Contribution of Dolutegravir to Obesity and Cardiovascular Disease

Phase 4

Completed

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

• Registration Number: NCT04340388
• Lead Sponsor: 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.

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 Timeline

• Study First Submitted: 2020-04-01
• Study First Submitted QC: 2020-04-07
• Study First Posted: 2020-04-09
• Study Start: 2020-09-17
• Primary Completion: 2022-06-17
• Study Completion: 2023-02-25
• Status Verified: 2023-07
• Last Update Submitted: 2023-07-25
• Last Update Posted: 2023-07-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 10

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Continue on non-integrase inhibitor based regimen	Antiretroviral/Anti HIV	Participants not currently on an integrase based regimen who remain on current suppressive therapy will remain on current antiretroviral regimen.
Switch from a non-integrase based regimen to dolutegravir	Dolutegravir 50 MG	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.

Primary Outcome Measures

Name	Time	Method
Change in Weight	24 weeks	Change from baseline kilograms (kg) of weight at 24 weeks

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Augusta University; 🇺🇸 Augusta, Georgia, United States