What is the treatment for hepatitis B (HBV)?

Treatment of Hepatitis B

There is no cure for hepatitis B, but treatment with entecavir or tenofovir is highly effective at suppressing viral replication and preventing progression to cirrhosis, liver failure, and hepatocellular carcinoma. 1, 2

Current Treatment Goal

• HBV cannot be eradicated because covalently closed circular DNA (cccDNA) persists in the nuclei of infected hepatocytes, making complete viral elimination impossible with current therapies 3
• The realistic goal is persistent suppression of viral replication to undetectable levels and ALT normalization to halt disease progression 3, 1
• The ideal endpoint is HBsAg loss with or without anti-HBs seroconversion, though this occurs in only a minority of patients 2

First-Line Treatment Options

Entecavir and tenofovir are the preferred first-line agents due to their superior potency and high genetic barrier to resistance 3, 1, 2

Entecavir

• Dosing: 0.5 mg daily orally 1
• Efficacy: Achieves virologic suppression (HBV DNA <50 IU/mL) in 83% at 96 weeks and >90% after 3 years 1, 2
• Resistance: No genotypic resistance detected after 8 years in treatment-naive patients 2
• Critical caveat: Never use in lamivudine-experienced patients due to archived resistance mutations in cccDNA that dramatically increase entecavir resistance risk 3, 2, 4

Tenofovir

• Dosing: Tenofovir disoproxil fumarate (TDF) 300 mg daily or tenofovir alafenamide (TAF) with improved renal/bone safety 1, 2
• Efficacy: Achieves 93% virologic suppression at 48 weeks, maintains efficacy even with baseline viral loads ≥9 log10 copies/mL 2
• Resistance: Minimal to no resistance detected after 8 years 2
• Preferred in: Lamivudine-experienced patients, those with renal concerns (TAF formulation) 1, 2

Peginterferon Alfa-2a

• Dosing: 180 mg weekly subcutaneous injection for 48 weeks 3, 1
• Advantages: Finite treatment duration, no resistance development, higher rates of HBsAg loss compared to oral agents 1
• Best candidates: HBV genotype A or B, high ALT (>2× ULN), low HBV DNA, younger age, HBeAg-positive with wild-type virus 3, 1
• Absolute contraindication: Decompensated cirrhosis due to risk of further decompensation 2

Treatment Indications by Clinical Scenario

HBeAg-Positive Patients

• Treat when: HBV DNA >20,000 IU/mL AND ALT >2× ULN 2
• Also treat if: HBV DNA >20,000 IU/mL and age >30 years, regardless of ALT or histology 5
• First-line: Entecavir, tenofovir, or peginterferon alfa-2a 3, 1

HBeAg-Negative Patients

• Treat when: HBV DNA >2,000 IU/mL AND ALT >2× ULN 3, 2
• First-line: Entecavir or tenofovir (long-term treatment required) 3, 1
• Note: Relapse rates reach 80-90% if treatment stopped within 1-2 years 2

Compensated Cirrhosis

• Treat when: HBV DNA ≥2,000 IU/mL, regardless of ALT level 3, 2
• Preferred agents: Entecavir or tenofovir (peginterferon may be considered in select patients) 1, 2
• Avoid lamivudine: High resistance rates could precipitate decompensation 2

Decompensated Cirrhosis

• Treat immediately: Any detectable HBV DNA, regardless of level, HBeAg status, or ALT 3, 2
• Preferred: Entecavir 1 mg daily or tenofovir; consider combination therapy (tenofovir plus lamivudine or entecavir monotherapy) to minimize resistance 2
• Absolutely contraindicated: Peginterferon due to risk of further decompensation 2

Additional Treatment Indications

• Liver stiffness >9-12 kPa with HBV DNA >2,000 IU/mL, regardless of ALT 5
• Family history of cirrhosis/HCC with HBV DNA >2,000 IU/mL 5
• Moderate histological lesions on biopsy with HBV DNA >2,000 IU/mL, regardless of ALT 3, 5

Agents to Avoid as First-Line

Do not use lamivudine, adefovir, or telbivudine as first-line therapy due to inferior efficacy and/or high resistance rates 3, 2

• Lamivudine: Resistance rates up to 70% after 5 years 2, 6, 7
• Adefovir: Inferior efficacy compared to tenofovir, ~30% resistance at 5 years 3, 7
• Telbivudine: High resistance rates despite potent activity, plus risk of serious muscle complications 2

Treatment Duration

HBeAg-Positive Patients

• Continue oral agents for at least 1 year after HBeAg seroconversion, then an additional 3-6 months of consolidation therapy 2
• Monitor closely after discontinuation due to risk of severe hepatitis flares 1, 8

HBeAg-Negative Patients

• Long-term or indefinite treatment typically required 3, 1, 2
• Relapse rates are 80-90% if stopped within 1-2 years 2

Cirrhotic Patients

• Lifelong treatment recommended until HBsAg loss occurs 2
• Do not discontinue even after HBeAg seroconversion due to ongoing HCC risk 2

Peginterferon

• Fixed duration: 48 weeks 3, 1
• Consider stopping if no HBsAg decline at week 12 1

Monitoring During Treatment

• HBV DNA and ALT: Every 3-6 months 1, 2, 8
• HBeAg status: Regularly in HBeAg-positive patients 1, 2
• Renal function: Particularly with tenofovir DF; monitor serum creatinine and spot urine protein/creatinine ratio every 6 months 3, 8
• Bone density: Consider monitoring in patients on tenofovir DF with risk factors 2
• After discontinuation: Close clinical and laboratory monitoring for at least several months to detect hepatitis flares 9

Managing Inadequate Response

• First verify medication adherence - this is the most common cause of breakthrough, not true resistance 2
• For partial virologic response: Switch to tenofovir (DF or TAF) if on lamivudine/telbivudine, or add tenofovir if on entecavir 2
• For confirmed resistance: Switch to tenofovir or combine entecavir with tenofovir 2

Critical Pitfalls to Avoid

• Never use entecavir in lamivudine-experienced patients, even if prior exposure was brief, due to archived resistance mutations 3, 2, 4
• Do not discontinue therapy prematurely in HBeAg-negative patients or those with cirrhosis - this can trigger severe hepatitis flares 1, 8
• Do not use combination therapy as initial treatment in treatment-naive patients unless decompensated cirrhosis is present 2
• Do not assume virologic breakthrough represents resistance without first confirming medication adherence 2
• Do not use peginterferon in decompensated cirrhosis - it is absolutely contraindicated 2

Special Populations

Pregnancy

• Telbivudine or tenofovir may be used in the last trimester to prevent vertical transmission in women with high viremia 3

HIV/HBV Co-infection

• Use triple antiretroviral therapy including two agents active against HBV (emtricitabine/tenofovir or lamivudine/tenofovir as fixed-dose combinations) 3

Immunosuppression/Chemotherapy

• Prophylactic treatment indicated to prevent HBV reactivation 5

Long-Term Considerations

• HCC surveillance should continue lifelong in patients with significant fibrosis or cirrhosis, even after HBsAg loss 8
• Serious adverse effects to monitor include lactic acidosis and severe hepatomegaly with steatosis (hepatotoxicity), particularly in women and obese patients on long-term nucleoside analogue therapy 4, 9
• Post-treatment exacerbations can occur after discontinuation, with some cases resulting in fatalities; close monitoring for several months after stopping treatment is essential 9