Lifestyle Intervention Targetting Obesity and Insulin Resistance in Chronic Hepatitis C
Condition: Obesity; Insulin Resistance; Metabolic Syndrome; Hepatitis C
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Obesity; Metabolic Syndrome; Insulin Resistance
Study type: Interventional

Summary: 
      Chronic hepatitis C (CHC) infection affects approximately 1 in 100 Canadians. Untreated, CHC
      has significant long-term consequences including cirrhosis, liver cancer and liver failure.
      CHC is intrinsically linked to both obesity and insulin resistance (IR) or "pre-diabetes",
      their co-existence worsens overall health outcomes. We have demonstrated that obesity (BMI
      ≥30kg/m2) is over twice as common amongst patients with CHC (28.8%) compared with the general
      Canadian population. Obesity superimposed on CHC reduces the success of antiviral treatment
      and promotes liver scarring (hepatic fibrosis), fatty liver (steatosis) and increases the
      risk of liver cancer. Both CHC and obesity contribute to IR putting these patients at risk of
      type 2 diabetes. IR, like obesity in CHC, reduces antiviral success rates. We have shown that
      diabetics are at higher risk of developing liver cancer compared with non-diabetics. It is
      therefore timely to address lifestyle modification to delay the onset of diabetes. We will
      examine the impact of a multidisciplinary lifestyle program on the insulin resistance in 52
      obese "pre-diabetic" patients with current or past CHC. The 24 week program comprises an
      individualized nutritional and exercise plan supported by behavior modification counseling.
      Through gaining a better understanding of links between obesity, insulin resistance and
      hepatitis C infection we hope to delay the onset of diabetes and reduce the likelihood of all
      their untoward effects on the liver.
    

Detailed description: 
      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.
    

Intervention name(s): Lifestyle intervention
Intervention type(s): Other
Intervention description(s): The 3-pronged lifestyle intervention is designed to deliver a period of intensive contact (week 0-12) and less-intensive contact (weeks 12-24):
i) Behavior Modification Counseling: The principles of motivational enhancement and cognitive-behavior therapy (MET/CBT) will be utilized at each visit and telephone contact to provide individually tailored counseling. The goal is to enhance internal motivation and facilitate changes in lifestyle that are adaptable to each participant's usual habits.
ii) Physical activity target: increment in activity of at least 3000 steps/day above the baseline, or total activity of 10,000 steps/day (whichever is greater).
iii) Dietary assessment and nutritional plan: A diet plan designed to both lose weight and improve insulin resistance will be provided.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: obesity; insulin resistance; metabolic syndrome; hepatitis C; adipokine; TNF; leptin; adiponectin; fatigue; mood; depression; exercise; diet; counseling; behavior modification