Aerobic Exercise Training in Patients With Chronic Hepatitis B and Hepatic Steatosis

Study Overview
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Brief Summary
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This study is a randomised, controlled, unblinded, clinical intervention trial consisting of 12 weeks of aerobic exercise training. Thirty persons with chronic hepatitis B (CHB) and hepatic steatosis are randomised to either aerobic exercise training (intervention group, n=15) or no intervention (control group, n=15). The study will investigate the effects of the exercise intervention on the liver and the hypothesis is that the exercise group will reduce the fat-fraction of the liver after the intervention.

Detailed Description
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Primary aim: To investigate whether regular aerobic exercise training will decrease the fat-fraction of the liver in persons with CHB and hepatic steatosis shown by magnetic resonance imaging (MRI) by use of Iterative Decomposition of water and fat with Echo Asymmetry and Least squares estimation (IDEAL-IQ). Secondary aim: To investigate the effects of aerobic exercise training on hepatokine secretion in persons with CHB and hepatic steatosis. Also, to investigate if regular physical exercise will improve lipid- and glucose metabolism, liver status, markers of inflammation, body composition, and blood pressure. Study participants will undergo pre and post the interventioon: Clinical examination with ECG, blood pressure measurements, blood sampling, oral glucose tolerance test, a hormone infusion of somatostatin and glucagon, -increasing the glucagon/insulin ratio mimicking an acute exercise bout, measuring the effect on circulating hepatokines and cytokines, fibroscan, VO2-max test, DXA scan, AX3 activity monitoring, nail fold capillaryscopy, IQOLA SF-36 and IPAQ-SF questionnaire, 24H food intake registration, MRI scan of the liver and optional liver biopsy. 6 and 12 months follow-up is planned. The exercise intervention will be randomised 1:1 with no stratification: The training program includes three weekly supervised training sessions of 40 minutes/session over 12 weeks. Participants are instructed not to change their lifestyles during the intervention.

Official Title
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Effect of Aerobic Exercise Training on Fat-fraction of the Liver in Patients With Chronic Hepatitis B and Hepatic Steatosis: a Randomised Controlled Intervention Trial. The Fit Liver Study

Conditions
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Hepatitis B, Chronic, Hepatic Steatosis

Intervention / Treatment
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* Behavioral: High Intensity Interval Training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic hepatitis B defined by HBsAg positive >6 months Positive HBV-DNA Age >30 Hepatic steatosis diagnosed by Controlled Attenuated Parameter (CAP) >250 assessed by Transient Elastography or by ultrasound defined hepatic steatosis Exclusion Criteria: HIV, HCV, HDV-co infection Primary biliary cholangitis Wilsons Disease Autoimmune hepatitis Hepatocellular carcinoma Antiviral medication Steatogenic medication (systemic corticosteroids, amiodarone, tamoxifen, valproic acid, and methotrexate) Average alcohol intake >30 g for men and >20 g for women pr. day Contraindications for MRI scan Coronary artery disease contraindicating HIIT Unable to understand and read written information for participants written consent Pregnancy

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exercise Intervention Arm<br>Three high intensity interval exercise sessions per week of 40 minutes duration per session. Exercise will be performed on ergometerbikes. | Behavioral: High Intensity Interval Training<br>* A training session consists of 40 minutes as follows: 4x4 minutes at > 85% of heart rate maximum (HRmax) alternated by 3x3 minutes active recovery at (50-70% of HRmax) and a 10-min-warm-up (60-79% of HRmax) and 5- minute cool-down at   warm up intensity. HRmax was determined during the VO2max test at baseline visit. Minutes spent in the different heart rate zones is monitored during the session (zone 1: 60-69%, zone 2: 70-74%, zone 3: 75-79%, zone 4: 80-84%, zone 5: >85% of HRmax).<br>|
| No Intervention: No Intervention<br>No lifestyle changes | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fat-Fraction of the Liver | Hepatic fat-fraction measured by MRI with IDEAL-IQ (%) | From baseline to follow-up at 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fibroblast growth factor 21 (FGF21) secretion | FGF21 (ng/L) secretion during a hormone infusion of somatostatin and glucagon | From baseline to follow-up at 12 weeks | 
| Follistatin secretion | Follistatin (ng/L) secretion during a hormone infusion of somatostatin and glucagon | From baseline to follow-up at 12 weeks | 
| Growth/differentiation factor 15 (GDF15) secretion | GDF15 (ng/L) secretion during a hormone infusion of somatostatin and glucagon | From baseline to follow-up at 12 weeks | 
| Angiopoietin-like 4 (ANGPTL4) secretion | ANGPTL4 (μg/L) secretion during a hormone infusion of somatostatin and glucagon | From baseline to follow-up at 12 weeks | 
| C-reactive protein (CRP) secretion | CRP (mg/L) secretion during a hormone infusion of somatostatin and glucagon | From baseline to follow-up at 12 weeks | 
| Interferon-ϒ secretion | Interferon-ϒ (pg/mL) secretion during a hormone infusion of somatostatin and glucagon | From baseline to follow-up at 12 weeks | 
| Interleukin-10 secretion | Interleukin-10 (pg/mL) secretion during a hormone infusion of somatostatin and glucagon | From baseline to follow-up at 12 weeks | 
| Interleukin-8 secretion | Interleukin-8 (pg/mL) secretion during a hormone infusion of somatostatin and glucagon | From baseline to follow-up at 12 weeks | 
| Interleukin-6 secretion | Interleukin-6 (pg/mL) secretion during a hormone infusion of somatostatin and glucagon | From baseline to follow-up at 12 weeks | 
| Interleukin-1 secretion | Interleukin-1 (pg/mL) secretion during a hormone infusion of somatostatin and glucagon | From baseline to follow-up at 12 weeks | 
| TNFα secretion | TNFα (pg/mL) secretion during a hormone infusion of somatostatin and glucagon | From baseline to follow-up at 12 weeks | 
| Visceral fat | Visceral fat assessed by MRI (kg) | From baseline to follow-up at 12 weeks | 
| Total fat mass | Total fat mass assessed by DXA scan (kg) | From baseline to follow-up at 12 weeks | 
| Total free fat mass | Total free fat mass assessed by DXA scan (kg) | From baseline to follow-up at 12 weeks | 
| Total lean body mass | Total lean body mass assessed by DXA scan (kg) | From baseline to follow-up at 12 weeks | 
| Body weight | Body weight (kg) | From baseline to follow-up at 12 weeks | 
| Blood pressure measurements | Systolic blood pressure (mmHg) and diastolic blood pressure (mmHg) | From baseline to follow-up at 12 weeks | 
| Physical fitness (VO2max) | Physical fitness assessed by VO2max (mL/kg/min) | From baseline to follow-up at 12 weeks | 
| Total physical activity | Total physical activity assessed by activity monitor (hours, minutes) | From baseline, at 6 weeks to follow-up at 12 weeks | 
| Moderate and vigorous physical activity (MVPA) | Moderate and vigorous physical activity (MVPA) activity monitor (hours, minutes) | From baseline, at 6 weeks to follow-up at 12 weeks | 
| Sedentary time (SED) | Sedentary time (SED) activity monitor (hours, minutes) | From baseline, at 6 weeks to follow-up at 12 weeks | 
| Hepatitis B virus (DNA) | Hepatitis B virus (DNA) (IU/mL) | From baseline to follow-up at 12 weeks | 
| Oral glucose tolerance test | Oral glucose tolerance test (mmol/L) | From baseline to follow-up at 12 weeks | 
| Glycated haemoglobin type 1AC (HbA1c) | Glycated haemoglobin type 1AC (HbA1c) (mmol/mL) | From baseline to follow-up at 12 weeks | 
| Fasting glucose | Fasting glucose (mmol/L) | From baseline to follow-up at 12 weeks | 
| Fasting Insulin | Fasting Insulin (pmol/L) | From baseline to follow-up at 12 weeks | 
| Lipid measurements | Total cholesterol (mmol/L), total triglyceride (mmol/L), low density lipoprotein (LDL) (mmol/L), high density lipoprotein (HDL) (mmol/L) | From baseline to follow-up at 12 weeks | 
| Alanine transaminase (ALT) | Alanine transaminase (ALT) (U/L) | From baseline to follow-up at 12 weeks | 
| Aspartate transaminase (AST) | Aspartate transaminase (AST) (U/L) | From baseline to follow-up at 12 weeks | 
| Fibrosis-4 (FIB-4) | Fibrosis-4 (FIB-4) | From baseline to follow-up at 12 weeks | 
| International Normalised Ratio (INR) | International Normalised Ratio (INR) | From baseline to follow-up at 12 weeks |