Disease relevance of SQ 34676

• Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B [1].
• BACKGROUND & AIMS: Entecavir is a novel and selective nucleoside analogue with potent activity against hepatitis B virus (HBV) [2].
• Safety and efficacy of oral entecavir given for 28 days in patients with chronic hepatitis B virus infection [3].
• Adefovir or entecavir is preferred in patients with decompensated cirrhosis who require long duration of treatment, due to the lower rate of development of resistance [4].
• Effect of antiviral treatment with entecavir on age- and dose-related outcomes of duck hepatitis B virus infection [5].

High impact information on SQ 34676

• METHODS: In this phase III, double-blind trial, hepatitis B e antigen-positive patients who were refractory to lamivudine therapy (persistent viremia or documented YMDD mutations while receiving lamivudine) were randomized to switch to entecavir 1 mg daily (n = 141) or continue lamivudine 100 mg daily (n = 145) for a minimum of 52 weeks [1].
• CONCLUSIONS: In patients with lamivudine-refractory chronic hepatitis B, switching to entecavir provides superior histologic improvement, viral load reduction, and ALT normalization compared with continuing lamivudine, with a comparable adverse event profile [1].
• Significantly higher proportions of patients achieved normalization of alanine aminotransferase levels on entecavir 1.0, 0.5, and 0.1 mg (68%, 59%, and 47%, respectively) than on lamivudine (6%) [6].
• Inhibition of hepatitis B virus polymerase by entecavir [7].
• Although the rtL180M+S202G+M204V variant, that prevailed at the end of entecavir therapy, did not show the highest viral genome replication capacity, it conferred one of the strongest resistance levels to entecavir [8].

Chemical compound and disease context of SQ 34676

• Entecavir (ETV; Baraclude) is a novel deoxyguanosine analog with activity against hepatitis B virus (HBV) [7].
• Interferon, ADV or ETV are the preferable drugs in HBV naive patients who do not require HIV therapy [9].
• Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J, Cross A, DeHertogh D, Wilber R, Colonno R, Apelian D; BEHoLD AI463022 Study Group. BACKGROUND: Entecavir is a potent and selective guanosine analogue with significant activity against hepatitis B virus (HBV) [10].
• Lamivudine has been approved, and several other compounds (such as adefovir dipivoxil, emtricitabine and entecavir) are under clinical development, for the treatment of hepatitis B virus infections [11].
• Search terms included, but were not limited to, entecavir, BMS-200475, hepatitis B, pharmacology, pharmacokinetics, adverse events, and therapeutic use [12].

Biological context of SQ 34676

• A double-blind, placebo-controlled, multiple oral dose escalation study was conducted to investigate the pharmacokinetics, safety, and tolerability of entecavir in healthy subjects [13].
• Potential drug interactions and adverse events associated with the use of entecavir are also reviewed [12].
• Entecavir reduces HBV load more effectively than the other therapies, but it is associated with increased drug resistance in patients with lamivudine-resistant HBV [14].
• In clinical studies, entecavir revealed excellent suppression of hepatitis B virus replication without significant side effects or evidence of mitochondrial toxicity [15].

Anatomical context of SQ 34676

• The ability of entecavir (ETV) to inhibit Duck hepatitis B virus (DHBV) infection in duck hepatocytes and ducklings was examined using lamivudine (3TC) as a comparator drug [16].

Associations of SQ 34676 with other chemical compounds

• METHODS: In a 24-week, double-blind, randomized, multicenter, phase II clinical trial, the safety and efficacy of entecavir (0.01 mg/day, 0.1 mg/day, or 0.5 mg/day orally) were compared with lamivudine (100 mg/day orally) [2].
• However, while entecavir is associated with a low incidences of resistance, emtricitabine is associated with a relatively high incidence of resistance which limits its use as a monotherapy [17].
• The potential for drug interactions with entecavir appears to be minimal, although medications that inhibit tubular secretion of drugs (eg, probenecid) may be expected to prolong serum concentrations of entecavir [12].

Gene context of SQ 34676

• There are four approved drugs for the treatment of CHB which include interferon alpha (IFN), lamivudine (LAM), entecavir (ETV) and adefovir dipivoxil (ADV) [9].
• (ClinicalTrials.gov number, NCT00035789.). [Abstract reproduced by permission of N Engl J Med 2006;354:1011-1020] A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B [10].
• More patients in the entecavir group than in the lamivudine group had undetectable serum HBV DNA levels according to a polymerase-chain-reaction assay (67 percent vs. 36 percent, P<0.001) and normalization of alanine aminotransferase levels (68 percent vs. 60 percent, P=0.02) [18].
• We discuss two major groups of treatments--immunomodulators (interferon alfa, thymosin alpha1, therapeutic vaccines) and nucleoside analogues (lamivudine, adefovir, entecavir, emtricitabine, beta-L-2'-deoxythymidine) [19].

Analytical, diagnostic and therapeutic context of SQ 34676

• In patients treated with entecavir 0.5 mg/day, 83.7% had an HBV-DNA level below the lower limit of detection of the Quantiplex branched DNA (bDNA) assay (Bayer-Versant Diagnostics, formerly Chiron Diagnostics, Emeryville, CA), compared with 57.5% treated with 100 mg/day lamivudine (P = 0.008) [2].
• Entecavir (ETV) is a potent and selective inhibitor of hepatitis B virus (HBV) replication in vitro and in vivo that is currently in clinical trials for the treatment of chronic HBV infections [20].
• Entecavir therapy combined with DNA vaccination for persistent duck hepatitis B virus infection [21].
• Entecavir is eliminated primarily in the urine via glomerular filtration and tubular secretion (62%-73%) [12].
• In view of the experimental and clinical data, the capacity of new antiviral strategies based on combination of new inhibitors, including adefavir and entecavir, with immune modulators needs to be further evaluated in animal models and clinical trials to prevent the emergence of resistant viral strains [22].

References