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Effect on Liver Fat and Metabolic Parameters When Switching a Protease Inhibitor or Efavirenz to Raltegravir (OBERAL)

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ClinicalTrials.gov Identifier: NCT03374358
Recruitment Status : Completed
First Posted : December 15, 2017
Last Update Posted : February 20, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Jussi Sutinen, Helsinki University Central Hospital

Brief Summary:

This study will provide data on the switch from a protease inhibitor or efavirenz to the new formulation of raltegravir (RAL) dosed once daily. The study group consists of patients with metabolic risk factors and co-morbidities, in need of optimization of their current ART to minimize the drug-related metabolic side effects as standard of care.

The primary objective of this study is to investigate whether switching a protease inhibitor (PI) or efavirenz to raltegravir once daily reduces liver fat in patients who are overweight or obese and have at least one metabolic syndrome component. For this purpose, the liver fat content will be analyzed using the proton magnetic resonance spectroscopy.

In addition, the aim is to clarify the change in the body composition and metabolism in this study group. For this purpose the visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volumes will be measured and subcutaneous tissue samples will be collected for future analyses of adipose tissue function.


Condition or disease Intervention/treatment Phase
HIV Seropositivity Metabolic Syndrome Fatty Liver Drug: Raltegravir Phase 4

Detailed Description:

The prevalences of overweight (body-mass-index, BMI 25-30 kg/m2) and obesity (BMI>30 kg/m2) are steadily increasing among HIV-infected patients globally. In parallel, the risk of non-alcoholic fatty liver disease (NAFLD) increases. Clinically alarming are the data which suggest that HIV infected have higher rates of progressive form of NAFLD than non-HIV infected age, gender and BMI matched controls.

As the treatment for HIV is life-long, it is crucial to understand the effects of different antiretroviral therapy (ART) regimens on metabolism. Some antiretroviral agents appear to promote unfavourable changes in metabolism (e.g. in blood lipids) and predispose to trunk fat redistribution and liver fat accumulation.

Raltegravir has been demonstrated to have beneficial impact on some metabolic parameters compared to the protease inhibitor class or efavirenz. In this study, the aim is to investigate whether switching a protease inhibitor or efavirenz to raltegravir reduces liver fat in patients who are overweight or obese and have at least one metabolic syndrome component. For this purpose, the proton magnetic resonance spectroscopy will be used.

In addition, the aim is to clarify the change in the body composition in this study group. For this purpose, the visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volumes will be measured using MRI.

To acquire more knowledge on metabolic effects in adipose tissue level, subcutaneous adipose tissue biopsies will be collected together with blood, saliva and feces samples.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This study is a randomized, open, parallel design study.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effect on Liver Fat, Adipose Tissue and Metabolic Parameters When Switching a Protease Inhibitor or Efavirenz to Once Daily Raltegravir in HIV+ Patients With Body Mass Index Over 25 kg/m2 and With at Least One Metabolic Syndrome Component
Actual Study Start Date : January 10, 2018
Actual Primary Completion Date : November 2, 2019
Actual Study Completion Date : November 30, 2019


Arm Intervention/treatment
No Intervention: No intervention arm.
Study subjects will continue their current antiretroviral regimens, which include a protease inhibitor or efavirenz plus two nucleoside analog reverse-transcriptase inhibitors (NRTIs).
Experimental: Raltegravir arm.
Study subjects will switch their protease inhibitor or efavirenz to once daily raltegravir plus continue current nucleoside analog reverse-transcriptase inhibitors (NRTIs).
Drug: Raltegravir
The aim of this study is to investigate whether switching a protease inhibitor (PI) or efavirenz to raltegravir has effect on liver fat and metabolism in HIV-infected patients who are overweight or obese and have at least one metabolic syndrome component .
Other Name: Isentress




Primary Outcome Measures :
  1. Change in Liver Fat [ Time Frame: Baseline and 24 weeks ]
    Change in Liver Fat, measured by proton magnetic resonance spectroscopy.


Secondary Outcome Measures :
  1. Change in subcutaneous and visceral adipose tissue volume [ Time Frame: Baseline and 24 weeks ]
    Change in subcutaneous and visceral adipose tissue volume measured by magnetic resonance imaging.

  2. Change in total body fat and lean tissue mass [ Time Frame: Baseline and 24 weeks ]
    Change in total body fat and lean tissue mass measured by Bioelectrical Impedance Analysis.


Other Outcome Measures:
  1. Change in Liver Stiffness [ Time Frame: Baseline and 24 weeks ]
    Change in Liver Stiffness measured by transient elastography (Fibroscan ®).

  2. Change in Glucose Metabolism [ Time Frame: Baseline and 24 weeks ]
    Change in Glucose Metabolism including fasting glucose, insulin, 2-h oral glucose tolerance test.

  3. Change in Lipid Profile [ Time Frame: Baseline and 24 weeks ]
    Change in Lipid Profile (LDL and HDL cholesterol, Triglyceride).

  4. Change in Metabolic and Inflammatory Biomarkers [ Time Frame: Baseline and 24 weeks ]
    Change in Metabolic and Inflammatory Biomarkers (e.g. high-sensitivity C-reactive protein (hsCRP), adiponectin, etc).

  5. Tolerability and safety of raltegravir will be assessed by CTCAE v4.0 [ Time Frame: Baseline to 24 weeks ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  6. Determination of the fatty liver adipose allele [ Time Frame: Baseline ]
    Determination of the fatty liver adipose allele (B-PNPLA3).

  7. Determination of basal metabolic rate [ Time Frame: Baseline and 24 weeks ]
    Determination of basal metabolic rate by indirect calorimetry.

  8. Subcutaneous adipose tissue gene expression studies [ Time Frame: Baseline and 24 weeks ]
    Change in gene expression (mRNA) of e.g. adipokines and inflammatory markers in subcutaneous adipose tissue.

  9. Stool microbiome studies [ Time Frame: Baseline and 24 weeks ]
    Change in the components of fecal microbiome (genetic characterization)

  10. Saliva microbiome studies [ Time Frame: Baseline and 24 weeks ]
    Change in the components of oral microbiome (genetic characterization)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent (IC) obtained.
  • HIV-positive adult (age over 18) subjects currently on stable ART, with no changes in the ART regimens during the past 6 months.
  • Current ART includes either a protease inhibitor or efavirenz.
  • No documented or suspected resistance to integrase inhibitors or to NRTIs.
  • No prior history of virologic failure. Failure is defined as a confirmed plasma viral load > 200 cop/ml measured no less than six months after initiation or modification of therapy.
  • Virological blips accepted only if a single viral load measurement has been between 50-200 cop/ml followed by viral load < 50 cop/ml without the need to initiate a change in ART and no blip within 12 month window period prior to screening.
  • Documented evidence of at least two HIV viral load < 50 cop/ml measurements during the past 12 months prior to inclusion: one within 6 months prior to screening.
  • HIV viral load < 50 cop/ml at screening.
  • BMI>25 kg/m2 and one metabolic syndrome condition, which are

    • BP ≥ 130/≥ 85 mmHg or hypertension medication currently in use or
    • fasting glucose ≥ 5.6 mmol/l or B-HbA1C > 42 mmol/mol or diabetes medication currently in use or
    • HDL < 1.0 mmol/l in men and < 1.3 mmol/l in women or triglycerides ≥ 1.7 mmol/l or a cholesterol-lowering regimen currently in use or
    • waist circumference > 94 cm in men and >80 cm in women (or respective cut off values for non-European ethnic groups as defined by International Diabetes Federation). OR
  • ultrasound or biopsy proven hepatosteatosis.

Exclusion Criteria:

  • Within 12 month window period prior to screening, HIV viral load measurement of >50 cop/ml.
  • More than one consecutive HIV viral load measurements of > 50 cop/ml in the treatment history after initial viral suppression with ART.
  • Chronic hepatitis B or C.
  • Daily alcohol consumption ≥ 30 g for men and ≥ 20 g for women.
  • Pregnancy or planned pregnancy during the study period.
  • Lipid or glucose lowering regimen or hormonal supplement started within 3 months before the planned study start.
  • Psychiatric disorder, which prevents a study subject to understand the study protocol.
  • Other serious disease, which prevents a study subject to participate in the study.
  • For MRI/spectroscopy imaging: metal objects in the body or claustrophobia.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03374358


Locations
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Finland
Aurora hospital, Department of Infectious Diseases
Helsinki, Finland
Sponsors and Collaborators
Helsinki University Central Hospital
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Jussi Sutinen, MD PhD Helsinki University Central Hospital
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Responsible Party: Jussi Sutinen, Consultant, MD, PhD, Helsinki University Central Hospital
ClinicalTrials.gov Identifier: NCT03374358    
Other Study ID Numbers: OBERAL
First Posted: December 15, 2017    Key Record Dates
Last Update Posted: February 20, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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HIV Seropositivity
Fatty Liver
Metabolic Syndrome
Syndrome
Disease
Pathologic Processes
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Liver Diseases
Digestive System Diseases
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Raltegravir Potassium
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
HIV Integrase Inhibitors
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action