Clinical Emergence of Entecavir-Resistant Hepatitis B Virus Requires Additional Substitutions in Virus Already Resistant to Lamivudine
Daniel J. Tenney,Steven Levine,Ronald E. Rose,Ann W. Walsh,S P Weinheimer,Linda Discotto,Mary Jane Plym,Kevin A. Pokornowski,Cheng-Fang Yu,Peter W Angus,A Ayres,Angeline Bartholomeusz,William Sievert,Geoff Thompson,Nadia Warner,Stephen Locarnini,Richard J. Colonno +16 more
TLDR
Infrequent ETV resistance can emerge during prolonged therapy, with selection of additional RT substitutions within a 3TCr HBV background, leading to reduced ETV susceptibility and treatment failure.Abstract:
Entecavir (ETV) exhibits potent antiviral activity in patients chronically infected with wild-type or lamivudine (3TC)-resistant (3TC r ) hepatitis B virus (HBV). Among the patients treated in phase II ETV clinical trials, two patients for whom previous therapies had failed exhibited virologic breakthrough while on ETV. Isolates from these patients (arbitrarily designated patients A and B) were analyzed genotypically for emergent substitutions in HBV reverse transcriptase (RT) and phenotypically for reduced susceptibility in cultures and in HBV polymerase assays. After 54 weeks of 3TC therapy, patient A (AI463901-A) received 0.5 mg of ETV for 52 weeks followed by a combination of ETV and 100 mg of 3TC for 89 weeks. Viral rebound occurred at 133 weeks after ETV was started. The 3TC r RT substitutions rtV173L, rtL180M, and rtM204V were present at study entry, and the additional substitutions rtI169T and rtM250V emerged during ETV-3TC combination treatment. Reduced ETV susceptibility in vitro required the rtM250V substitution in addition to the 3TC r substitutions. For liver transplant patient B (AI463015-B), previous famciclovir, ganciclovir, foscarnet, and 3TC therapies had failed, and RT changes rtS78S/T, rtV173L, rtL180M, rtT184S, and rtM204V were present at study entry. Viral rebound occurred after 76 weeks of therapy with ETV at 1.0 mg, with the emergence of rtT184G, rtI169T, and rtS202I substitutions within the preexisting 3TC r background. Reduced susceptibility in vitro was highest when both the rtT184G and the rtS202I changes were combined with the 3TC r substitutions. In summary, infrequent ETV resistance can emerge during prolonged therapy, with selection of additional RT substitutions within a 3TC r HBV background, leading to reduced ETV susceptibility and treatment failure.read more
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Chronic hepatitis B: Update 2009
Anna S.F. Lok,Brian J. McMahon +1 more
TL;DR: The 2009 update of the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines for Management of Chronic Hepatitis B is now posted online at www.aasld.org, and the recommendation for first-line oral antiviral medications has been changed to tenofovir or entecavir, and adefovir has been moved to second-line Oral antiviral medication.
Journal ArticleDOI
A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B
Ting-Tsung Chang,Robert G. Gish,Robert A. de Man,Adrián Gadano,Jose D. Sollano,You Chen Chao,Anna S. Lok,Kwang Hyub Han,Zachary Goodman,J. Zhu,Anne Cross,Deborah DeHertogh,R B Wilber,Richard J. Colonno,David Apelian +14 more
TL;DR: Among patients with HBeAg-positive chronic hepatitis B, the rates of histologic, virologic, and biochemical improvement are significantly higher with entecavir than with lamivudine, and the safety profile of the two agents is similar.
Journal ArticleDOI
Entecavir versus Lamivudine for Patients with HBeAg-Negative Chronic Hepatitis B
Ching-Lung Lai,Daniel Shouval,Anna S. Lok,Ting-Tsung Chang,Hugo Cheinquer,Zachary Goodman,Deborah DeHertogh,R B Wilber,Richard C. Zink,Anne Cross,Richard J. Colonno,Lori Fernandes +11 more
TL;DR: Among patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue, the rates of histologic improvement, virologic response, and normalization of alanine aminotransferase levels were significantly higher at 48 weeks with entecavir than with lamivudine.
Journal ArticleDOI
Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy.
Daniel J. Tenney,Ronald E. Rose,Carl J. Baldick,Kevin A. Pokornowski,Betsy J. Eggers,Jie Fang,Michael Wichroski,Dong Xu,Joanna Yang,R B Wilber,Richard J. Colonno +10 more
TL;DR: Long‐term monitoring showed low rates of resistance in nucleoside‐naïve patients during 5 years of ETV therapy, corresponding with potent viral suppression and a high genetic barrier to resistance, support ETV as a primary therapy that enables prolonged treatment with potentiral suppression and minimal resistance.
Journal ArticleDOI
Hepatitis B virus resistance to nucleos(t)ide analogues.
TL;DR: It is important to continue basic research into HBV replication and pathogenic mechanisms to identify new therapeutic targets, develop novel antiviral agents, design combination therapies that prevent drug resistance, and decrease the incidence of complications of CHB.
References
More filters
Journal ArticleDOI
Hepatitis B virus infection [1] (multiple letters)
Journal ArticleDOI
Hepatitis B virus infection.
TL;DR: This review addresses many aspects of HBV infection, including the role of the immune system in determining the outcome of clinical infection, recent developments in molecular studies of the virus, and new treatments capable of eradicating chronic infection.
Journal ArticleDOI
Viral hepatitis B
TL;DR: Current available monotherapies-interferon, lamivudine, and adefovir dipivoxil-very rarely eradicate the virus, but greatly reduce its replication, necroinflammatory histological activity, and progression of fibrosis.
Journal ArticleDOI
Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis.
TL;DR: A meta-analysis of randomized, controlled trials was conducted to examine the efficacy of interferon treatment in patients with chronic HBV infection as determined by the loss of HBsAg, HBeAg, and HBV DNA.
Journal ArticleDOI
Identification and characterization of mutations in hepatitis B virus resistant to lamivudine
Marchelle I. Allen,Manon Deslauriers,C W Andrews,Graham Tipples,Kathie-Anne Walters,David L.J. Tyrrell,Nathaniel A. Brown,Lynn D. Condreay +7 more
TL;DR: A DNA sequence database that includes a 500–base pair region of the HBV polymerase gene from 20 patients with clinical manifestations of lamivudine resistance is reported, revealing two patterns of amino acid substitutions in the tyrosine, methionine, as partate, aspartate (YMDD) nucleotide‐binding locus of theHBV polymerases.