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Evaluation of the Impact of a Combined Program of Diet, Exercise and Behavior Modification on the Insulin Resistance and Adipokine Profile in Obese Patients With Current and Cured Chronic Hepatitis C.

18 Years
65 Years
Not Enrolling
Obesity, Insulin Resistance, Metabolic Syndrome, Hepatitis C

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Trial Information

Evaluation of the Impact of a Combined Program of Diet, Exercise and Behavior Modification on the Insulin Resistance and Adipokine Profile in Obese Patients With Current and Cured Chronic Hepatitis C.

The hepatitis C virus (HCV) chronically infects an estimated 240,000 in Canada and 170
million worldwide. Untreated, CHC is associated with significant long-term clinical
consequences including cirrhosis, liver failure and hepatocellular cancer (HCC), and it is
the most common indication for liver transplantation in North America. CHC is associated
with metabolic manifestations independent of the degree of hepatic fibrosis which include
insulin resistance (IR) and type 2 diabetes (T2DM), which have a significantly higher
prevalence in CHC compared with the general population. Patients with CHC and T2DM have an
increased risk of HCC in addition to morbidity from systemic complications.

Our previous work demonstrates that the prevalence of obesity (BMI ≥30kg/m2) amongst
patients with CHC is 28.8%, over twice the prevalence in the Canadian population, and the
presence of obesity is independently associated with viremia (positive HCV-RNA). Obesity
promotes hepatic fibrosis progression and is independently associated with IR in
non-cirrhotic CHC; the prevalence of IR increases with higher BMI in CHC. Insulin resistance
can be reversed if viral clearance is achieved; however loss of IR is less likely to occur
in the obese even if they have cleared the virus. Obesity and IR are associated with
non-response to antiviral therapy. Whilst IR has been improved with the use of metformin in
patients with CHC, this was ineffective in increasing rates of response to antiviral
treatment. The aims of our study are:

1. To evaluate the effect of a three-pronged lifestyle intervention comprising diet,
exercise and behavior modification on insulin resistance in obese patients with current
and cured chronic hepatitis C.

2. To formulate specific recommendations for lifestyle changes to improve insulin
resistance and lose weight, thereby reducing the risk of diabetes and other metabolic
complications, and potentially enhancing response to antiviral therapy in obese
patients with CHC.

3. To examine the impact of this intervention on IR, insulin sensitivity and serum
adipokine levels for the purpose of investigating the mechanism of insulin resistance
in obesity with and without viremia due to chronic hepatitis C infection.

We will utilize a multidisciplinary approach by collaborating with the disciplines of
gastroenterology, nutrition, endocrinology, exercise physiology and psychiatry. This
prospective study will include 13 non-cirrhotic and 13 cirrhotic, insulin resistant (HOMA-IR
≥2.1) and obese patients (non-Genotype 3, as the latter have marked fatty liver in absence
of obesity); as well as 13 non-cirrhotic and 13 cirrhotic, insulin resistant and obese
patients with successfully treated CHC (ie now non-viremic) to act as controls. Assessments
for measures of IR and obesity (including oral glucose tolerance test to calculate insulin
sensitivity index (ISI), serum adipokines, free fatty acids, anthropometry and body
composition by abdominal DEXA) will be made. The HOMA-IR (measuring hepatic IR) will be the
primary outcome for the experimental maneuver, which will take place over 24 weeks. It will
comprise 3 components:

1. Diet: participants will be advised on an individually tailored diet of low glycemic
foods, low total fat (but rich in omega-3 fatty acid) and high fiber aimed at both
weight loss and improvement of insulin resistance.

2. Exercise: physical activity will be measured with the use of a personal pedometer, and
participants given a step target of 10000 steps per day, or an increment of 3000 steps
per day from their baseline activity (whichever is greater).

3. Behavior Modification: the change in diet and physical activity will be facilitated by
a 12-week face-to face program followed by a 12-week telephone program based on the
principals of motivational interviewing and behavior theory.

The intercurrence of obesity and IR in subjects chronically infected with hepatitis C
exacerbates their poor current and future health status. As the pathophysiology of IR in
patients with CHC may differ from those who are obese but no longer infected, we will
quantify the benefits of the lifestyle intervention in these two patient groups as gauged by
fall in HOMA-IR score and improvement in ISI. Our long-term goals are to improve the outcome
of antiviral therapy and reduce the burden of CHC, obesity and type 2 diabetes related
morbidity. This we hope to achieve through gaining a better understanding of the mechanisms
involved in the development of IR in the obese with and without current CHC.

Inclusion Criteria:

- obese (BMI >/= 30)

- insulin resistant (HOMA-IR >/= 2.1)

Exclusion Criteria:

- Genotype 3 patients

- Women with ongoing pregnancy or who are breast-feeding

- Patients with any other other underlying liver disease (viral, alcoholic,
druginduced, autoimmune, metabolic, genetic).

- Patients currently on antiviral therapy, or who have ceased therapy within 6 months
of recruitment to the study.

- Patients with other causes for insulin resistance e.g., excess counter-regulatory
hormones: glucocorticoids, catecholamines, growth hormone, polycystic ovary

- Patients on steroids or other drug that affects insulin resistance, which are unable
to be stopped for 3 days prior to IR testing.

- Patients with overt diabetes (based on results of fasting plasma glucose) will be
excluded from participation as we are focusing on insulin resistance in the absence
of diabetes.

- Conditions which preclude a sudden increase in physical activity:

- History or other evidence of chronic pulmonary disease associated with
functional limitation.

- History of severe cardiac disease (e.g., NYHA Functional Class III or IV,
myocardial infarction within 6 months, ventricular tachyarrhythmias requiring
ongoing treatment, unstable angina or other significant cardiovascular

- Unable to 10000 steps/day eg physical disability, morbid obesity.

- Evidence of ongoing substance use (including alcohol consumption >20g/day for men and
>10g/day for women) within one year of study recruitment.

- Poor veins (inadequate venous access)

- Inability or unwillingness to provide informed consent or abide by study requirements
eg severe psychiatric illness, lives remotely, time commitment.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Outcome Time Frame:

12 and 24 weeks

Safety Issue:


Principal Investigator

Elizabeth J Heathcote, MD FRCPC

Investigator Role:

Principal Investigator

Investigator Affiliation:

University Health Network, Toronto


Canada: Ethics Review Committee

Study ID:




Start Date:

November 2008

Completion Date:

August 2011

Related Keywords:

  • Obesity
  • Insulin Resistance
  • Metabolic Syndrome
  • Hepatitis C
  • obesity
  • insulin resistance
  • metabolic syndrome
  • hepatitis C
  • adipokine
  • TNF
  • leptin
  • adiponectin
  • fatigue
  • mood
  • depression
  • exercise
  • diet
  • counseling
  • behavior modification
  • Hepatitis
  • Hepatitis A
  • Hepatitis, Chronic
  • Hepatitis C
  • Insulin Resistance
  • Obesity
  • Metabolic Syndrome X
  • Hepatitis C, Chronic