A Dose-Ranging Study of the Efficacy and Tolerability of Entecavir in Lamivudine-Refractory Chronic Hepatitis B Patients

Chang, Ting‐Tsung; Gish, Robert G.; Hadziyannis, Stephanos J.; Cianciara, J; Rizzetto, Mario; Schiff, Eugene R.; Pastore, Giuseppe; Bacon, Bruce R.; Poynard, Thierry; Joshi, Shobha; Klesczewski, K.; Thiry, Alexandra; Rose, Ronald E.; Colonno, Richard J.; Hindes, R.

doi:10.1053/j.gastro.2005.06.055

Cited by 237 publications

(178 citation statements)

References 46 publications

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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: 94%

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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Section: Discussionmentioning

confidence: 94%

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

Yamada

Sugiyama

Nitta

et al. 2017

Hepatology Communications

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“…Entecavir has been shown in clinical trials to be effective in suppressing lamivudine-resistant HBV but a higher dose (1.0 mg daily) should be used. 68 Preexisting LAM-resistant mutations increase the risk of entecavir resistance 47,62 ; therefore, entecavir is not an optimal treatment for patients with lamivudine-resistant HBV. If entecavir is used, lamivudine should be discontinued.…”

Section: Monitoring and Treatment Of Antiviralresistant Hbv (A) Monitmentioning

confidence: 99%

Antiviral drug-resistant HBV

et al. 2007

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“…In vitro studies have shown that entecavir effectively suppresses the replication of lamivudine-resistant HBV with an EC 50 of 0.026 lM [22]. The selection of the 1 mg dose of entecavir for evaluation in the current study in lamivudine-refractory patients resulted from a multinational phase II dose-ranging study in which entecavir 1 mg demonstrated superior efficacy to continued lamivudine 100 mg, and yielded the greatest viral load reduction compared with the other doses of entecavir studied (0.5 and 0.1 mg) [23]. The results of a large, multinational phase III study conducted outside China have recently been reported and demonstrate that switching lamivudine-refractory patients to entecavir results in significantly improved rates of histologic, virologic, and biochemical response [24].…”

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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A Dose-Ranging Study of the Efficacy and Tolerability of Entecavir in Lamivudine-Refractory Chronic Hepatitis B Patients

Cited by 237 publications

References 46 publications

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

Resistance mutations of hepatitis B virus in entecavir‐refractory patients

Antiviral drug-resistant HBV

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

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