Clinical trial NCT04340388: Contribution of Dolutegravir to Obesity and Cardiovascular Disease
Official title: Contribution of the Integrase Inhibitor Dolutegravir to Obesity and Cardiovascular Disease in Persons Living With HIV
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: 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
Lead sponsor: Augusta University
Sponsor class: OTHER
First posted: 2020-04-09
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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).
Primary purpose: BASIC_SCIENCE

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.

Eligibility 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.

Primary outcomes:
measure: Change in Weight
timeFrame: 24 weeks
Secondary outcomes:
measure: Change in body mass index (BMI)
timeFrame: 24 weeks
measure: Change in vascular endothelial function
timeFrame: 24 weeks
measure: Height
timeFrame: 24 weeks
Other outcomes:
measure: Change in cholesterol
timeFrame: 24 weeks
measure: Change in triglycerides
timeFrame: 24 weeks
measure: Change in high density lipoprotein (HDL)
timeFrame: 24 weeks
measure: Change in low density lipoprotein (LDL)
timeFrame: 24 weeks
measure: Change in HIV-1 RNA viral load
timeFrame: 24 weeks
measure: Change in fasting serum glucose level
timeFrame: 24 weeks
measure: Change in quantity of food consumption
timeFrame: 24 weeks
Locations:
city: Augusta
country: United States
facility: Augusta University
state: Georgia
Study officials:
affiliation: Augusta University
name: Jonell B Poe, MPAS
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.