This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Multiple randomized clinical trials have shown that the highest overall sustained virologic response (SVR) rates in chronic hepatitis C patients have been achieved with peginterferon and ribavirin. Genotype is the strongest predictor of response, with SVR rates being the lowest in genotype 1 (G1) patients. Studies have shown that less that 50% of patients with HCV G1 achieve SVR rates with standard therapy. In those patients that do not respond to initial combination therapy with interferon and ribavirin, several studies have shown that re-treatment with pegIFN and ribavirin only achieves SVR rates of 4-12%. Recent studies have also implicated obesity and insulin resistance (IR) to be strong predictors of treatment failure in HCV G1 patients. Accumulating data also suggests that TNF-a, a pro-inflammatory cytokine, plays a direct role in IR and the metabolic syndrome. It is well documented that exercise induces several anti-inflammatory cytokines and may inhibit TNF-induced IR. Physical activity has a known beneficial effect on insulin sensitivity in normal as well as IR subjects. It is also well-documented that modifiable risk factors such as obesity and insulin resistance can be reversed, if not improved, with exercise. The purpose of our study is to exercise insulin resistant patients with genotype 1 Hepatitis C virus who have failed standard anti-viral therapy in anticipation of improving their re-treatment outcome. This is a pilot study.
Aims : 1. To determine the prevalence of insulin resistance (IR) in obese versus non-obese HCV genotype 1 (G1) patients who failed previous combination therapy (IFN/RBV or pegIFN/RBV). 2. To determine if IR in HCV G1 patients who failed previous therapy with IFN or pegIFN + RBV is modifiable with regular physical activity.3. To determine if improved IR with exercise in HCV G1 patients who failed previous therapy with IFN or pegIFN + RBV will be associated with improved re-treatment outcomeMethods: 1. Measurements of obesity and IR: Recruited subjects will get baseline measurements of BMI, insulin resistance (via OGTT and HOMA-IR) and cytokine levels. 2. Intervention: Subjects with IR will be randomized into two groups: diet + exercise or diet only. They will be randomized in a 2:1 fashion, favoring diet + exercise group. Baseline DEXA scans will be acquired. The diet + exercise group will be required to train once per day, 5 days/week, 60 minutes/session for 6 weeks. The diet will consist of a standardized handbook on healthy eating and dietary recommendations. OGTT, HOMA-IR, DEXA scan and cytokine levels will be repeated at the end of the 6 week session to assess if regular physical activity has an effect on IR and serum cytokine levels.3. Re-treatment: Ten subjects from the exercise plus diet group will be selected and further divided into two groups of 5 based on those that improved their IR and those that did not. All subjects will begin anti-viral treatment with Peg-IFN and Ribavirin. All subjects will be required to complete an additional 4 weeks of exercise. Viral kinetics will be measured to assess treatment response.
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