Contribution of Dolutegravir to Obesity and Cardiovascular Disease
Condition: 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
MeSH terms: 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
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Dolutegravir 50 MG; Antiretroviral/Anti HIV
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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 intervention name(s): Tenofovir alafenamide; Tenofovir disoproxil fumarate; Abacavir; Lamivudine; Darunavir; Cobicistat; Rilpivirine; Combivir; Zidovudine; Antiretroviral Combinations
Intervention MeSH terms: Tenofovir; Lamivudine; Zidovudine; Dolutegravir; Darunavir; Abacavir; Cobicistat; Rilpivirine; Anti-Retroviral Agents
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