What is the recommended treatment and dosage of Entecavir (entecavir) for hepatitis B?

Entecavir Treatment for Chronic Hepatitis B

Entecavir 0.5 mg once daily is the recommended first-line dose for treatment-naïve adults with chronic hepatitis B, while 1 mg once daily is required for lamivudine-resistant patients or those with decompensated cirrhosis. 1, 2

Dosing Recommendations

Treatment-Naïve Patients with Compensated Liver Disease

• Standard dose: 0.5 mg once daily for nucleoside-naïve adults and adolescents ≥16 years old 2
• Must be taken on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal) 2
• This dose achieves >90% viral suppression (HBV DNA <300 copies/mL) after 3 years of continuous therapy 1

Lamivudine-Resistant or Telbivudine-Resistant Patients

• Increased dose: 1 mg once daily for patients with documented lamivudine resistance mutations (rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L) 2
• This higher dose is necessary because archived resistance mutations in HBV cccDNA reduce entecavir's clinical efficacy 1
• Critical caveat: Patients with any history of lamivudine use should not receive entecavir monotherapy due to substantially higher resistance rates (51% at 5 years versus 1.2% in treatment-naïve patients) 1, 3

Decompensated Cirrhosis

• Required dose: 1 mg once daily regardless of prior treatment history 1, 2
• Entecavir is preferred over peginterferon alfa, which is contraindicated in decompensated cirrhosis 1

Renal Dose Adjustments

Dosage reduction is mandatory for creatinine clearance <50 mL/min: 2

• CrCl 30-49 mL/min: 0.5 mg every 48 hours (or 1 mg every 48 hours for lamivudine-resistant/decompensated patients)
• CrCl 10-29 mL/min: 0.5 mg every 72 hours (or 1 mg every 72 hours)
• CrCl <10 mL/min or hemodialysis/CAPD: 0.5 mg every 7 days (or 1 mg every 7 days)
• For hemodialysis patients, administer after the dialysis session 2

Treatment Duration

HBeAg-Positive Patients

• Minimum 12 months after achieving HBeAg seroconversion, plus an additional 3-6 months of consolidation therapy 4, 5
• Without HBeAg seroconversion, long-term or indefinite therapy is required due to very high risk of virologic relapse upon discontinuation 4, 5
• At 5 years of continuous therapy, 31% of patients achieved cumulative HBeAg seroconversion 1

HBeAg-Negative Patients

• Long-term or indefinite treatment is generally required as these patients rarely achieve HBsAg loss 4, 5
• Selected non-cirrhotic patients may consider discontinuation after HBV DNA has been undetectable for at least 3 years, but only with close follow-up 5

Cirrhotic Patients (Compensated or Decompensated)

• Indefinite treatment is mandatory to prevent disease progression and hepatic decompensation 1, 5
• Long-term therapy can lead to regression of fibrosis and even reversal of cirrhosis 1
• Discontinuation carries significant risk of hepatic decompensation 5

Clinical Efficacy

Virologic Response

• At 48 weeks: 67% of treatment-naïve HBeAg-positive patients achieved HBV DNA <300 copies/mL (versus 36% with lamivudine) 1
• At 5 years: 94% maintained HBV DNA <300 copies/mL with continued therapy 1, 6
• Mean HBV DNA reduction of 6.9 log₁₀ copies/mL at 48 weeks 1

Histologic Improvement

• 72% of patients showed histologic improvement at 48 weeks (versus 62% with lamivudine) 1
• 74% of cirrhotic patients (Ishak score 5-6) had regression of cirrhosis after 5 years of tenofovir therapy in pooled analyses 1

Biochemical Response

• 68% achieved ALT normalization at 48 weeks (using 1× ULN cutoff) 1
• 80% maintained normal ALT levels at 5 years 1, 6

Resistance Profile

Entecavir has an exceptionally low resistance rate in treatment-naïve patients: 1, 3

• 1.2% genotypic resistance after 5 years in nucleoside-naïve patients 1, 3, 7
• Only one patient developed entecavir resistance through 5 years in long-term follow-up studies 6
• However, 51% resistance rate at 5 years in lamivudine-experienced patients 1, 3

Safety Profile

Common Adverse Events

• Headache (17-23%), upper respiratory tract infection (18-20%), cough (12-15%), fatigue (10-13%), dizziness (9%), nausea (6-8%) 8
• Only 1% of patients discontinued therapy due to adverse events in long-term studies 1, 3
• Safety profile is favorable over several years, though safety over decades remains unknown 1

Serious Warnings

Three boxed warnings exist: 2

1. Severe acute exacerbations of hepatitis B upon discontinuation: Monitor hepatic function closely with clinical and laboratory follow-up for at least several months after stopping therapy 2

2. HIV/HBV coinfection risk: Entecavir is NOT recommended for HIV/HBV coinfected patients not receiving HAART due to potential development of HIV resistance 2

3. Lactic acidosis and hepatomegaly with steatosis: Fatal cases reported with nucleoside analogues, particularly in patients with severely impaired liver function 3, 2

Warning Signs Requiring Immediate Attention

• Lactic acidosis: Trouble breathing, fast or irregular heartbeat 3
• Hepatotoxicity: Jaundice, dark urine, light-colored stools, lower abdominal pain 3

Monitoring Requirements

During Treatment

• HBV DNA levels every 3-6 months to confirm continued viral suppression 4, 5
• Liver function tests every 3 months for cirrhotic patients 1
• Renal function monitoring before and during therapy, especially in patients with multiple risk factors for renal impairment 1, 5
• ALT levels to assess biochemical response 4

After Discontinuation

• Close clinical and laboratory monitoring for at least several months due to risk of severe hepatitis B exacerbations 2

Treatment Selection Rationale

Entecavir and tenofovir are the only recommended first-line oral agents due to superior potency and favorable resistance profiles compared to lamivudine, adefovir, and telbivudine 1, 4

• Lamivudine has high resistance rates and is inferior to entecavir 1
• Adefovir has inferior efficacy and resistance profile compared to tenofovir 1
• Telbivudine has intermediate resistance rates and cannot be considered first-line 1
• Peginterferon alfa-2a is an alternative first-line option but requires subcutaneous injection, has more difficult tolerability, and is contraindicated in decompensated cirrhosis 1

Special Populations

Pregnancy

• Telbivudine or tenofovir are preferred during pregnancy (pregnancy category B) rather than entecavir 1, 4

No Hepatic Dose Adjustment

• No dose adjustment necessary for hepatic impairment alone 2