Entecavir for Treatment of Lamivudine-Refractory, HBeAg-Positive Chronic Hepatitis B

Sherman, Morris; Yurdaydın, Cihan; Sollano, José D.; Silva, Marcelo; Liaw, Yun–Fan; Cianciara, J; Boroń-Kaczmarska, Anna; Martin, Paul; Goodman, Zachary; Colonno, Richard J.; Cross, Anne; Denisky, Gail; Kreter, Bruce; Hindes, R.

doi:10.1053/j.gastro.2006.04.007

Cited by 396 publications

(354 citation statements)

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“…In previously published results of a multinational clinical trial, entecavir demonstrated potent inhibition of viral replication in HBeAg-positive, lamivudine-refractory patients infected with a variety of HBV genotypes (A-D) [28,30]. In that trial, after 48 weeks of treatment with entecavir 1 mg daily, the mean change from baseline in HBV DNA was -5.11 log 10 copies/mL, and 19% of patients achieved HBV DNA of [300 copies/mL.…”

Section: Discussionmentioning

confidence: 97%

“…Entecavir is a guanosine nucleoside analog that has demonstrated efficacy against nucleoside-naive and lamivudine-refractory CHB [26][27][28][29]. In global clinical studies, patients with lamivudine-refractory CHB treated with entecavir 1 mg daily for 48 weeks experienced reduction in HBV DNA levels of more than 5 log copies/mL and improvements in hepatic necroinflammation and fibrosis [28,29].…”

Section: Introductionmentioning

confidence: 99%

“…In global clinical studies, patients with lamivudine-refractory CHB treated with entecavir 1 mg daily for 48 weeks experienced reduction in HBV DNA levels of more than 5 log copies/mL and improvements in hepatic necroinflammation and fibrosis [28,29]. Treatment for up to 96 weeks resulted in continued improvement of virologic, biochemical, and serologic end points [30].…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and resistance of entecavir following 3 years of treatment of Japanese patients with lamivudine-refractory chronic hepatitis B

et al. 2010

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Purpose Lamivudine treatment of chronic hepatitis B (CHB) is associated with frequent resistance and loss of clinical benefit. We present outcomes of lamivudinerefractory Japanese patients treated with entecavir for 3 years. Methods Eighty-two patients refractory to lamivudine therapy received entecavir 0.5 or 1 mg daily for 52 weeks in phase II study ETV-052, directly entered rollover study ETV-060, and received entecavir 1 mg daily. Responses were evaluated among patients with available samples.Results After 96 weeks in ETV-060 (148 weeks total entecavir treatment time), 55% (36/65) of patients had hepatitis B virus (HBV) DNA of [400 copies/mL, 85% (52/61) had alanine aminotransferase (ALT) of C1 9 upper limit of normal (ULN), and 14.6% (7/48) achieved HBe seroconversion. A subset of 42 patients received entecavir 1 mg from phase II baseline through 148 weeks: 54% (19/35) had HBV DNA of [400 copies/mL, 84% (27/32) had ALT of C1 9 ULN, and 15% (4/27) achieved HBe seroconversion. Sixteen patients in the 1-mg subset had baseline and week 148 evaluable biopsy pairs: 81% (13/16) showed histologic improvement and 38% (6/16) showed 123Hepatol Int (2010) 4:414-422 DOI 10.1007/s12072-009-9162-x improvement in fibrosis. Genotypic resistance to entecavir emerged in 31 patients for a 3-year cumulative resistance probability of 35.9%. Entecavir was generally well tolerated during ETV-060, with no on-treatment ALT flares. Conclusions Long-term entecavir treatment of lamivudine-refractory CHB resulted in virologic suppression, ALT normalization, and improvements in liver histology. Resistance was consistent with that observed in worldwide studies.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy and resistance of entecavir following 3 years of treatment of Japanese patients with lamivudine-refractory chronic hepatitis B

et al. 2010

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“…Such high‐level ETV resistance attributable to these mutations may be peculiar to the ETV refractory patient‐derived clone, and other amino acid residues in the RT region or other regions may be associated with this ETV resistance. These data suggest that the switch to or add‐on of ETV to LAM treatment‐failure patients described in reports was not recommended 22, 23…”

Section: Discussionmentioning

confidence: 95%

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

Yamada

Sugiyama

Nitta

et al. 2017

Hepatology Communications

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The emergence of resistance mutations in the reverse transcriptase gene of hepatitis B virus (HBV) is associated with treatment failure. Entecavir (ETV) is one of the most potent anti‐HBV reagents; it has a very low resistance rate and is used as the first‐line treatment for chronic hepatitis B. In this study, we isolated HBVs in 4 ETV‐refractory patients (2 with viral breakthrough, 1 with partial virological response, and 1 with flare‐up) and assessed ETV resistance using replication‐competent 1.38‐fold HBV genome‐length molecular clones. The full genome sequences of infected HBVs in ETV‐refractory patients were determined. The HBV molecular clones were generated with the patient‐derived sequences. After transfection of these molecular clones into HepG2 cells, viral replications and ETV susceptibilities were evaluated by measuring the amount of intracellular core‐particle‐associated HBV DNA using Southern blotting and real‐time polymerase chain reaction. Among these cases, ETV‐resistant variants were detected in 2 patients with viral breakthrough and responsible amino acid mutations in reverse transcriptase were successfully identified in these variants. No ETV‐resistant mutation was detected in the other cases. The identified ETV‐resistant mutations did not confer resistance to tenofovir disoproxil fumarate. Conclusion: The HBV replication model with patient‐derived sequences is useful for assessing replication efficiency, susceptibility to anti‐HBV reagents, and responsible resistance mutations and can aid in choosing the appropriate treatment strategy for treatment‐failure cases of chronic hepatitis B. (Hepatology Communications 2017;1:110‐121)

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“…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]. However, the reduction of HBV DNA was less than in nucleoside-naive patients; only 19% of lamivudine-refractory patients having HBV DNA of \300 copies/mL (*60 IU/mL) compared with the 67% of nucleoside-naive patients [15].…”

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confidence: 99%

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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Entecavir for Treatment of Lamivudine-Refractory, HBeAg-Positive Chronic Hepatitis B

Cited by 396 publications

References 37 publications

Efficacy and resistance of entecavir following 3 years of treatment of Japanese patients with lamivudine-refractory chronic hepatitis B

Efficacy and resistance of entecavir following 3 years of treatment of Japanese patients with lamivudine-refractory chronic hepatitis B

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

The saga of entecavir

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