Evolution of hepatitis B virus sequence from a liver transplant recipient with rapid breakthrough despite hepatitis B immune globulin prophylaxis and lamivudine therapy.
Recurrent hepatitis B virus (HBV) infection after liver transplantation can be prevented by prophylactic hepatitis B immune globulin (HBIG) and lamivudine therapy. However, reinfection may still occur due to the emergence of immune escape mutants and mutants of the YMDD motif. The full spectrum of mutations within the HBV genome during recurrent HBV infection remains to be documented. In this study, serial HBV isolates were characterized from a patient with lamivudine resistance prior to liver transplantation who developed recurrent HBV infection within 2 months of transplantation despite a high dose of HBIG and lamivudine therapy. Sequence analysis of full-length viral genome before transplantation revealed many point mutations as compared with a wild-type genotype C sequence, including the T1753G/A1762T/G1764A triple mutation in the basal core promoter and the G1896A nonsense mutation in the precore region. After transplantation and therapy, several point mutations in the HBV genome emerged or became dominant. These mutations caused L426I/L526M/M550I triple mutation (equivalent to L428I/L528M/M552I in previous reports) in the polymerase, and D144E mutation in the "a" determinant of HBsAg. Transfection experiments revealed that the D144E mutation reduced HBsAg affinity to anti-HBs, confirming its active role for immune escape. Our study suggests that mutations in the HBsAg (D144E) and the polymerase (L426I/L526M/M550I) of HBV genome may be responsible for viral breakthrough despite HBIG prophylaxis and lamivudine therapy.
Kim
Kyun-Hwan
KH
Institute of Gastroenterology, College of Medicine, Department of Internal Medicine, Yonsei University College of Medicine, CPO Box 8044, Seoul, Korea.
Lee
Kwang-Hee
KH
Chang
Hye-Young
HY
Ahn
Sang Hoon
SH
Tong
Shuping
S
Yoon
Young Joon
YJ
Seong
Baik L
BL
Kim
Soon Il
SI
Han
Kwang-Hyub
KH
D001483:Base Sequence; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D016679:Genome, Viral; D006509:Hepatitis B / Q000188:drug therapy / Q000821:virology*; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D007116:Immunization, Passive; D007136:Immunoglobulins / Q000008:administration & dosage; D019259:Lamivudine / Q000008:administration & dosage / Q000494:pharmacology; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D017422:Sequence Analysis, DNA
D007136:Immunoglobulins; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; C045213:hepatitis B hyperimmune globulin