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Entecavir

A Review of its Use in Chronic Hepatitis B

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Summary

Abstract

Entecavir (Baraclude®), a nucleoside analogue, is rapidly phosphorylated to the active intracellular 5′-triphosphate form that inhibits replication of hepatitis B virus (HBV). Oral entecavir is approved in the US, EU and several countries worldwide for the treatment of chronic HBV infection in adults (≥16 years of age) with evidence of active viral replication and persistently elevated serum ALT and/or AST levels, and/or histological evidence of active disease.

In several randomized, double-blind, multicentre trials, oral entecavir was an effective and generally well tolerated treatment in nucleoside-naive and lamivudine-refractory adult patients with chronic HBV infection, irrespective of whether patients were hepatitis B e antigen (HBeAg)-positive or -negative. Furthermore, it was more efficacious, associated with a lower risk of resistance, and more cost effective than lamivudine in these patient populations, with both drugs having a similar tolerability profile. In the EARLY trial, entecavir was significantly more effective than and as well tolerated as adefovir dipivoxil therapy in nucleoside-naive patients. In addition, in a double-blind, multicentre trial, entecavir plus lamivudine-based highly active antiretroviral therapy (HAART) was more effective than placebo plus lamivudine-based HAART in patients co-infected with HBV and HIV. Although the exact position of entecavir relative to other agents, such as tenofovir disoproxil fumarate and adefovir dipivoxil, for the treatment of chronic HBV infection remains to be fully determined, an important aspect in this positioning is the emergence of drug resistance. Hence, entecavir therapy provides a valuable first-line option in nucleoside-naive patients with chronic HBV infection and is a useful alternative in lamivudine-refractory patients.

Pharmacological Properties

The active 5′-triphosphate of entecavir competes with the natural substrate (deoxyguanosine triphosphate) of HBV polymerase to inhibit HBV replication at all three steps of the synthesis process. It is a highly selective, potent inhibitor of HBV replication in vitro and suppresses chronic viral infection in animal models of HBV infection. In in vitro studies, it was up to 2200-fold more potent than lamivudine in reducing the replication of viral HBV DNA and showed reduced activity against other viruses, including HIV-1, influenza and herpes simplex viruses. Entecavir may also have beneficial effects on immune responses to HBV infection based on in vitro studies and limited clinical data. In clinical trials, the development of phenotypic resistance to entecavir was rare in nucleoside-naive patients and, in lamivudine-refractory patients, it required the presence of pre-existing mutations associated with lamivudine resistance and multiple mutations in HBV viral polymerase. Respective 5-year entecavir-resistance rates in nucleoside-naive and lamivudine-refractory patients were 1.2% and 51%.

Oral entecavir is rapidly absorbed in a dose-dependent manner. Mean maximum plasma concentrations (Cmax) at steady state after 0.5 or 1.0 mg doses (4.23 and 8.24 ng/mL) were attained in a median of 1.0 and 0.75 hours. Respective values for the mean area under the plasma concentration-time curve (AUC) during the dosage interval were 14.78 and 26.38 ng · h/mL, with steady-state concentrations of entecavir achieved after 6–10 days. There was an approximately 2-fold accumulation of the drug at steady state. Administration of entecavir with a high-fat meal resulted in an approximately 45% decrease in Cmax and an approximately 20% decrease in AUC. Entecavir is extensively distributed into tissues and shows approximately 13% binding to plasma proteins in vitro. The drug is primarily eliminated via the renal route, with a mean terminal elimination half-life of 129.90 and 148.89 hours after multiple 0.5 and 1.0 mg doses; respective mean renal clearance values were 360 and 471 mL/min (21.6 and 28.26 L/h). There were no clinically relevant effects on the pharmacokinetics of entecavir based on age, sex, race or hepatic function. Renal impairment resulted in increased accumulation of entecavir, with dosage adjustments required in patients with a creatinine clearance of <50 mL/min (<3 L/h).

Therapeutic Efficacy

In two large (n >630 per trial), 52-week, double-blind, multinational trials, oral entecavir 0.5 mg once daily was more effective than oral lamivudine 100mg once daily in adult nucleoside-naive HBeAg-positive or -negative patients with chronic HBV infection. Significantly more entecavir (≈71% of patients) than lamivudine recipients (≈61%) achieved a histological response (defined as a ≥2 point reduction from baseline in Knodell inflammatory score, with no worsening of Knodell fibrosis score) at 48 weeks (primary endpoint). Secondary endpoints also generally favoured entecavir therapy at 48 weeks, including the mean change from baseline in serum HBV DNA levels, ALT normalization rates and the proportion of patients with undetectable serum HBV DNA. In a large (n = 519), similarly designed trial conducted in China, 90% of entecavir (mixed population of HBeAg-positive or -negative patients) and 67% of lamivudine patients achieved the primary composite endpoint of an HBV DNA level of <0.7 MEq/mL and a serum ALT level of <1.25 × the upper limit of normal (ULN; ALT normalization) at 48 weeks (primary endpoint). There were generally no between-group differences in serological response rates in these trials.

In the 52-week, randomized, open-label, multinational EARLY trial (n = 65), entecavir was significantly more effective than adefovir dipivoxil therapy in nucleoside-naive, HBeAg-positive patients.

In lamivudine-refractory, HBeAg-positive patients, entecavir 1.0 mg once daily was significantly more effective than lamivudine 100 mg once daily after 48 weeks, in terms of the coprimary endpoints and most secondary endpoints in a 52-week, double-blind, international, phase III trial (n = 286). Over half of entecavir-treated patients experienced a histological improvement compared with less than one-third of those receiving lamivudine (coprimary endpoint). In addition, over 10-fold more entecavir-than lamivudine-treated patients achieved the composite endpoint of an HBV DNA level of <0.7 MEq/mL and a serum ALT level <1.25 × ULN (coprimary endpoint). The efficacy of entecavir in lamivudine-refractory patients was confirmed in two smaller (n <200 per trial) double-blind trials, one of which was conducted in Japan.

In both nucleoside-naive and lamivudine-refractory patients, after long-term entecavir treatment (≤5 years in rollover studies) in patients who had not responded to initial double-blind treatment (i.e. HBV DNA level of ≥0.7 MEq/mL), most patients achieved a virological and/or biochemical response. In patients who responded to the initial double-blind treatment with entecavir in clinical trials and were followed-up off-treatment for 24 weeks, virological responses were sustained in 3–79% of patients at 24 weeks follow-up, with biochemical responses maintained in approximately 49–77% of patients. Furthermore, after a median of 280 weeks of entecavir therapy, both nucleoside-naive and lamivudine-refractory patients experienced significant improvements in liver histology and had sustained virological responses.

In a double-blind trial, treatment with entecavir plus lamivudine-based HAART provided better efficacy than placebo plus lamivudine-based HAART in adult patients co-infected with HBV and HIV. Changes from baseline in mean HBV DNA at 24 weeks were significantly greater in entecavir than placebo recipients (primary endpoint), with significant differences favouring entecavir treatment from week 2.

Pharmacoeconomic Considerations

In several cost-effectiveness analyses that used a decision-tree or Markov model, entecavir was predicted to be cost effective relative to lamivudine and/or adefovir dipivoxil treatment in nucleoside-naive patients with chronic HBV infection in analyses conducted from the Spanish, Polish or US healthpayer, a Hong Kong public hospital or the Chinese Social Security Program perspective (most analyses are available as preliminary reports), with incremental cost-effectiveness ratios falling below the acceptable threshold for paying in the relevant country. In other pharmacoeconomic evaluations in nucleoside-naive patients, tenofovir disoproxil fumarate was predicted to be the dominant strategy compared with other treatment options, including entecavir and lamivudine, in studies conducted from the Spanish and US healthpayer perspective. From the Spanish healthpayer perspective, entecavir was shown to be the dominant strategy compared with adefovir dipivoxil in lamivudine-refractory patients. In all of these studies, cost-effectiveness estimates were robust when subjected to univariate and/or probabilistic sensitivity analyses.

Tolerability

Oral entecavir 0.5 or 1.0 mg once daily was generally well tolerated in nucleoside-naive and lamivudine-refractory patients with chronic HBV infection participating in clinical trials and extension studies (≤5 years’ treatment), with most adverse events being of mild to moderate severity. Based on a descriptive pooled analysis of data from four clinical trials in 1720 patients with chronic HBV infection receiving entecavir or lamivudine for up to 2 years, the most common (incidence ≥3%) adverse events of any severity that were at least possibly related to entecavir treatment were headache, fatigue, dizziness and nausea, whereas those associated with lamivudine treatment were headache, fatigue and dizziness. Very few patients in either treatment group discontinued therapy because of an adverse event or abnormal laboratory tests (1% vs 4% in the lamivudine group). Entecavir was generally as well tolerated as lamivudine or adefovir dipivoxil in individual clinical trials.

In the pooled analysis, post-treatment exacerbations of hepatitis or an ALT flare (i.e. ALT level >10 × ULN and >2 × reference value) occurred in 2% of entecavir-treated and 9% of lamivudine-treated HBeAg-negative, nucleoside-naive patients; respective hepatitis exacerbation rates in HBeAg-positive, nucleoside-naive patients were 8% and 11%. In lamivudine-refractory patients, exacerbation rates in entecavir and lamivudine recipients were 12% and 0%.

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References

  1. Papatheodoridis GV, Manolakopoulos S, Dusheiko G, et al. Therapeutic strategies in the management of patients with chronic hepatitis B virus infection. Lancet Infect Dis 2008; 8(3): 167–78

    Article  PubMed  CAS  Google Scholar 

  2. Iloeje UH, Yang HI, Jen CL, et al. Risk and predictors of mortality associated with chronic hepatitis B infection. Clin Gastroenterol Hepatol 2007; 5(8): 921–31

    Article  PubMed  Google Scholar 

  3. Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006; 130(3): 678–86

    Article  PubMed  Google Scholar 

  4. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295(1): 65–73

    Article  PubMed  CAS  Google Scholar 

  5. Yao G. Entecavir is a potent anti-HBV drug superior to lamivudine: experience from clinical trials in China. J Anti-microb Chemother 2007; 60(2): 201–5

    CAS  Google Scholar 

  6. Sorrell MF, Belongia EA, Costa J, et al. National Institutes of Health Consensus Development Conference statement: management of hepatitis B. Ann Intern Med 2009; 150(2): 104–10

    PubMed  Google Scholar 

  7. European Association for the Study of the Liver Clinical Practice Guidelines Panel. EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol 2009; 50(2): 227–42

    Article  Google Scholar 

  8. Keefe EB, Dieterich DT, Han S-H, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol 2008; 6: 1315–41

    Article  Google Scholar 

  9. Langley DR, Walsh AW, Baldick CJ, et al. Inhibition of hepatitis B virus polymerase by entecavir. J Virol 2007; 81(8): 3992–4001

    Article  PubMed  CAS  Google Scholar 

  10. Robinson DM, Scott LJ, Plosker GL. Entecavir: a review of its use in chronic hepatitis B. Drugs 2006; 66(12): 1605–22; discussion 1623-4

    Article  PubMed  CAS  Google Scholar 

  11. Tchesnokov EP, Obikhod A, Schinazi RF, et al. Delayed chain-termination protects the anti-HBV drug entecavir from excision by HIV-1 reverse transcriptase. J Biol Chem 2008; 283(49): 34218–28

    Article  PubMed  CAS  Google Scholar 

  12. Bristol-Myers Squibb Co. Baraclude® (entecavir) US prescribing information [online]. Available from URL: http://www.baraclude.com/pi.html [Accessed 2009 Jan 5]

  13. European Medicines Agency. Baraclude: summary of product characteristics [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/baraclude/H-623-PI-en.pdf [Accessed 2009 Apr 5]

  14. Innaimo SF, Seifer M, Bisacchi GS, et al. Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus. Antimicrob Agents Chemother 1997; 41(7): 1444–8

    PubMed  CAS  Google Scholar 

  15. Mazzucco CE, Hamatake RK, Colonno RJ, et al. Entecavir for treatment of hepatitis B virus displays no in vitro mitochondrial toxicity or DNA polymerase gamma inhibition. Antimicrob Agents Chemother 2008; 52(2): 598–605

    Article  PubMed  CAS  Google Scholar 

  16. Ono SK, Kato N, Shiratori Y, et al. The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance. J Clin Invest 2001; 107(4): 449–55

    Article  PubMed  CAS  Google Scholar 

  17. Lin PF, Nowicka-Sans B, Terry B, et al. Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge. Antimicrob Agents Chemother 2008; 52(5): 1759–67

    Article  PubMed  CAS  Google Scholar 

  18. Domaoal RA, McMahon M, Thio CL, et al. Pre-steady-state kinetic studies establish entecavir 5′-triphosphate as a substrate for HIV-1 reverse transcriptase. J Biol Chem 2008; 283(9): 5452–9

    Article  PubMed  CAS  Google Scholar 

  19. Audsley J, Sasadeusz J, Mijch A, et al. The anti-HIV activity of entecavir: serum HIV RNA decreases and selection of the M184V mutation occurs in both ART-naive and — experienced HIV/HBV-co-infected individuals [abstract no. 63]. 15th Conference on Retroviruses and Opportunistic Infections; 2008 Feb 3–6; Boston (MA)

  20. Jain MK, Zoellner CL. Entecavir can select for M184V of HIV-1: a case of an HIV/hepatitis B (HBV) naive patient treated for chronic HBV [letter]. AIDS 2007; 21(17): 2365–6

    Article  PubMed  Google Scholar 

  21. Jakobsen MR, Arildsen H, Krarup HB, et al. Entecavir therapy induces de novo HIV reverse-transcriptase M184V mutation in an antiretroviral therapy-naive patient. Clin Infect Dis 2008; 46(9): 88–91

    Article  Google Scholar 

  22. Castel H, Bocket L, Tamalet C, et al. Entecavir mono-therapy selects M184V mutation in lamivudine-naive and lamivudine experienced HIV-HBV co-infected patients [abstract no. 938]. Hepatology 2008; 48 (4 Suppl.): 728

    Article  Google Scholar 

  23. McMahon MA, Jilek BL, Brennan TP, et al. The HBV drug entecavir: effects on HIV-1 replication and resistance. N Engl J Med 2007; 356(25): 2614–21

    Article  PubMed  CAS  Google Scholar 

  24. Wolters LMM, Hansen BE, Niesters HGM, et al. Viral dynamics during and after entecavir therapy in patients with chronic hepatitis B. J Hepatol 2002; 37(1): 137–44

    Article  PubMed  CAS  Google Scholar 

  25. Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance in nucleoside-naive patients is rare through 5 years of therapy. Hepatology. Epub 2009 Feb 4

  26. Tenney DJ, Rose RE, Baldick CJ, et al. Two-year assessment of entecavir resistance in lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present. Antimicrob Agents Chemother 2007; 51(3): 902–11

    Article  PubMed  CAS  Google Scholar 

  27. Colonno RJ, Rose R, Baldick CJ, et al. Entecavir resistance is rare in nucleoside-naive patients with hepatitis B. Hepatology 2006; 44(6): 1656–65

    Article  PubMed  CAS  Google Scholar 

  28. Baldick CJ, Tenney DJ, Mazzucco CE, et al. Comprehensive evaluation of hepatitis B virus reverse transcriptase substitutions associated with entecavir resistance. Hepatology 2008; 47(5): 1473–82

    Article  PubMed  CAS  Google Scholar 

  29. Villet S, Ollivet A, Pichoud C, et al. Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient. J Hepatol 2007; 46(3): 531–8

    Article  PubMed  CAS  Google Scholar 

  30. Baldick CJ, Eggers BJ, Fang J, et al. Hepatitis B virus quasispecies susceptibility to entecavir confirms the relationship between genotypic resistance and patient virologic response. J Hepatol 2008; 48(6): 895–902

    Article  PubMed  CAS  Google Scholar 

  31. Guo JJ, Li QL, Shi XF, et al. Dynamics of hepatitis B virus resistance to entecavir in a nucleoside/nucleotide-naive patient. Antiviral Res 2009; 81(2): 180–3

    Article  PubMed  CAS  Google Scholar 

  32. Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006; 354(10): 1001–10

    Article  PubMed  CAS  Google Scholar 

  33. Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B [published erratum appears in N Engl J Med 2006; 354 (17):1863]. N Engl J Med 2006; 354(10): 1011–20

    Article  PubMed  CAS  Google Scholar 

  34. Sherman M, Yurdaydin C, Sollano J, et al. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology 2006; 130(7): 2039–49

    Article  PubMed  CAS  Google Scholar 

  35. Suzuki F, Suzuki Y, Akuta N, et al. Changes in viral loads of lamivudine-resistant mutants during entecavir therapy. Hepatol Res 2008; 38(2): 132–40

    PubMed  CAS  Google Scholar 

  36. Kobashi H, Fujioka S-i, Kumada H, et al. Emergence of hepatitis B virus gene mutation related to entecavir-resistance in chronic hepatitis B patients participated in the phase 2 clinical studies of entecavir in Japan [abstract no. 963]. Hepatology 2007 Oct 1; 46 (4 Suppl. 1): 666

    Google Scholar 

  37. Mukaide M, Tanaka Y, Orito E, et al. Three-year assessment of entecavir resistance in genotype C chronic hepatitis B patients in Japan reveals different clinical outcomes regarding breakthrough hepatitis predicted by the resistance substitutions using recently developed INNO-LiPA HBV assay [abstract no. 1003]. Hepatology 2007; 46 (4 Suppl. 1): 685

    Google Scholar 

  38. Jiang Y, Wang F, Liu Y, et al. The host immunity response of hepatitis B patients after adefovir dipivoxil and entecavir therapy [abstract no. 1610]. Hepatology 2008; 48 (4 Suppl.): 1020–1

    Article  Google Scholar 

  39. Lu GF, Tang FA, Zheng PY, et al. Entecavir up-regulates dendritic cell function in patients with chronic hepatitis B. World J Gastroenterol 2008; 14(10): 1617–21

    Article  PubMed  CAS  Google Scholar 

  40. You J, Sriplung H, Geater A, et al. Impact of viral replication inhibition by entecavir on peripheral T lymphocyte subpopulations in chronic hepatitis B patients. BMC Infect Dis 2008; 8: 123

    Article  PubMed  Google Scholar 

  41. Yan JH, Bifano M, Olsen S, et al. Entecavir pharmacokinetics, safety, and tolerability after multiple ascending doses in healthy subjects. J Clin Pharmacol 2006; 46(11): 1250–8

    Article  PubMed  CAS  Google Scholar 

  42. Bifano M, Yan JH, Smith RA, et al. Absence of a pharmacokinetic interaction between entecavir and adefovir. J Clin Pharmacol 2007; 47(10): 1327–34

    Article  PubMed  CAS  Google Scholar 

  43. Zhu M, Bifano M, Xu X, et al. Lack of an effect of human immunodeficiency virus coinfection on the pharmacokinetics of entecavir in hepatitis B virus-infected patients. Antimicrob Agents Chemother 2008; 52(8): 2836–41

    Article  PubMed  CAS  Google Scholar 

  44. Lampertico P, Vigano M, Facchetti F, et al. Effectiveness of entecavir for the treatment of NUC-naive chronic hepatitis B patients: a large multicenter cohort study in clinical practice [abstract no. 896]. Hepatology 2008; 48 (4 Suppl.): 707–8

    Article  Google Scholar 

  45. Suzuki F, Toyoda J, Katano Y, et al. Efficacy and safety of entecavir in lamivudine-refractory patients with chronic hepatitis B: randomized controlled trial in Japanese patients. J Gastroenterol Hepatol 2008; 23(9): 1320–6

    Article  PubMed  CAS  Google Scholar 

  46. Chang TT, Gish RG, Hadziyannis SJ, et al. A dose-ranging study of the efficacy and tolerability of entecavir in lamivudine-refractory chronic hepatitis B patients. Gastroenterology 2005 Oct; 129(4): 1198–209

    Article  PubMed  CAS  Google Scholar 

  47. Yao G, Chen C, Lu W, et al. Efficacy and safety of entecavir compared to lamivudine in nucleoside-naive patients with chronic hepatitis B: a randomized double-blind trial in China. Hepatol Int 2007; 1: 365–72

    Article  PubMed  Google Scholar 

  48. Yao G, Zhou X, Xu D, et al. Entecavir for the treatment of lamivudine-refractory chronic hepatitis B patients in China. Hepatol Int 2007; 1(3): 373–81

    Article  PubMed  Google Scholar 

  49. Gish RG, Lok AS, Chang TT, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology 2007; 133(5): 1437–44

    Article  PubMed  CAS  Google Scholar 

  50. Han S, Chang TT, Chao YC, et al. Four-year entecavir treatment in nucleoside-naive HBEAG(+) patients: results from studies ETV-022 and -901 [abstract no. 938]. Hepatology 2007; 46 (4 Suppl. 1): 654

    Google Scholar 

  51. Han S-H, Chang T-T, Chao Y-C, et al. Five years of continuous entecavir for nucleoside-naive HBEAG(+) chronic hepatitis B: results from study ETV-901 [abstract no 893]. Hepatology 2008; 48 (4 Suppl.): 705–6

    Google Scholar 

  52. Leung N, Peng C-Y, Hann H-W, et al. Early hepatitis B virus DNA reduction in HBeAg-positive patients with chronic hepatitis B: a randomized international study of entecavir versus adefovir. Hepatology 2009; 49(1): 72–9

    Article  PubMed  CAS  Google Scholar 

  53. Leung N, Peng CY, Sollano J, et al. Entecavir results in higher HBV DNA reduction versus adefovir in antiviral-naive HBeAg(+) adults with high HBV DNA: week 96 results (E.A.R.L.Y. study) [abstract no. 998]. J Hepatol 2008; 48 Suppl. 2: 373–4

    Article  Google Scholar 

  54. Senturk H, Lurie Y, Gadano A, et al. ETV re-treatment of nucleoside-naive HBeAg(−) patients [abstract no. 517]. J Hepatol 2007; 46 Suppl. 1: 197

    Article  Google Scholar 

  55. Shouval D, Lai C-L, Chang T-T, et al. Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy. J Hepatol 2009; 50(2): 289–95

    Article  PubMed  CAS  Google Scholar 

  56. Shouval D, Akarca US, Hatzis G, et al. Continued virologic and biochemical improvement through 96 weeks of entecavir treatment in HBeAg(−) chronic hepatitis B patients (Study ETV-027) [abstract no. 45]. J Hepatol 2006; 44 Suppl. 2: 21–2

    Article  Google Scholar 

  57. Shouval D, Lai C, Chang T, et al. Three years of entecavir (ETV) re-treatment of HBeAg(−) ETV patients who previously discontinued ETV treatment: results from study ETV-901 [abstract no. 927]. Hepatology 2008; 48 (4 Suppl.): 722

    Google Scholar 

  58. Yao G, Chen CW, Lu WL, et al. Virologic, serologic, and biochemical outcomes through 2 years of treatment with entecavir or lamivudine in nucleoside-naive Chinese patients with chronic hepatitis B: a randomized, multicentre study. Hepatol Int 2008: DOI 10.1007/s12072-1008-9088-8

  59. Yao GB, Xu DZ, Ren H, et al. Three-years of continuous treatment with entecavir results in high proportions of Chinese nucleoside-naive patients with undetectable HBV DNA: results from studies ETV-023 and -050 [abstract no. 714]. J Hepatol 2008; 48 (2 Suppl.): 266–7

    Article  Google Scholar 

  60. Mochida S, Takaguchi K, Yokosuka O, et al. Long term efficacy, safety and resistance analyses of entecavir treatment in Japanese nucleoside-naive patients with chronic hepatitis B [abstract no. 703]. J Hepatol 2008; 48 Suppl. 2: 262

    Article  Google Scholar 

  61. Katano Y, Kumada H, Kobashi H, et al. Histologic assessment of long-term entecavir treatment in chronic hepatitis B patients [abstract no. 889]. Hepatology 2008; 48 (4 Suppl.): 703–4

    Google Scholar 

  62. Chang TT, Wu SS, Chao YC, et al. Long-term entecavir therapy results in reversal of fibrosis/cirrhosis and continued histologic improvement in patients with HBeAg(+) and (−) chronic hepatitis B: results from studies ETV-022, -027 and -901 [abstract plus poster no. PE119]. 19th Conference of the Asian Pacific Association for the Study of the Liver; 2009 Feb 13–16; Hong Kong

  63. Lee J, Kim H, Park J, et al. Comparison between clevudine and entecavir treatment for antiviral naive patients with chronic hepatitis B [abstract no. P0920]. Gut 2008; 57 Suppl. 2: 288

    CAS  Google Scholar 

  64. Sherman M, Yurdaydin C, Simsek H, et al. Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks. Hepatology 2008 Jul; 48(1): 99–108

    Article  PubMed  CAS  Google Scholar 

  65. Pellicelli AM, Barbaro G, Barbarini G, et al. Efficacy of entecavir as rescue therapy in lamivudine-resistant patients with HBV liver cirrhosis and waiting for orthotopic liver transplantation [abstract no. 885]. Hepatology 2008; 48 (4 Suppl.): 701–2

    Google Scholar 

  66. Kamar N, Milioto O, Alric L, et al. Entecavir therapy for adefovir-resistant hepatitis B virus infection in kidney and liver allograft recipients. Transplantation 2008; 86(4): 611–4

    Article  PubMed  CAS  Google Scholar 

  67. Schiff E, Simsek H, Lee WM, et al. Efficacy and safety of entecavir in patients with chronic hepatitis B and advanced hepatic fibrosis or cirrhosis. Am J Gastroenterol 2008; 103(11): 2776–83

    Article  PubMed  CAS  Google Scholar 

  68. Dienstag JL, Wei LJ, Xu D, et al. Cross-study analysis of the relative efficacies of oral antiviral therapies for chronic hepatitis B infection in nucleoside-naive patients. Clin Drug Investig 2007; 27(1): 35–49

    Article  PubMed  CAS  Google Scholar 

  69. Pessoa MG, Gazzard B, Huang AK, et al. Efficacy and safety of entecavir for chronic HBV in HIV/HBV coinfected patients receiving lamivudine as part of anti-retroviral therapy. AIDS 2008; 22(14): 1779–87

    Article  PubMed  CAS  Google Scholar 

  70. Brosa M, Buti M, Staginnus U, et al. Modeling the long term consequences of suppressing viral replication in chronic hepatitis B: a cost-effectiveness analysis of entecavir in Spain [abstract no. PIN35]. Value Health 2007; 10(6): A446. Plus poster presented at the International Society for Pharmacoeconomic Outcomes and Research 10th Annual European Congress; 2007 Oct 20–23; Dublin

    Article  Google Scholar 

  71. Deniz B, Buti M, Brosa M, et al. Cost-effectiveness simulation analysis of tenofovir disoproxil fumarate (tenofovir), lamivudine, adefovir dipivoxil (adefovir) and entecavir of HBEAG negative patients with chronic hepatitis-B in Spain [abstract no. 558]. J Hepatology 2008; 48 Suppl. 2: 209. Plus poster presented at the 43rd Annual Meeting of the European Association for the Study of the Liver; 2008 Apr 23–27; Milan

    Article  Google Scholar 

  72. Deniz HB, Everhard F. Cost-effectiveness simulation analysis of tenofovir disoproxil fumarate, lamivudine, adefovir dipivoxil and entecavir in HBEAG negative (−) patients with chronic hepatitis B in the USA [abstract no. 976]. Hepatology 2008; 48 (4 Suppl.): 744–5. Plus poster presented at the 59th Annual Meeting of the American Association for the Study of Liver Diseases; 2008 Oct 31–Nov 4; San Francisco (CA)

    Google Scholar 

  73. Buti M, Brosa M, Casado MA, et al. Modeling the long-term cost-effectiveness of chronic hepatitis B therapies in Spain [poster no. PG112]. International Society for Pharmacoeconomic Outcomes and Research 11th Annual European Congress; 2008 Nov 8–11; Athens

  74. Orlewska E, Cerri KH, Kutikova L, et al. The cost-effectiveness analysis of entecavir in the treatment of chronic hepatitis B patients in Poland [abstract no. PIN12]. Value Health 2007; 10(6): A162–3. Plus poster presented at the 12th International Meeting of the International Society for Pharmacoeconomics and Outcomes Research; 2007 May 19–23; Arlington (VA)

    Article  Google Scholar 

  75. Lee KK, Lee VWY, Yuan Y. Cost-effectiveness of substituting lamivudine with entecavir in chronic hepatitis B patients in the public sector of Hong Kong [abstract no. PIN11]. Value Health 2007; 10(6): 162. Plus poster presented at the 12th International Meeting of the International Society for Pharmacoeconomic Outcomes and Research; 2007 May 19–23; Arlington (VA)

    Article  Google Scholar 

  76. Yuan Y, Iloeje UH, Hay J, et al. Evaluation of the cost-effectiveness of entecavir versus lamivudine in hepatitis BeAg-positive chronic hepatitis B patients. J Manage Care Pharm 2008; 14(1): 21–33

    Google Scholar 

  77. Veenstra DL, Sullivan SD, Clarke L, et al. Cost effectiveness of entecavir versus lamivudine with adefovir salvage in HBeAg-positive chronic hepatitis B. Pharmacoeconomics 2007; 25(11): 963–77

    Article  PubMed  CAS  Google Scholar 

  78. Yuan Y, Iloeje U, Li H, et al. Economic implications of entecavir treatment in suppressing viral replication in chronic hepatitis B (CHB) patients in China from a perspective of the Chinese Social Security program. Value Health 2008; 11 Suppl. 1: 11–22

    Article  Google Scholar 

  79. Lok ASF, McMahon BJ. AASLD practice guidelines: chronic hepatitis B. Hepatology 2007; 45(2): 507–39

    Article  PubMed  CAS  Google Scholar 

  80. Liaw Y-F, Leung N, Kao J-H, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int 2008; 2(3): 263–83

    Article  PubMed  Google Scholar 

  81. Dienstag JL. Drug therapy: hepatitis B virus infection. N Engl J Med 2008; 359(14): 1486–500

    Article  PubMed  CAS  Google Scholar 

  82. Liaw Y-F, Chu C-M. Hepatitis B virus infection. Lancet 2009; 373: 582–92

    Article  PubMed  CAS  Google Scholar 

  83. Hirsch MS. Entecavir surprise. N Engl J Med 2007; 356(25): 2641–3

    Article  PubMed  CAS  Google Scholar 

  84. Gaglio PJ, Sterling R, Daniels E, et al. Hepatitis B virus and HIV coinfection: results of a survey on treatment practices and recommendations for therapy. Clin Infect Dis 2007; 45(5): 618–23

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Wolters Kluwer Health ¦ Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, Auckland, 0754, New Zealand

    Lesley J. Scott & Gillian M. Keating

  2. Wolters Kluwer Health, Philadelphia, Pennsylvania, USA

    Lesley J. Scott & Gillian M. Keating

Authors
  1. Lesley J. Scott
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  2. Gillian M. Keating
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Correspondence to Lesley J. Scott.

Additional information

Various sections of the manuscript reviewed by: H. Bhally, Infectious Diseases Service, Waitemata District Health Board, Auckland, New Zealand; C.-L. Lai, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong; N.W.Y. Leung, Alice Ho Miu Nethersole Hospital, Department of Medicine, Taipo, and The Chinese University of Hong Kong, Shatin New Territories, Hong Kong; S. Mauss, Center for HIV and Hepatogastroenterology, Duesseldorf, Germany; L. Rostaing, Department of Nephrology, Haemodialysis and Transplantation, CHU Toulouse, University Hospital, Toulouse, France; D.L. Veenstra, Department of Pharmacy, University of Washington, Seattle, Washington, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘entecavir’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health ∣ Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘entecavir’ and ‘hepatitis B’. Searches were last updated 10 May 2009.

Selection: Studies in patients with chronic hepatitis B who received entecavir. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Entecavir, hepatitis B, nucleoside analogue, pharmacodynamics, pharmacokinetics, therapeutic use, pharmacoeconomics, tolerability.

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Scott, L.J., Keating, G.M. Entecavir. Drugs 69, 1003–1033 (2009). https://doi.org/10.2165/00003495-200969080-00005

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