Clinical trial NCT03374358: Effect on Liver Fat and Metabolic Parameters When Switching a Protease Inhibitor or Efavirenz to Raltegravir
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Seropositivity
Metabolic Syndrome
Fatty Liver
Lead sponsor: Helsinki University Central Hospital
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2017-12-15
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study is a randomized, open, parallel design study.
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Change in Liver Fat
timeFrame: Baseline and 24 weeks
Secondary outcomes:
measure: Change in Subcutaneous and Visceral Adipose Tissue Volume
timeFrame: Baseline and 24 weeks
measure: Change in Body Weight and Total Body Fat
timeFrame: Baseline and 24 weeks
Other outcomes:
measure: Change in Liver Stiffness
timeFrame: Baseline and 24 weeks
measure: Change in Fasting Plasma Glucose
timeFrame: Baseline and 24 weeks
measure: Change in Fasting Serum Lipid Profile
timeFrame: Baseline and 24 weeks
measure: Change in Metabolic and Inflammatory Biomarkers: hsCRP
timeFrame: Baseline and 24 weeks
measure: Change in Metabolic and Inflammatory Biomarkers: IL-6
timeFrame: Baseline and 24 weeks
Locations:
city: Helsinki
country: Finland
facility: Aurora hospital, Department of Infectious Diseases
Study officials:
affiliation: Helsinki University Central Hospital
name: Jussi Sutinen, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hanttu A, Vuoti S, Kivela P, Arkkila P, Lundbom N, Hakkarainen A, Lundbom J, Lehtimaki T, Viskari H, Lehtinen V, Pietilainen KH, Sutinen J. Liver Fat, Adipose Tissue, and Body Composition Changes After Switching from a Protease Inhibitor or Efavirenz to Raltegravir. AIDS Patient Care STDS. 2021 Sep;35(9):335-341. doi: 10.1089/apc.2021.0106.