The mission of the Massachusetts General Hospital (MGH) is to advance medical care through innovative research and improve the health of the community. More than 4 millions Americans have hepatitis C virus (HCV) infection and 75% develop chronic disease, significantly impacting the health of our community. Chronic hepatitis C (CHC) infection leads to decompensated liver failure, hepatocellular carcinoma and is the most common indication for liver transplantation in the United States. Unfortunately, standard therapy with pegylated interferon (PEGIFN) and ribavirin (RBV) leads to a sustained virologic response (SVR) in only 50% of genotype 1 patients, the predominant form of hepatitis C in Americans. The inability to cure half of patients has prompted investigation of the HCV life cycle for therapeutic targets. Preliminary findings reveal that host lipids play an important role in HCV replication and may be a target for therapy.
The specific aims of this proposal are to elucidate the relationship between HCV infection and host serum lipids and evaluate whether lipid lowering therapy can improve virologic response (VR) rates. Our long-term goal is to define HCV-lipid interactions, develop novel methods for predicting SVR and develop new therapies. Understanding the HCV lifecycle and improving CHC treatment will fulfill our institutional mission.
Specific Aims : 1. Demonstrate our hypothesis that CHC infection results in lower serum lipid levels compared to uninfected controls. We will perform a cross sectional study to examine the relationship between HCV infection and serum lipid levels using both the National Health and Nutrition Examination Survey (NHANES) database as well as a pre-existing MGH cohort of patients with CHC infection. 2. Demonstrate that lipid levels are predictive of VR in patients with both acute and chronic hepatitis C infection and to analyze the impact of HCV treatment on lipid homeostasis. Using an existing acute HCV cohort we will evaluate how serum lipid levels change during infection. In addition, we hypothesize that low serum lipid levels correlate with increased rates of SVR. We will retrospectively and prospectively evaluate two separate cohorts of patients treated for CHC to determine whether serum lipid levels predict SVR. 3. Demonstrate that the use of fluvastatin in combination with PEGIFN monotherapy in CHC patients with end stage renal disease (ESRD) will improve VR rate when compared to monotherapy alone. Fluvastatin has been shown to have in vitro anti-HCV activity and act synergistically with interferon. To test fluvastatin's in vivo anti-HCV action, we will perform a clinical trial of fluvastatin with PEGIFN in ESRD patients.
| Corey, K E; Mendez-Navarro, J; Barlow, L L et al. (2011) Acute hepatitis C infection lowers serum lipid levels. J Viral Hepat 18:e366-71 |
