A severe clinical course of hepatitis B virus (HBV) infection in several liver transplant recipients after the emergence of lamivudine resistance has been observed. This was found to be associated with high viral load in the blood.
Researchers from Germany and Australia characterized the molecular mechanisms underlying drug-dependent enhanced replication of particular lamivudine-resistant HBV mutants selected in liver transplant recipients. These events were associated with sudden onset of liver failure.
The team found that the clinical course of infection was characterized by a sudden rise in serum bilirubin, prothrombin time, and transaminase.
HBV sequence analysis of these patients revealed both mutations in the ‘a-determinant' of the envelope and the YMDD (tyrosine, methionine, aspartate, aspartate) motif (domain C) of the polymerase protein.
| Mutations in the YMDD motif of the polymerase protein conferred resistance to lamivudine.
| Gastroenterology |
Transfection experiments with replication competent vectors indicated that the ‘a-determinant' changes were not associated with resistance. However, mutations in the YMDD motif conferred resistance to lamivudine.
More importantly, combinations of mutations in the ‘a-determinant' and the YMDD motif in patients with a severe hepatitis were not only resistant to lamivudine treatment, but showed enhanced replication in vitro in the presence of lamivudine.
This observation was confirmed in separate laboratories.
Dr C.-Thomas Bock, of the Medical School of Hannover, Germany, said on behalf of fellow colleagues, "Severe and fatal hepatitis B infection can occur during lamivudine therapy. This may be associated with certain HBV mutants selected during sequential nucleoside and HBIg treatment.
"The lamivudine-enhanced replication shown by these mutants suggests that continuation of therapy with lamivudine could be deleterious in some patients," it was concluded.