Pharmacology Update: Entecavir Tablets and Oral Solution (Baraclude)
By William T. Elliott, MD, FACP, Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco, and James Chan, PhD, PharmD, Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan are Associate Editors of Internal Medicine Alert.
Entecavir is a nucleoside analog approved for the treatment of chronic hepatitis B viremia (HBV). It has demonstrated antiviral activity against both wild-type and lamivudine-resistant virus. Entecavir is marketed by Bristol-Myers-Squibb as BaracludeTM.
Indications
Entecavir is indicated for the treatment of chronic HBV in adults with evidence of active viral replication and either evidence of persistent serum transaminases (ALT or AST) or histologically active disease.1
Dosage
The recommended dose is 0.5 mg once daily in nucleoside treatment-naïve patients. The dose is 1 mg for patients with a history of HBV while receiving lamivudine or known lamivudine resistance. Entecavir should be taken on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal).1
Entecavir is available as 0.5 mg and 1 mg tablets and a 0.05 mg/mL oral solution.
Potential Advantages
Entecavir is more potent that lamivudine and has shown activity against lamivudine-resistant HBV.1-3 Emergence of resistance to entecavir may take longer to develop than lamivudine as additional mutations other than that involving the catalytic domain of HBV polymerase are required.2 Mutation encoding adefovir resistance appears to remain susceptible to entecavir.1,4 HBV from lamivudine-refractory patients that failed entecavir therapy were reported to be susceptible to adefovir.1
Potential Disadvantages
While still active against lamivudine-resistant HBV a 20-30 fold higher concentration is required.2 The common side effects are headache, dizziness, and fatigue.
The frequency of moderate-to-severe headache and fatigue is 3-4%.1 Lactic acidosis and severe heptomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs.1 Resistance, perhaps infrequent, can emerge with prolonged therapy.5
Comments
Entecavir is a carbocyclic deoxyguanosine analog which is a potent agent against HBV. The safety and efficacy of entecavir were compared to lamivudine in 2 phase III studies in nucleoside treatment-naïve patients (n = 1347) who were either HBeAg-positive or negative and had compensated liver disease.1 Histologic improvement at 48 weeks was 70-72% for entecavir (0.5 mg) and 61-62% for lamivudine (100 mg). The proportion of patients with HBV DNA < 300 copies/mL was 67% for entecavir and 36% for lamivudine in HBeAg-positive patients. The corresponding values were 90% and 72% for HBeAg-negative patients. Additional change (log10 copies/mL) in HBV DNA from baseline were approximately -1.5 and -0.5 for entecavir respectively. All these differences were significant at P < 0.05. Entecavir was also assessed in patients’ refractory to lamivudine.1 In this study, patients who were refractory to lamivudine and switched to entecavir (1 mg) had a histologic improvement of 55% compared to 28% who remained on lamivudine (100 mg).1 Entecavir appears to be well tolerated compared to lamivudine. Hepatitis B symptoms may worsen or become serious after entecavir has been discontinued. Patients should be monitored for at least several months.1 The combination of entecavir and lamivudine appears to be less synergistic or additive than adefovir and lamivudine.6 The wholesale cost of entecavir is $20 per day for both strengths.
Clinical Implications
HBV is a serious disease affecting approximately 5% of the world population. High percentage of primary liver cancers are caused by chronic hepatitis B. Pharmacologic therapy includes alpha-interferon, lamivudine, and adefovir. Interferon generally has a low viral response rate, higher frequency of adverse events, and requires injection. Resistance develops to lamivudine and adefovir with prolonged therapy albeit less frequent with adefovir. Entecavir appears to be potent, less prone to resistance, and well tolerated.
References
1. Baraclude Product Information. Bristol-Myers Squibb Company. March, 2005.
2. Levine S et al. Antimicrob Agents Chemother. 2002; 46(8):2525-32.
3. Lai CL, et al. Gastroenterology. 2002;123(6);1831-1838.
4. Shaw T, Locarnini S. Expert Rev Anti Infect Ther. 2004;2(6):853-871.
5. Tenney DJ, et al. Antimicrob Agents Chemother. 2004; 48(9):3498-507.
6. Delaney WE, et al. Antimicrob Agents Chemother. 2004;48(10):3702-10.
Entecavir is a nucleoside analog approved for the treatment of chronic hepatitis B viremia. It has demonstrated antiviral activity against both wild-type and lamivudine-resistant virus.
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