Contribution of Dolutegravir to Obesity and Cardiovascular Disease

Contribution of the Integrase Inhibitor Dolutegravir to Obesity and Cardiovascular Disease in Persons Living With HIV

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.

Study Overview

• Status: Completed
• Conditions: Vascular Diseases; Body Weight Changes; Cardiovascular Abnormalities; HIV-1-infection; Body Fat Disorder; HIV-Associated Lipodystrophy Syndrome; Antiviral Drug Adverse Reaction; Abnormality of Adipose Tissue
• Intervention / Treatment: Drug: Dolutegravir 50 MG; Drug: Antiretroviral/Anti HIV

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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; Combivir; Abacavir; Rilpivirine; Lamivudine; Zidovudine; Darunavir; Cobicistat; Tenofovir disoproxil fumarate
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 Names: Antiretroviral Combinations

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Weight	Change from baseline kilograms (kg) of weight at 24 weeks	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in body mass index (BMI)	Total change in body mass index -height and weight will be combined to report BMI (Kilogram/Height in centimeters^2)	24 weeks
Change in vascular endothelial function	Change from baseline vessel diameter (millimeters) at 24 weeks	24 weeks
Height	Measurement of height (centimeters) from baseline to 24 weeks	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cholesterol	Change from baseline cholesterol (mg/dL) at 24 weeks	24 weeks
Change in triglycerides	Change from baseline triglycerides (mg/dL) at 24 weeks	24 weeks
Change in high density lipoprotein (HDL)	Change from baseline HDL (mg/dL) at 24 weeks	24 weeks
Change in low density lipoprotein (LDL)	Change from baseline LDL (mg/dL) at 24 weeks	24 weeks
Change in HIV-1 RNA viral load	Change from baseline HIV-1 viral load (copies) at 24 weeks	24 weeks
Change in fasting serum glucose level	Change from baseline serum glucose level (mg/dL) at 24 weeks	24 weeks
Change in quantity of food consumption	Change from baseline of calorie consumption (kcal) at 24 weeks	24 weeks

Collaborators and Investigators

• Sponsor: Augusta University
• Investigators: Principal Investigator: Jonell B Poe, MPAS, Augusta University

Publications and helpful links

General Publications

• Cottrell ML, Hadzic T, Kashuba AD. Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet. 2013 Nov;52(11):981-94. doi: 10.1007/s40262-013-0093-2.

Study record dates

Study Major Dates

• Study Start (Actual): September 17, 2020
• Primary Completion (Actual): June 17, 2022
• Study Completion (Actual): February 25, 2023

Study Registration Dates

• First Submitted: April 1, 2020
• First Submitted That Met QC Criteria: April 7, 2020
• First Posted (Actual): April 9, 2020

Study Record Updates

• Last Update Posted (Actual): July 27, 2023
• Last Update Submitted That Met QC Criteria: July 25, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Metabolic Diseases; Skin Diseases; 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; Lipid Metabolism Disorders; HIV Infections; Skin Diseases, Metabolic; Urogenital Diseases; Genital Diseases; Cardiovascular Diseases; Vascular Diseases; Congenital Abnormalities; Body Weight; Body Weight Changes; Drug-Related Side Effects and Adverse Reactions; Cardiovascular Abnormalities; Lipodystrophy; HIV-Associated Lipodystrophy Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Antimetabolites; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Integrase Inhibitors; Integrase Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Tenofovir; Cobicistat; Lamivudine; Zidovudine; Darunavir; Anti-Retroviral Agents; Dolutegravir; Rilpivirine; Abacavir
• Other Study ID Numbers: 1553691-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing Time Frame: Following publication. No end date.
• IPD Sharing Access Criteria: To achieve aims in the approved proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• 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