Variants in IL28B in liver recipients and donors correlate with response to peg-interferon and ribavirin therapy for recurrent hepatitis C.
OBJECTIVE
Patients with hepatitis C virus (HCV)-related liver disease frequently undergo orthotopic liver transplantation, but recurrent hepatitis C is still a major cause of morbidity. Patients are treated with peg-interferon and ribavirin (PEG-IFN/RBV), which has substantial side effects and is costly. We investigated genetic factors of host, liver donor, and virus that might predict sensitivity of patients with recurrent hepatitis C to PEG-IFN/RBV.


METHODS
Liver samples were analyzed from 67 HCV-infected recipients and 41 liver donors. Liver recipient and donor DNA samples were screened for single nucleotide polymorphisms near the IL28B genes (rs12980275 and rs8099917) that affect sensitivity to PEG-IFN/RBV. HCV RNA was isolated from patients and analyzed for mutations in the core, the IFN sensitivity-determining region, and IFN/RBV resistance-determining regions in nonstructural protein 5A.


RESULTS
In liver recipients and donors, the IL28B single nucleotide polymorphism rs8099917 was significantly associated with a sustained viral response (SVR; P = 0.003 and P = .025, respectively). Intrahepatic expression of IL28 messenger RNA was significantly lower in recipients and donors that carried the minor alleles (T/G or T/T) in rs8099917 (P = .010 and .009, respectively). Genetic analyses of IL28B in patients and donors and of the core and nonstructural protein 5A regions encoded by HCV RNA predicted an SVR with 83% sensitivity and 82% specificity; this was more effective than analysis of any single genetic feature.


CONCLUSIONS
In patients with recurrent HCV infection after orthotopic liver transplantation, combination analyses of single nucleotide polymorphisms of IL28B in recipient and donor tissues and mutations in HCV RNA allow prediction of SVR to PEG-IFN/RBV therapy.
Fukuhara
Takasuke
T
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Taketomi
Akinobu
A
Motomura
Takashi
T
Okano
Shinji
S
Ninomiya
Akinori
A
Abe
Takayuki
T
Uchiyama
Hideaki
H
Soejima
Yuji
Y
Shirabe
Ken
K
Matsuura
Yoshiharu
Y
Maehara
Yoshihiko
Y
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D004337:Drug Carriers; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics*; D012367:RNA, Viral / Q000032:analysis; D011994:Recombinant Proteins; D012008:Recurrence; D012254:Ribavirin / Q000627:therapeutic use*; D014019:Tissue Donors; D016896:Treatment Outcome; D000095022:Interferon Lambda
D000998:Antiviral Agents; D004337:Drug Carriers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D012333:RNA, Messenger; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C100416:peginterferon alfa-2a