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.
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).
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.
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.
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%.
KeywordsLamivudine Tenofovir Disoproxil Fumarate Entecavir Adefovir Dipivoxil Entecavir Treatment
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