What is the recommended treatment for Hepatitis B (HBV) infection?

Treatment of Hepatitis B Infection

For chronic hepatitis B, first-line treatment should be entecavir 0.5 mg daily or tenofovir (either disoproxil fumarate 300 mg or alafenamide) once daily, as these agents provide the highest potency with minimal resistance risk and have demonstrated superior long-term outcomes including regression of cirrhosis. 1, 2

Treatment Indications Based on Clinical Parameters

HBeAg-Positive Patients

• Treat when HBV DNA ≥20,000 IU/mL AND ALT >2× upper limit of normal (ULN) 1, 3
  • ULN is defined as 30 IU/L for men and 19 IU/L for women 1
• If HBV DNA ≥20,000 IU/mL but ALT is normal, obtain liver biopsy or transient elastography 1
  • Treat if significant fibrosis or inflammation is present
  • If no biopsy performed, monitor ALT every 3 months for first year, then every 6-12 months 1
• Consider treatment even with lower ALT if family history of hepatocellular carcinoma or cirrhosis exists 2

HBeAg-Negative Patients

• Treat when HBV DNA ≥2,000 IU/mL AND ALT >2× ULN 1, 3
• If HBV DNA ≥2,000 IU/mL with normal ALT, consider biopsy or elastography 1
  • Treat if disease present on histology
  • Otherwise observe for ALT elevation with monitoring every 6-12 months 1

Compensated Cirrhosis

• Treat if HBV DNA ≥2,000 IU/mL regardless of ALT level 1, 2, 3
• Strongly prefer entecavir or tenofovir over lamivudine due to high resistance rates that could precipitate decompensation 2

Decompensated Cirrhosis

• Immediately treat ALL patients with any detectable HBV DNA, regardless of viral load level, HBeAg status, or ALT 2, 3
• 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 2

First-Line Treatment Selection

Preferred Agents

• Entecavir 0.5 mg daily: Achieves 83% virologic suppression (HBV DNA <50 IU/mL) at 96 weeks with no genotypic resistance after 8 years in treatment-naïve patients 2
• Tenofovir disoproxil fumarate (TDF) 300 mg daily: Demonstrates 93% virologic suppression at 48 weeks with no resistance after 8 years 2
• Tenofovir alafenamide (TAF): Equally effective as TDF but with improved renal and bone safety profile, particularly important for patients at risk of renal dysfunction or metabolic bone disease 2

Critical Caveat for Drug Selection

• Never use entecavir in patients with any prior lamivudine exposure, even if brief, due to risk of archived resistance mutations in HBV covalently closed circular DNA 2
  • For lamivudine-experienced patients, use tenofovir (DF or AF) instead 2

Agents to Avoid as First-Line Therapy

• Do not use lamivudine, adefovir, telbivudine, or clevudine as first-line therapy 2
  • Lamivudine: resistance rates up to 70% over 5 years 1
  • Adefovir: inferior efficacy compared to tenofovir 2
  • Telbivudine: high resistance rates despite potent activity, plus risk of serious muscle complications 2

Treatment Duration

HBeAg-Positive Patients

• Continue nucleos(t)ide analogue for minimum 1 year, then 3-6 months after HBeAg seroconversion 1, 3
• Do not discontinue in cirrhotic patients even after HBeAg seroconversion due to ongoing risk of hepatocellular carcinoma and disease progression 2

HBeAg-Negative Patients

• Long-term or indefinite treatment typically required 1, 3
• Relapse rates reach 80-90% if stopped within 1-2 years 1
• Some data from Taiwan suggest finite therapy of 2-3 years may increase HBsAg loss rates up to 30% at 5 years, but this requires intensive monitoring for hepatitis flares 4

Cirrhotic Patients

• Continue therapy until HBsAg loss occurs 2
• Never discontinue prematurely as this can lead to severe hepatitis flares 2

Managing Inadequate Response

Verify Adherence First

• Medication non-adherence is the most common cause of breakthrough, not true resistance 2
• Confirm adherence before assuming resistance 2

Confirmed Virologic Breakthrough

• If on lamivudine or telbivudine: switch to tenofovir (DF or AF) 2
• If on entecavir: add tenofovir 2
• For adefovir-resistant patients: switch to tenofovir monotherapy or tenofovir/entecavir combination 2
  • Patients with both rtA181T/V and rtN236T mutations may have inferior response to tenofovir monotherapy and require close monitoring 2

Treatment Goals and Endpoints

Primary Goal

• Sustained suppression of HBV DNA to undetectable levels to prevent progression to cirrhosis, liver failure, and hepatocellular carcinoma 1, 2

Secondary Goals

• ALT normalization 1, 2
• Histologic improvement 1

Ideal Endpoint

• HBsAg loss with or without anti-HBs seroconversion 2, 3
• This occurs in only a minority of patients receiving antiviral therapy 1
• Represents the best stopping rule for HBeAg-negative patients, including those with cirrhosis 5

Monitoring During Treatment

• HBV DNA and ALT every 3-6 months 2, 3
• HBeAg status regularly in HBeAg-positive patients 2
• Renal function, particularly with tenofovir DF 2
• Consider bone density monitoring in patients on tenofovir DF with risk factors 2
• Hepatocellular carcinoma surveillance every 6 months with ultrasound and alpha-fetoprotein in high-risk patients (Asian men >40 years, Asian women >50 years, cirrhosis, family history of HCC, Africans >20 years) 1, 6

Special Populations

Pregnancy

• For women requiring treatment during pregnancy: use lamivudine, telbivudine, or tenofovir during third trimester 1
• Tenofovir or telbivudine preferred due to pregnancy category B classification 3
• For women with HBV DNA ≥10^7 copies/mL and elevated ALT, or who already have HBsAg-positive child, antiviral therapy is indicated to reduce transmission risk 1

HIV Coinfection

• Entecavir is not recommended unless patient is also receiving HAART 7
• HIV resistance may emerge in chronic hepatitis B patients with unrecognized or untreated HIV infection 8
• Offer HIV testing to all patients prior to initiating treatment 8

Renal Dysfunction

• Switch from tenofovir DF to entecavir or tenofovir AF based on prior treatment history 2
• Adefovir requires dose adjustment: creatinine clearance 30-49 mL/min = 10 mg every 48 hours; 10-29 mL/min = 10 mg every 72 hours; hemodialysis = 10 mg every 7 days following dialysis 8

Common Pitfalls to Avoid

• Do not use combination therapy as initial treatment in treatment-naïve 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
• Do not discontinue therapy prematurely in HBeAg-negative patients or those with cirrhosis 2
• Do not use entecavir in lamivudine-experienced patients 2
• Do not coadminister adefovir with tenofovir-containing products 8