Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin.
OBJECTIVE
Hepatitis C virus (HCV) modulates host lipid metabolism for its replication and lifecycle. Our aims were to assess changes in the serum lipid and distal (post-squalene) cholesterol biosynthesis metabolite profile of HCV genotypes (GT) 2 and 3 patients treated with sofosbuvir+ribavirin.


METHODS
Serum samples [baseline, treatment week 12, 4weeks post-treatment] were analyzed for apolipoproteins B and E (apoB/E), total cholesterol, HDL, LDL, and 11 post-squalene sterol metabolites using a GC/MS platform.


RESULTS
We selected 127 patients (GT2 n=50, GT3 n=77), 50% cirrhotic patients, and 42% who experienced a virological relapse. At baseline, GT3 patients had lower level of serum lipids, apoB/E, 7-dehydrocholesterol, desmosterol, lathosterol, compared to GT2 (p<0.006). Baseline lathosterol was lower in relapsers with cirrhosis compared to cirrhotic patients with SVR (p=0.003). From baseline to treatment week 12, serum lipids, apoB/E, and key sterol pathway metabolites (7-dehydrocholesterol, desmosterol, lathosterol, lanosterol) increased in GT3. In contrast, in GT2 patients, apoB/E and dihydrolanosterol decreased with viral suppression (p<0.025). At follow-up week 4, cirrhotic SVR patients showed substantially greater increases in apoB and total sterols compared to cirrhotic relapsers regardless of HCV genotype. After adjustment for genotype and gender, baseline lathosterol was independently associated with virologic response (p=0.04).


CONCLUSIONS
HCV GT3 is associated with reduced circulation of lipids involved in the distal cholesterol biosynthesis pathway, resulting in relative hypocholesterolemia. HCV suppression during sofosbuvir+ribavirin restores distal sterol metabolites indicating viral interference with de novo lipogenesis or selective retention by hepatocytes.
Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, United States; Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States. Electronic address: zobair.younossi@inova.org.
Zobair M
ZM
Younossi
Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States.
Maria
M
Stepanova
Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States.
Michael
M
Estep
University of Geneva, Geneva, Switzerland.
Francesco
F
Negro
University of Queensland, Brisbane, Australia.
Paul J
PJ
Clark
Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, United States; Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States.
Sharon
S
Hunt
Gilead Sciences, Foster City, CA, United States.
Qinghua
Q
Song
Gilead Sciences, Foster City, CA, United States.
Matthew
M
Paulson
Gilead Sciences, Foster City, CA, United States.
Luisa M
LM
Stamm
Gilead Sciences, Foster City, CA, United States.
Diana M
DM
Brainard
Gilead Sciences, Foster City, CA, United States.
G Mani
GM
Subramanian
Gilead Sciences, Foster City, CA, United States.
John G
JG
McHutchison
Division of Gastroenterology, Duke University Medical Center, Durham, NC, United States.
Keyur
K
Patel
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage*; D002784:Cholesterol / Q000096:biosynthesis*; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012254:Ribavirin / Q000008:administration & dosage*; D000069474:Sofosbuvir / Q000008:administration & dosage*
D000998:Antiviral Agents; D012254:Ribavirin; D002784:Cholesterol; D000069474:Sofosbuvir
HCV; Lipid metabolism; Ribavirin; Sofosbuvir