Identification and characterization of mutations in hepatitis B virus resistant to lamivudine

Abstract

Chronic hepatitis B virus (HBV) infection can result in severe liver disease with eventual progression to cirrhosis and hepatocellular carcinoma. 1 Roughly 5% of the world' s population (over 350 million persons) are chronically infected with HBV. 2 Although interferon alfa remains the only licensed drug for the treatment of chronic HBV infection, the overall response rate to this immunotherapy is less than 40%. 3 Therefore, other effective antiviral therapies for patients with HBV infection are needed.Lamivudine [(-)2Ј-deoxy-3Ј-thiacytidine, 3TC] is a member of a class of antiviral nucleoside analogs that inhibit hepadnavirus replication specifically by terminating viral DNA synthesis. 4 Lamivudine is currently being evaluated in Phase III clinical trials for the treatment of both patients chronically infected with HBV and patients with HBV reinfection of an allograft after orthotopic liver transplantation.In Phase II trials, 5-7 lamivudine treatment was shown to rapidly reduce serum HBV DNA to levels below the detection limit of standard commercial assays, and to be well tolerated with no major toxicities. However, as with other antivirals, 7-11 resistance to lamivudine therapy can emerge in some patients. Recent investigations have reported the development of lamivudine-resistant HBV in six orthotopic liver transplantation patients on therapy. [12][13][14] In each patient, sequence analysis of serum HBV DNA revealed the presence of specific mutations in the tyrosine, methionine, aspartate, aspartate (YMDD) amino acid motif of the viral polymerase. This YMDD motif is a conserved domain of all reverse transcriptases (RT) and is required for polymerization activity. However, various other amino acid changes in the polymerase were also described in these reports.To determine the significance of various mutations in the development of lamivudine-resistant HBV, a more comprehensive study was undertaken. In this study, DNA sequences were determined from HBV isolates from 20 patients experiencing breakthrough HBV reactivation while on lamivudine therapy. From this larger series of 20 clinical HBV isolates, the database of lamivudine-resistant HBV sequences was expanded to confirm viral DNA mutations associated with lamivudine resistance in vivo. To explore the biological significance of the key observed mutations, putative resis-

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

“…The identified mutations, rtV173L/L180M/M204V, are known to be LAM resistant 19. Among these, rtL180M/M204V have been reported previously to confer LAM resistance associated with a decline in replication efficiency 20. The rtV173L mutation did not affect susceptibility to LAM but instead enhanced viral replication 19.…”

Prevention of hepatitis B reactivation with lamivudine in hepatitis B virus carriers with hematologic malignancies treated with chemotherapy—A prospective case series

“…Nevertheless, long-term administration of lamivudine is associated with rise of resistant HBV mutants in 40% of the patients after 1 year and even more frequently in more prolonged treatment [15,34]. This is caused by mutations in the YMMD (tyrosine, methionine, aspartate, aspartate) motif of the active site of the virus DNA polymerase [43]. The clinical significance of this phenomenon, in view of the fact that these strains are less replicationcompetent in vitro than wild-type HBV, remains to be elucidated [34].…”

Intramuscular hepatitis B immune globulin combined with lamivudine for prophylaxis against hepatitis B recurrence after liver transplantation

“…21,22 However, high rates of lamivudine-resistant escape mutants have been reported in transplant recipients, therefore limiting its effectiveness as a single prophylactic agent for long-term use. [23][24][25][26][27] The characteristic mutation involves a base-pair substitution in the highly conserved YMDD motif in subdomain C of the DNA polymerase, where methionine 552 is replaced by either isoleucine (YIDD mutant) or valine (YVDD mutant). The same mutations have been found in the HIV reverse-transcriptase gene for HIV-infected patients receiving lamivudine treatment.…”