A Comparison of Entecavir and Lamivudine for HBeAg-Positive Chronic Hepatitis B

Chang, Ting Tsung; Gish, Robert G.; Man, Robert De; Gadano, Adrián; Sollano, José D.; You, Chao; Lok, Anna S.; Han, Kwang Hyub; Goodman, Zachary; Zhu, Jin Liang; Cross, Anne; DeHertogh, Deborah; Wilber, Richard B.; Colonno, Richard J.; Apelian, David

doi:10.1056/nejmoa051285

Cited by 1,325 publications

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“…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].…”

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confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…The model for end-stage liver disease (MELD) score was calculated using serum creatinine, bilirubin, and INR of prothrombin time 11 according to the following formula: 9.57 Â Ln (creatinine mg/dL) þ 3.78 Â Ln (bilirubin mg/dL) þ 11.20 Â Ln INR þ 6.43. 24 Radiologic cirrhosis was defined as coarse liver echotexture with nodularity and small liver size or the presence of features of portal hypertension (e.g., ascites, splenomegaly, and varices) noted on liver imaging.…”

Section: Methodsmentioning

confidence: 99%

“…[8][9][10] Entecavir is a more potent antiviral agent than lamivudine and adefovir. [11][12][13] Most entecavir-treated patients achieve maintained viral suppression and low Abbreviations: ALT, alanine aminotransferase; anti-HBe, antibody against hepatitis B e antigen; CHB, chronic hepatitis B; CI, confidence interval; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HR, hazard ratio; INR, international normalized ratio; MELD, model for end-stage liver disease; SBP, spontaneous bacterial peritonitis.…”

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Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients With liver cirrhosis

et al. 2013

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Entecavir is a potent antiviral agent with high genetic barrier to resistance, hence it is currently recommended as first-line antiviral therapy for chronic hepatitis B (CHB). The aim of this study was to investigate the efficacy of entecavir on clinical outcomes and deaths. It was a retrospective-prospective cohort study based on two cohorts of patients. The entecavir cohort included consecutive CHB patients who had received entecavir 0.5 mg/day for at least 12 months. The historical control cohort included untreated patients recruited since 1997 who underwent routine clinical care. The primary outcome was the 5-year cumulative probability of hepatic events, defined as any cirrhotic complications, hepatocellular carcinoma (HCC), and/or liver-related mortality. A total of 1,446 entecavir-treated patients (72% men; age, 51 6 12 years; follow-up, 36 6 13 months) and 424 treatment-naïve patients (65% men; age, 41 6 13 years; follow-up, 114 6 31 months) were studied. Overall, there was no difference in hepatic events between the entecavir and control cohorts. Among patients with liver cirrhosis (482 entecavir-treated, 69 treatment-naïve), entecavir-treated patients had reduced risks of all clinical outcomes when compared with treatment-naïve patients with cirrhosis after adjusted for model for end-stage liver disease score: hepatic events (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.34-0.78; P 5 0.002), HCC (HR, 0.55; 95% CI, 0.31-0.99; P 5 0.049), liver-related mortality (HR, 0.26; 95% CI, 0.13-0.55; P < 0.001), and all-cause mortality (HR, 0.34; 95% CI, 0.18-0.62; P < 0.001). Entecavir-treated patients with cirrhosis who failed to achieve undetectable hepatitis B virus DNA (105/482 [22%]) had comparable risk of hepatic events as the untreated patients. Conclusion: Entecavir therapy reduces the risks of hepatic events, HCC, liver-related and all-cause mortality of CHB patients with liver cirrhosis in 5 years, particularly among those who had maintained viral suppression. (HEPATOLOGY 2013;58:1537-1547 C hronic hepatitis B (CHB) is the leading cause of liver cirrhosis and hepatic events, including various cirrhotic complications and hepatocellular carcinoma (HCC) in Asia. 1 A high level of hepatitis B virus (HBV) DNA has been consistently shown to be an independent risk factor for the development of cirrhosis and HCC. 2,3 Antiviral therapy is effective in suppressing HBV DNA and reducing the risk of hepatic events and HCC. 4,5 Lamivudine, the first generation oral nucleoside analogue was shown to reduce the incidence of hepatic events in patients with advanced fibrosis or compensated cirrhosis by 50%. 6 However, the clinical benefit may be negated by lamivudine resistance and virologic relapse after cessation of treatment. 6,7 Therefore, lamivudine is no longer the firstline antiviral therapy for CHB. Instead, nucleos(t)ide analogues with high genetic barrier to resistancenamely, entecavir and tenofovir disoproxil fumarateare recommended by international guidelines. [8][9][10] Entecavir is a more potent ...

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“…Two phase III pivotal trials of entecavir 0.5 mg daily versus lamivudine 100 mg daily in 715 HBeAg-positive patients and 648 HBeAg-negative patients have shown that entecavir is superior to lamivudine at week 48 of treatment [15,16]. Entecavir has also been found to be superior to 10 mg of adefovir at week 48 of treatment in an open-label study of 69 treatment-naive, HBeAg-positive patients [17].…”

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confidence: 99%

“…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]. By week 48, 1.4% of patients had virologic rebound due to the emergence of entecavir-resistant mutants, with seven other patients (of 134 tested) identified to have entecavir-resistant mutants at baseline without virologic rebound.…”

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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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A Comparison of Entecavir and Lamivudine for HBeAg-Positive Chronic Hepatitis B

Cited by 1,325 publications

References 27 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

Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients With liver cirrhosis

The saga of entecavir

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