Hepatitis C Virus Infection and Its Clearance Alter Circulating Lipids: Implications for Long-Term Follow-Up

Over four million Americans are infected with chronic hepatitis C. Current best therapy consists of pegylated interferon and ribavirin which results in sustained virologic response (SVR) in only half of patients.(1) Ongoing research into the HCV lifecycle has demonstrated a strong interaction between the virus and intracellular lipids, suggesting that host lipids play an important role in viral replication. Several important lipid-HCV interactions have recently been elucidated. First, host serum lipids play a role in hepatitis C virion circulation and hepatocyte entry. A proportion of circulating hepatitis C viral particles are complexed with host triacylglycerol-rich lipoproteins, known as lipo-viroparticles.(2, 3) Lipo-viroparticles use LDL receptors on hepatocytes as points of entry and are associated with high rates of infectivity.(3–5) Once hepatitis C virions have entered hepatocytes their replication is again dependent on host lipid interactions. New hepatitis C virion formation requires viral binding to either a endoplasmic reticulum phospholipid membrane or to an endoplasmic reticulum-associated membranous web.(6) Additionally, HCV replication requires geranylgeranylation of the host protein FBL2, a process dependent on the host cholesterol synthesis pathway.(7, 8) Geranylgeranylation requires the production of geranylgeranyl, a non-sterol isoprenoid produced via the mevalonate cholesterol synthesis pathway. Inhibition of this pathway with HMG-CoA reductase inhibitors (HMGR inhibitors) leads to dissolution of the HCV replication complex in vitro while the addition of geranylgeraniol to HMGR inhibitor treated cells rescues HCV replication.(7) Finally, there is evidence that HCV secretion is linked to secretion of apolipoprotein B with silencing of apolipoprotein B RNA significantly inhibiting HCV secretion.(4, 9) The importance of HCV-host lipid interactions has also been demonstrated clinically. Lower serum cholesterol levels have been noted in patients with chronic hepatitis C when compared to those with chronic hepatitis B.(10) A retrospective evaluation of a predominantly genotype 4 Egyptian cohort found that patients with chronic hepatitis C infection had significantly lower levels of LDL, cholesterol and triglycerides when compared to those who had never been infected with hepatitis C.(11) We hypothesize that HCV, by interrupting cholesterol synthesis and using host lipids for replication, decreases circulating lipids and while clearance of the virus results in rebound of lipid levels. To explore these hypotheses, we evaluated the effect of hepatitis C infection on lipid homeostasis in U.S. subjects without and with chronic hepatitis C; we also evaluated the impact of viral clearance in subjects with chronic hepatitis C who received antiviral therapy. Additionally, and uniquely to our study, we sought to evaluate whether any post-HCV treatment lipid rebounds reached levels that are associated with increased risk of developing coronary heart disease and warrant treatment per the National Cholesterol Education Program Guidelines (NCEP)