Contribution of Dolutegravir to Obesity and Cardiovascular Disease

Vascular Diseases Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04340388
• Other study ID #: 1553691-1
• Status: Completed
• Phase: Phase 4
• Start date: September 17, 2020
• Est. completion date: February 25, 2023

Study information

• Verified date: July 2023
• Source: Augusta University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: February 25, 2023
• Est. primary completion date: June 17, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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.

Related Conditions & MeSH terms

• Abnormality of Adipose Tissue
• Antiviral Drug Adverse Reaction
• Body Fat Disorder
• Body Weight
• Body Weight Changes
• Cardiovascular Abnormalities
• Cardiovascular Diseases
• Congenital Abnormalities
• Drug-Related Side Effects and Adverse Reactions
• HIV-1-infection
• HIV-Associated Lipodystrophy Syndrome
• Lipodystrophy
• Vascular Diseases

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Augusta University	Augusta	Georgia

Sponsors (1)

Lead Sponsor	Collaborator
Augusta University

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in cholesterol	Change from baseline cholesterol (mg/dL) at 24 weeks	24 weeks
Other	Change in triglycerides	Change from baseline triglycerides (mg/dL) at 24 weeks	24 weeks
Other	Change in high density lipoprotein (HDL)	Change from baseline HDL (mg/dL) at 24 weeks	24 weeks
Other	Change in low density lipoprotein (LDL)	Change from baseline LDL (mg/dL) at 24 weeks	24 weeks
Other	Change in HIV-1 RNA viral load	Change from baseline HIV-1 viral load (copies) at 24 weeks	24 weeks
Other	Change in fasting serum glucose level	Change from baseline serum glucose level (mg/dL) at 24 weeks	24 weeks
Other	Change in quantity of food consumption	Change from baseline of calorie consumption (kcal) at 24 weeks	24 weeks
Primary	Change in Weight	Change from baseline kilograms (kg) of weight at 24 weeks	24 weeks
Secondary	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
Secondary	Change in vascular endothelial function	Change from baseline vessel diameter (millimeters) at 24 weeks	24 weeks
Secondary	Height	Measurement of height (centimeters) from baseline to 24 weeks	24 weeks