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

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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03374358

Acronym

OBERAL

Enrollment

Registered

2017-12-15

Start date

2018-01-10

Completion date

2019-11-30

Last updated

2021-09-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Fatty Liver, HIV Seropositivity, Metabolic Syndrome

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.

Interventions

DRUGRaltegravir

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 .

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

This study is a randomized, open, parallel design study.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Change in Liver Fat	Baseline and 24 weeks	24 week value minus baseline value, liver fat % measured by proton magnetic resonance spectroscopy.

Secondary

Measure	Time frame	Description
Change in Subcutaneous and Visceral Adipose Tissue Volume	Baseline and 24 weeks	24 week value minus baseline value: change in subcutaneous (SAT) and visceral (VAT) adipose tissue volume (mL) measured by magnetic resonance imaging. Analysis included a series of T1-weighted trans-axial images from 8 cm above to 8 cm below the 4th and 5th lumbar intervertebral disc (16 slices, field of view 375 x 500 mm2, slice thickness 10 mm).
Change in Body Weight and Total Body Fat	Baseline and 24 weeks	24 week value minus baseline value, change in body weight (kg) and total body fat (kg) measured by Bioelectrical Impedance Analysis.

Other

Measure	Time frame	Description
Change in Metabolic and Inflammatory Biomarkers: hsCRP	Baseline and 24 weeks	24 week value minus baseline value, change in circulating metabolic and inflammatory biomarkers: high sensitivity C-reactive protein (hsCRP mg/L)
Change in Liver Stiffness	Baseline and 24 weeks	24 week minus baseline value, change in liver stiffness (kPa) measured by transient elastography (Fibroscan ®).
Change in Metabolic and Inflammatory Biomarkers: IL-6	Baseline and 24 weeks	24 week value minus baseline value, change in circulating metabolic and inflammatory biomarkers: interleukin 6 (IL-6 pg/mL)
Change in Fasting Plasma Glucose	Baseline and 24 weeks	24 week value minus baseline value, change in fasting plasma glucose (mg/dL).
Change in Fasting Serum Lipid Profile	Baseline and 24 weeks	24 week value minus baseline value, change in fasting serum lipid profile: LDL and HDL cholesterol, triglyceride (all values in mmol/L)

Countries

Finland

Participant flow

Participants by arm

Arm	Count
Control (= 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).	24
Raltegravir Arm. Study subjects will switch their protease inhibitor or efavirenz to once daily raltegravir plus continue current nucleoside analog reverse-transcriptase inhibitors (NRTIs). 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 .	19
Total	43

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Withdrawal by Subject	0	2

Baseline characteristics

Characteristic	Control (= no Intervention Arm).	Raltegravir Arm.	Total
Age, Continuous	50 years	49 years	49 years
Body weight	98.8 kg	85.9 kg	93.2 kg
Fasting plasma glucose	6.0 mmol/L	5.5 mmol/L	5.7 mmol/L
Fasting serum HDL cholesterol	1.13 mmol/L	1.30 mmol/L	1.20 mmol/L
Fasting serum LDL cholesterol	3.2 mmol/L	3.2 mmol/L	3.2 mmol/L
Fasting serum triglyceride	1.3 mmol/L	1.3 mmol/L	1.3 mmol/L
Liver fat content	3.1 % hepatic fat fraction	2.3 % hepatic fat fraction	2.3 % hepatic fat fraction
Liver stiffness	4.7 kPa	4.1 kPa	4.4 kPa
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	1 Participants	1 Participants	2 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	22 Participants	18 Participants	40 Participants
Region of Enrollment Finland	24 participants	19 participants	43 participants
Serum high sensitivity CRP	2.4 mg/L	1.0 mg/L	1.3 mg/L
Serum IL-6	2.2 pg/mL	2.4 pg/mL	2.2 pg/mL
Sex: Female, Male Female	5 Participants	4 Participants	9 Participants
Sex: Female, Male Male	19 Participants	15 Participants	34 Participants
Subcutaneous adipose tissue volume	5377 mL	3979 mL	4468 mL
Total body fat	30.0 kg	20.3 kg	23.8 kg
Visceral adipose tissue volume	2053 mL	1795 mL	1906 mL

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 24	0 / 19
other Total, other adverse events	20 / 24	16 / 19
serious Total, serious adverse events	1 / 24	0 / 19