The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance

Ono, Suzane Kioko; Kato, Naoya; Shiratori, Yasushi; Kato, Jyoji; Goto, Tadashi; Schinazi, Raymond F.; Carrilho, Flair José; Omata, Masao

doi:10.1172/jci11100

Cited by 263 publications

(269 citation statements)

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“…Serum HBV DNA levels tend to be low initially because most antiviral-resistant HBV mutants have decreased replication fitness compared to wild-type HBV. 11,12 However, compensatory mutations that can restore replication fitness frequently accumulate during continued treatment leading to viral rebound -progressive increase in serum HBV DNA level that may exceed pretreatment value. 10 (iii) Biochemical Breakthrough.…”

Section: (A) Clinical Classification Of Antiviral Resistancementioning

confidence: 99%

“…The most common compensatory mutation associated with lamivudine resistance, rtL180M (leucine to methionine substitution) restores replication fitness of HBV polymerase that harbors the rtM204V/I mutation. 12 While no true competitive replication fitness assay has been developed, the current in vitro assays can determine relative replication yield phenotype to compare HBV DNA encoding specific mutations to the reference, consensus, or wild-type genetic framework. 15,16 For example, HBV replication competent clones encoding the rtV173L (valine to leucine substitution) ϩ rtL180M ϩ rtM204V were demonstrated to have an increased replication yield phenotype but no change in sensitivity to lamivudine relative to HBV clones encoding rtL180M ϩ rtM204V.…”

Section: Definition Of Genotypic Antiviral Resistancementioning

confidence: 99%

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Antiviral drug-resistant HBV: Standardization of nomenclature and assays and recommendations for management

et al. 2007

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Section: (A) Clinical Classification Of Antiviral Resistancementioning

confidence: 99%

Section: Definition Of Genotypic Antiviral Resistancementioning

confidence: 99%

Antiviral drug-resistant HBV: Standardization of nomenclature and assays and recommendations for management

et al. 2007

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“…Although efficacious and well tolerated, lamivudine therapy is associated with a high rate of viral resistance [6][7][8][9] that may reach up to 70% after 4 years of treatment [6,10,11]. While some studies have suggested that continuing lamivudine in the presence of resistance may promote HBeAg seroconversion and maintain lower alanine aminotransferase (ALT) and HBV DNA levels than were present at baseline [11][12][13], accumulated evidence now shows that there is no benefit to continuing lamivudine in this population.…”

Section: Introductionmentioning

confidence: 99%

Entecavir for the treatment of lamivudine-refractory chronic hepatitis B patients in China

Yao

Zhou

et al. 2007

Hepatol Int

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Purpose This randomized, double-blind, placebo-controlled study was undertaken to evaluate the efficacy and safety of entecavir in Chinese patients with lamivudinerefractory chronic hepatitis B.Methods One hundred forty-five lamivudine-refractory patients with chronic hepatitis B were randomized to double-blind treatment with oral entecavir 1 mg (n = 116) or placebo (n = 29) daily for 12 weeks, followed by 36 weeks of open-label entecavir treatment. The primary efficacy endpoint was the mean change from baseline in serum hepatitis B virus (HBV) DNA by polymerase chain reaction (PCR) assay at week 12.Results At week 12, the mean change from baseline in serum HBV DNA by PCR assay was -4.30 log 10 copies/ml for patients on entecavir compared to -0.15 log 10 copies/ ml for patients on placebo (P < .0001). Among patients with baseline serum alanine aminotransferase (ALT) >1 · upper limit of normal (ULN), a higher proportion of entecavir than placebo patients (68% vs. 6%, respectively) achieved ALT normalization by week 12 (P < .0001). After 48 weeks of entecavir treatment, the mean change in HBV DNA by PCR assay was -5.08 log 10 copies/ml, and 85% of patients with baseline ALT >1 · ULN had achieved ALT normalization. The safety profile of entecavir was similar to that of placebo during the first 12 weeks of blinded dosing. Entecavir was also well tolerated during 36 weeks of open-label treatment. Conclusions Lamivudine-refractory chronic hepatitis B patients treated with entecavir demonstrated marked HBV DNA reduction and normalization of ALT in most cases. Entecavir treatment for 48 weeks was well tolerated.

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“…Entecavir is also effective against lamivudine-resistant HBV, though the EC 50 values of entecavir for five lamivudine-resistant mutant viruses tested by Ono et al [23] are 2-778 times higher than those for wild-type HBV. A phase III, double-blind control trial in 286 lamivudinerefractory, HBeAg-positive patients showed that switching to entecavir (141 patients) with a 1 mg daily dose (twice the dose for nucleoside-naive patients) provided better histologic improvement, HBV DNA reduction, and ALT normalization than continuing lamivudine at week 48 [24].…”

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confidence: 94%

The saga of entecavir

Lai

Yuen

2009

Hepatol Int

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And the communication I have got to make is, that (it) has great expectations. -Charles Dickens Great ExpectationsChronic infection by hepatitis B virus (HBV) affects approximately 400 million people worldwide and is estimated to cause 1 million deaths annually [1]. The treatment of chronic hepatitis B has been radically altered in the past decade as a result of two developments. First, there are important new findings concerning its natural history. Second, the oral nucleoside/nucleotide analogues are now firmly established as an excellent alternative mode of therapy.Studies of the natural history of chronic hepatitis B suggest that other than the traditional endpoint of hepatitis B e antigen (HBeAg) seroconversion, sustained suppression of HBV DNA to very low levels, preferably to below the detection limit of sensitive polymerase chain reaction (PCR) assays, is an even more important endpoint of treatment [2][3][4][5]. The availability of nucleoside/nucleotide analogues makes the ideal of sustained viral suppression a reality. The rate of HBeAg seroconversion is slower with nucleoside/nucleotide analogues than with interferon therapy because they lack the immunomodulatory effects of interferon. Unlike interferon, nucleoside/nucleotide analogues can be given orally, and, except for mild and reversible nephrotoxicity (approximately 3% in 5 years) with adefovir [6], are almost without side effects. Even a relatively short period of treatment with lamivudine has been shown to decrease the risk for the development of cirrhosis complications and hepatocellular carcinoma (HCC) both in patients with established cirrhosis and in patients with precirrhotic disease [7,8]. The problem with long-term nucleoside/nucleotide analogue therapy is of course the potential for the development of resistant mutants.One of the most promising nucleoside analogues for long-term viral suppression with low rate of development of resistance is entecavir. Entecavir is a deoxyguanosine analogue that is rapidly phosphorylated intracellularly into its active 5 0 -triphosphate form. It inhibits HBV replication at three important steps: protein-linked priming of the HBV polymerase, synthesis of the first negative strand of the HBV DNA by reverse transcription, and synthesis of the second positive strand [9]. Its efficient phosphorylation and its triple action in the inhibition of HBV replication may explain its potency in the suppression of HBV DNA in small doses of 0.5-1 mg licensed for use. It has been approved for use in the treatment of chronic hepatitis B in the United States in 2005, and since then in the European Union, China, and several other countries worldwide.In the current issue of the journal, Shindo et al.[10] report a randomized, double-blind phase II study of the antiviral activity of once-daily oral dose of entecavir 0.01, 0.1, or 0.5 mg, or lamivudine 100 mg, over 24 weeks in 137 nucleoside-naive Japanese adults. This study confirmed the results of an international study of 169 patients including Asians and Westerners publish...

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The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance

Cited by 263 publications

References 50 publications

Antiviral drug-resistant HBV: Standardization of nomenclature and assays and recommendations for management

Antiviral drug-resistant HBV: Standardization of nomenclature and assays and recommendations for management

Entecavir for the treatment of lamivudine-refractory chronic hepatitis B patients in China

The saga of entecavir

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