Entecavir therapy for lamivudine‐refractory chronic hepatitis B

Sherman, Morris; Yurdaydın, Cihan; Şimşek, Halis; Silva, Marcelo; Liaw, Yun–Fan; Rustgi, Vinod K.; Sette, H; Tsai, Naoky; Tenney, Daniel J.; Vaughan, James; Kreter, Bruce; Hindes, R.

doi:10.1002/hep.22323

Cited by 157 publications

(169 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: 96%

“…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]. In contrast to the nucleoside-naive population, emergence of resistance to entecavir occurred more frequently in the lamivudine-refractory population [30,31].…”

Section: Introductionmentioning

confidence: 99%

“…Treatment for up to 96 weeks resulted in continued improvement of virologic, biochemical, and serologic end points [30]. In contrast to the nucleoside-naive population, emergence of resistance to entecavir occurred more frequently in the lamivudine-refractory population [30,31]. To date, there are limited data on the efficacy of entecavir treatment beyond 96 weeks in the lamivudine-refractory patient population.…”

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: 96%

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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“…Recent reports have shown that switching to ETV therapy in LAM-refractory patients with CHB resulted in superior viral suppression compared with continued LAM therapy, with a comparable safety profile. [13][14][15] However, the cumulative probability of genotypic ETV resistance development over 4 years was 43% in LAM-refractory patients, which is considerably greater than the 1.2% probability seen in NA-naïve patients. 16 In fact, a new treatment algorithm does not recommend ETV monotherapy as a rescue therapy for patients with CHB who had LAM resistance.…”

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confidence: 86%

Efficacy of Entecavir in Patients with Chronic Hepatitis B Resistant to Both Lamivudine and Adefovir or to Lamivudine Alone†

et al. 2009

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Entecavir (ETV) is currently recommended as a rescue therapy purely for adefovir (ADV)-resistant chronic hepatitis B virus (HBV) infections.We evaluated the efficacy of ETV in patients who were resistant to lamivudine (LAM)/ADV sequential therapy and in those resistant to LAM monotherapy. Fifty LAM/ADV-resistant and 38 LAM-resistant patients who received ETV 1 mg/day for at least 48 weeks were enrolled. Mean baseline serum HBV DNA and alanine aminotransferase (ALT) levels were significantly lower in the LAM/ADVresistant group, compared with the LAM-resistant group (6.90 versus 7.62 log 10 copies/mL and 102.6 versus 160.2 IU/L; both P < 0.05); hepatitis B e antigen (HBeAg) status and LAM-resistant mutation patterns were similar in the two groups. At week 48, mean reductions in HBV DNA and ALT levels were significantly less in the LAM/ADV-resistant group (؊2.96 versus ؊4.86 log 10 copies/mL and ؊68.3 versus ؊128.9 IU/L; both P < 0.05). Achievement of undetectable HBV DNA was also less common in the LAM/ADV-resistant group (10.0% versus 34.2%; P ‫؍‬ 0.006), although the rates of HBeAg loss and ALT normalization did not differ between the two groups. Resistance to both LAM and ADV was an independent risk factor for failure of HBV DNA negativity at week 48 (odds ratio, 0.138; P ‫؍‬ 0.019). In both LAM/ADV-resistant and LAM-resistant groups, primary responders (>1 log decline in HBV DNA at week 12) achieved a significantly greater decrease in HBV DNA levels over the 48-week period, compared with primary nonresponders (؊4.18 versus ؊0.97 and ؊5.37 versus ؊2.15 log 10 copies/mL, respectively; both P < 0.05). Conclusion:The 48-week ETV treatment was less effective in LAM/ADV-resistant than in LAM-resistant patients. Continuing ETV monotherapy could be determined based on the virological response at 12 weeks in LAM/ADV-resistant patients. (HEPATOLOGY 2009;50:1064-1071

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“…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. By week 96, 23 of 77 entecavir-treated patients had developed genotypic resistance to entecavir [25]. The cumulative genotypic resistant rates for entecavir on lamivudine-resistant disease are 6%, 15%, 36%, 46%, and 51% from years 1 to 5 [26].…”

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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 therapy for lamivudine‐refractory chronic hepatitis B

Cited by 157 publications

References 36 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

Efficacy of Entecavir in Patients with Chronic Hepatitis B Resistant to Both Lamivudine and Adefovir or to Lamivudine Alone†

The saga of entecavir

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