General Information

Baraclude (entecavir) is a nucleoside analog with selective activity against hepatitis B virus (HBV). 

Baraclude is specifically indicated for the treatment of chronic HBV infection in adults and children at least 2 years of age with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. 

Baraclude is supplied as both an oral tablet and an oral solution. Baraclude should be administered on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal).

Recommended Dosage in Adults

Compensated Liver Disease

• The recommended dose of Baraclude for chronic hepatitis B virus infection in nucleoside-inhibitor-treatment-naïve adults and adolescents 16 years of age and older is 0.5 mg once daily. The recommended dose of Baraclude in adults and adolescents (at least 16 years of age) with a history of hepatitis B viremia while receiving lamivudine or known lamivudine or telbivudine resistance substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once daily.

Decompensated Liver Disease

• The recommended dose of Baraclude for chronic hepatitis B virus infection in adults with decompensated liver disease is 1 mg once daily. 

Recommended Dosage in Pediatric Patients

The recommended dose of Baraclude for pediatric patients 2 years of age or older and weighing at least 10 kg is outlined in the table below. The oral solution should be used for patients with body weight up to 30 kg. Treatment naive children with body weight greater than 30 kg should receive 10 mL (0.5 mg) of oral solution or one 0.5 mg tablet once daily. Lamivudine experienced children with body weight greater than 30 kg should receive 20 mL (1 mg) of oral solution or one 1 mg tablet once daily.

Recommended Once-Daily Dose of Oral Solution (mL)

Mechanism of Action

Baraclude is a small-molecule guanosine nucleoside analog with selective activity against hepatitis B virus (HBV) polymerase. The drug is effectively phosporylated to the active triphosphate form, which competes with the natural substrate deoxyguanosine triphosphate, functionally inhibiting reverse transription actions of HBV polymerase, including base priming, negative strand DNA reverse transcription from RNA, and synthesis of the positive strand of HBV DNA. The drug produces only weak inhibition of normal cellular DNA polymerases and mitochondrial DNA polymerase.

Side Effects

Adverse events associated with the use of Baraclude may include, but are not limited to, the following:

• Headache
• Fatigue
• Dizziness
• Nausea
• Liver enzyme elevation

In addition, nucleoside analogs have been associated with lactic acidosis and severe hepatomegaly with steatosis, including fatal cases. Abrupt cessation of nucleoside therapy, including Baraclude, has been associated with severe acute exacerbations of HBV disease state. Patients are recommended to consult closely with their doctors regarding liver function both while taking Baraclude and before stopping treatment.

Clinical Trial Results

FDA approval of Baraclude was based on 3 phase III clinical trials, enrolling a combined total of 1633 patients 16 years of age or older with chronic HBV infection (serum HBsAg-positive for at least 6 months) accompanied by evidence of viral replication (detectable serum HBV DNA, as measured by the bDNA hybridization or PCR assay). Patients had persistently elevated ALT levels =1.3 times the upper limit of normal (ULN) and chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. This included two studies in nucleoside-therapy-naïve patients (Study AI463022, AI463027), and one in lamivudine refractory patients (AI463026).

Study AI463022
This multinational, double-blind study investigated the safety and efficacy of Baraclude, versus approved therapy with lamivudine. 709 subjects (of 715 randomized) nucleoside-naive patients with chronic HBV infection and detectable HBeAg were randomized to receive 0.5 mg once daily Baraclude or 100 mg once daily lamivudine for 52 weeks. in 709 (of 715 randomized) nucleoside-naive patients with chronic HBV infection and detectable HBeAg. At baseline, patients had a mean Knodell Necroinflammatory Score (a standard diagnostic scale) of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 9.66 log10 copies/mL, and mean serum ALT was 143 U/L.

Study AI463027
This multinational, double-blind study also investigated 0.5 mg once daily Baraclude versus 100 mg once daily lamivudine for 52 weeks. 638 (of 648 randomized) nucleoside-naive patients with HBeAg-negative (HBeAb-positive) chronic HBV infection were enrolled. At baseline, patients had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 7.58 log10 copies/mL, and mean serum ALT level was 142 U/L.

Results
In both studies Baraclude was found to be superior to lamivudine in the primary efficacy endpoint of histologic improvement, defined as a 2-point reduction or greater in Knodell Necroinflammatory Score, with no worsening in Knodell Fibrosis Score at week 48. Efficacy was also seen in secondary efficacy measures, including of reduction in viral load and ALT normalization.

Study AI463026:
This multinational, randomized, double-blind study enrolled 286 (of 293 randomized) patients with lamivudine-refractory chronic HBV infection, who either continued on 100 mg lamivudine, or began taking 1 mg Baraclude daily for 52 weeks. At baseline, patients had a mean Knodell Necroinflammatory Score of 6.5, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 9.36 log10 copies/mL, and mean serum ALT level was 128 U/L.

Results
Baraclude was shown to be superior to lamivudine in producing histological improvement, with 55% of individuals achieving improvement of 2 points or greater on the Knodell scale, vs 28% for continued lamivudine (p<0.01). Superiority was also seen in Ishtak Fibrosis Score with 34% achieving improvement vs. 16% for lamivudine (p<0.01). Significance was reached in a number of laboratory efficacy measures, including proportion of patients with undetectable HBV DNA levels (<300 copies/mL: 19% vs 1%, p<0.0001), mean change in viral DNA load from baseline (log10 copies/mL: -5.11% vs. -0.48%, p<0.0001) and percentage of patients achieving ALT level normalization (61% vs. 15%, p<0.0001).