What is the recommended treatment for hepatitis B (HBV)?

Treatment of Hepatitis B

First-Line Treatment Recommendations

For chronic hepatitis B, initiate treatment with either entecavir or tenofovir as first-line monotherapy, as these agents provide superior potency, achieve >90% virologic suppression, and have minimal to no resistance development. 1, 2

Preferred Agents

• Entecavir 0.5 mg daily achieves 83% virologic suppression (HBV DNA <50 IU/mL) at 96 weeks with no genotypic resistance detected after 8 years in treatment-naive patients 1, 2
• Tenofovir 300 mg daily demonstrates 93% virologic suppression at 48 weeks with no documented resistance through 8 years of treatment 3, 1, 2
• Tenofovir alafenamide (TAF) is equally effective as tenofovir disoproxil fumarate (TDF) but offers improved renal and bone safety, particularly important for patients at risk of renal dysfunction or metabolic bone disease 2

Alternative First-Line Option

• Peginterferon alfa-2a 180 mcg weekly subcutaneously for 48 weeks can be used in select patients, particularly those with HBV genotype A or B, high ALT, low HBV DNA, and younger age, as it achieves higher rates of HBeAg seroconversion (32%) and HBsAg loss compared to nucleos(t)ide analogues 3, 1

Treatment Indications Based on Clinical Scenario

HBeAg-Positive Patients

• Initiate treatment when HBV DNA >20,000 IU/mL AND ALT >2× ULN 3, 1, 4
• Consider treatment with family history of HCC or cirrhosis even if ALT <2× ULN 2

HBeAg-Negative Patients

• Initiate treatment when HBV DNA >2,000 IU/mL AND ALT >2× ULN 3, 1, 4
• Long-term treatment is required, as relapse rates reach 80-90% if stopped within 1-2 years 2, 4

Compensated Cirrhosis

• Treat if HBV DNA ≥2,000 IU/mL, regardless of ALT level 3, 1, 2
• Prefer entecavir or tenofovir over lamivudine due to high resistance rates with lamivudine that could precipitate decompensation 3, 2
• Peginterferon may be considered in select patients 1

Decompensated Cirrhosis

• Immediately treat all patients with any detectable HBV DNA, regardless of viral load level, HBeAg status, or ALT level 3, 2
• Use entecavir 1 mg daily or tenofovir 1
• Consider combination therapy with tenofovir plus lamivudine or entecavir monotherapy to minimize resistance risk 2
• Peginterferon is absolutely contraindicated due to risk of further decompensation 1, 2

HIV/HBV Co-infection

• All HIV-infected persons should be tested for HBsAg 3
• Co-infected patients should receive triple combination antiretroviral therapy including two agents active against HBV (emtricitabine/tenofovir or lamivudine/tenofovir, preferably as fixed-dose formulations) 3

Agents to Avoid as First-Line Therapy

• Do not use lamivudine due to resistance rates up to 70% over 5 years 3, 2, 5
• Do not use adefovir as it has inferior efficacy compared to tenofovir 3, 2, 6
• Do not use telbivudine despite potent antiviral activity, due to high resistance rates and risk of serious muscle-related complications 3, 2
• Monotherapy with lamivudine, emtricitabine, and telbivudine should be avoided if at all possible because of risk of resistance and difficulties with monitoring 3

Special Considerations for Drug Selection

Lamivudine-Experienced Patients

• Avoid entecavir in any patient with prior lamivudine exposure, even if brief, due to risk of archived resistance mutations in HBV covalently closed circular DNA 3, 1, 2, 7
• Use tenofovir instead 1, 2

Pregnant Women

• Telbivudine or tenofovir may be considered to prevent vertical transmission 1

Renal Impairment

• For creatinine clearance 30-49 mL/min: tenofovir 300 mg every 48 hours 8
• For creatinine clearance 10-29 mL/min: tenofovir 300 mg every 72-96 hours 8
• For hemodialysis patients: tenofovir 300 mg every 7 days or after approximately 12 hours of dialysis 8
• Consider switching from tenofovir DF to entecavir, tenofovir AF, or alternative based on prior treatment history 2

Treatment Duration

HBeAg-Positive Patients

• Continue nucleos(t)ide analogue for minimum 1 year, then 3-6 months after HBeAg seroconversion 1, 2, 4

HBeAg-Negative Patients

• Long-term or indefinite treatment is typically required, as relapse rates reach 80-90% if stopped within 1-2 years 1, 2, 4

Cirrhotic Patients

• Lifelong treatment is required due to risk of hepatic decompensation upon discontinuation 1, 2, 4
• Do not discontinue therapy even after HBeAg seroconversion due to ongoing risk of HCC and disease progression 2

Peginterferon

• Administer for 48 weeks 3, 1
• Consider stopping if no HBsAg decline at week 12 1

Monitoring During Treatment

• Monitor HBV DNA and ALT every 3-6 months to assess virologic and biochemical response 3, 1, 2, 4
• Monitor HBeAg status regularly in HBeAg-positive patients 1, 2, 4
• Monitor renal function (serum creatinine, spot urine protein/creatinine ratio if possible), particularly with tenofovir 3, 1, 2, 4
• For entecavir: measure ALT activities every 6 months 3
• For tenofovir: measure baseline serum creatinine, spot urine protein/creatinine ratio if possible, and ALT and serum creatinine every 6 months 3
• Consider monitoring bone density in patients on tenofovir DF with risk factors 2
• Monitor compliance in all patients 3

Managing Inadequate Response

Partial Virologic Response (HBV DNA detectable at 48 weeks)

• Switch to tenofovir if on lamivudine or telbivudine 2, 4
• Consider switching to tenofovir monotherapy or adding tenofovir if on entecavir with HBV DNA >1000 IU/mL at 1 year 4

Virologic Breakthrough

• Verify medication adherence first, as this is the most common cause of breakthrough rather than true resistance 2, 9
• If confirmed resistance, switch to tenofovir or add tenofovir if on entecavir 2, 4
• For adefovir-resistant patients, switch to tenofovir monotherapy or tenofovir/entecavir combination 2

Treatment Goals

• Primary goal: sustained suppression of HBV DNA to undetectable levels to prevent progression to cirrhosis, liver failure, and hepatocellular carcinoma 1, 2
• Secondary goals include ALT normalization and histologic improvement 1, 2
• Ideal endpoint is HBsAg loss with or without anti-HBs seroconversion 1, 2

Common Pitfalls to Avoid

• Do not use entecavir in patients with any prior lamivudine exposure, even if brief, due to risk of archived resistance mutations 2
• Do not discontinue therapy prematurely in HBeAg-negative patients or those with cirrhosis, as this can lead to severe hepatitis flares 2
• Do not use combination therapy as initial treatment in treatment-naive patients unless decompensated cirrhosis is present, as monotherapy with entecavir or tenofovir is equally effective and reduces cost and potential toxicity 2
• Do not assume virologic breakthrough represents resistance without first confirming medication adherence 2, 9
• Monitor hepatic function closely at repeated intervals for at least several months in patients who discontinue treatment, as severe acute exacerbations of hepatitis may occur 6