegravir increases body weight
  3. whether dolutegravir-mediated body weight gain increases the risk for CVD in PLWH.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The study design is a randomized control trial where patients will be randomized to the dolutegravir or non-dolutegravir arms by random number generation using the statistical software R. A unique identification (ID) key from 1 to 2n will be assigned to each patient.

Additionally, the investigators will utilize a parallel mouse model of HIV mimicking PLWH with stable viral load that can provide mechanistic insight and integrate experiments at the tissue level (adipose tissue) as well. Experiments in the parallel mouse model of HIV will also present the advantage to enable the study the direct effects of HIV viral infection on metabolic and cardiovascular function, a study not feasible in PWH who, for easily understandable ethical reasons, cannot remain without treatment for 6 months (duration of the study).

Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Contribution of the Integrase Inhibitor Dolutegravir to Obesity and Cardiovascular Disease in Persons Living With HIV
Estimated Study Start Date : June 2020
Estimated Primary Completion Date : January 2021
Estimated Study Completion Date : March 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Active Comparator: Switch from a non-integrase based regimen to dolutegravir
Participants with HIV-1 infection who have had viral suppression on a non-integrase based antiretroviral regimen for greater than or equal to 3 months will be switched to a dolutegravir based regimen dosed at 50 milligrams (MG) once daily. Background regimen will remain the same.
Drug: Dolutegravir 50 MG
15 participants will be randomized to remain on fully suppressive background antiretroviral therapy. The third agent will be switched to dolutegravir at the dose of 50 mg daily.
Other Names:
  • Tenofovir alafenamide
  • Tenofovir disoproxil fumarate
  • Abacavir
  • Lamivudine
  • Darunavir
  • Cobicistat
  • Rilpivirine
  • Combivir
  • Zidovudine

Active Comparator: Continue on non-integrase inhibitor based regimen
Participants not currently on an integrase based regimen who remain on current suppressive therapy will remain on current antiretroviral regimen.
Drug: Antiretroviral/Anti HIV
15 participants with suppressed HIV disease for greater than or equal to 3 months will be randomized to remain on their current 2 or 3 drug fully suppressive antiretroviral regimen.
Other Name: Antiretroviral Combinations




Primary Outcome Measures :
  1. Change in Weight [ Time Frame: 24 weeks ]
    Change from baseline kilograms (kg) of weight at 24 weeks


Secondary Outcome Measures :
  1. Change in body mass index (BMI) [ Time Frame: 24 weeks ]
    Total change in body mass index -height and weight will be combined to report BMI (Kilogram/Height in centimeters^2)

  2. Change in vascular endothelial function [ Time Frame: 24 weeks ]
    Change from baseline vessel diameter (millimeters) at 24 weeks

  3. Height [ Time Frame: 24 weeks ]
    Measurement of height (centimeters) from baseline to 24 weeks


Other Outcome Measures:
  1. Change in cholesterol [ Time Frame: 24 weeks ]
    Change from baseline cholesterol (mg/dL) at 24 weeks

  2. Change in triglycerides [ Time Frame: 24 weeks ]
    Change from baseline triglycerides (mg/dL) at 24 weeks

  3. Change in high density lipoprotein (HDL) [ Time Frame: 24 weeks ]
    Change from baseline HDL (mg/dL) at 24 weeks

  4. Change in low density lipoprotein (LDL) [ Time Frame: 24 weeks ]
    Change from baseline LDL (mg/dL) at 24 weeks

  5. Change in HIV-1 RNA viral load [ Time Frame: 24 weeks ]
    Change from baseline HIV-1 viral load (copies) at 24 weeks

  6. Change in fasting serum glucose level [ Time Frame: 24 weeks ]
    Change from baseline serum glucose level (mg/dL) at 24 weeks

  7. Change in quantity of food consumption [ Time Frame: 24 weeks ]
    Change from baseline of calorie consumption (kcal) at 24 weeks



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Subjects must meet the following criteria to be eligible for participation in this study:

  • Age greater than or equal to 18 years with HIV-1 who have been virologically suppressed (HIV-1 RNA < 50 copies for greater than or equal to 3 months on a non-integrase strand transfer inhibitor-based regimen
  • Have the ability to understand and sign an informed consent written in the English language

Exclusion Criteria:

Subjects meeting any of the following exclusion criteria are not to be enrolled in this study:

  • Age less than 18 years without HIV-1 infection
  • Has hypersensitivity or other contraindication to any of the components of the study
  • Has active diagnosis of untreated hepatitis due to any cause
  • Has a history or current evidence of any condition, laboratory abnormality or other circumstance ( including drug or alcohol use or dependence) that might confound the results of the study or interfere with the subject's participation for the full duration of the study
  • Is taking or is anticipated to require long term systemic immunosuppressive therapy, immune modulators, or any prohibited therapies from 60 days prior to Screening/Day 1 visit through to the end of study
  • Has documented or suspected dolutegravir-associated resistance mutations specifically:

Q148H/K/R/N in combination with E138K or G1402/A or N155H.

  • Has a life expectancy less than or equal to one year
  • Is pregnant, breastfeeding, or expecting to donate eggs or sperm or conceive or father a child at any time during the study and 6 weeks following the end of study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04340388


Contacts
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Contact: Ivy Tillman 706-721-1379 itillman@augusta.edu
Contact: Martha Farrough, RN 706-723-0106 mfarrough@augusta.edu

Sponsors and Collaborators
Augusta University
Investigators
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Principal Investigator: Jonell B Poe, MPAS Augusta University
Publications of Results:
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Responsible Party: Jonell Poe, Assistant Clinical Professor, Physician Assistant, Augusta University
ClinicalTrials.gov Identifier: NCT04340388    
Other Study ID Numbers: 1553691-1
First Posted: April 9, 2020    Key Record Dates
Last Update Posted: April 9, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The investigators plan to share de-identified all IPD included in this study and that de-identified IPD results that underlie applications for additional funding or for publication.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Following publication. No end date.
Access Criteria: To achieve aims in the approved proposal.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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HIV-Associated Lipodystrophy Syndrome
Cardiovascular Diseases
Vascular Diseases
Cardiovascular Abnormalities
Congenital Abnormalities
Lipodystrophy
Body Weight
Body Weight Changes
Drug-Related Side Effects and Adverse Reactions
Skin Diseases, Metabolic
Skin Diseases
Lipid Metabolism Disorders
Metabolic Diseases
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Chemically-Induced Disorders
Tenofovir
Lamivudine
Zidovudine
Darunavir
Abacavir
Dolutegravir
Cobicistat