What are the guidelines for managing hepatitis B (HBV)?

Hepatitis B Management Guidelines

First-Line Treatment Recommendations

For chronic hepatitis B, use entecavir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF) as first-line monotherapy—these are the only recommended nucleos(t)ide analogues due to their high genetic barrier to resistance and superior viral suppression rates. 1, 2

• Avoid first-generation agents (lamivudine, adefovir) due to high resistance rates reaching up to 70% at 5 years 3
• ETV maintains resistance rates <1% after 5 years, while TDF shows no resistance after 8 years of treatment 2
• TAF demonstrates less renal tubular dysfunction and bone mineral density loss compared to TDF through 96 weeks 2

Treatment Indications

Patients Without Cirrhosis

Initiate treatment when HBV DNA ≥2,000 IU/mL with elevated ALT and/or at least moderate histological lesions on biopsy. 1, 2

Start treatment immediately without liver biopsy if any of the following criteria are met:

• HBV DNA ≥20,000 IU/mL AND ALT >2× upper limit of normal (ULN) 1, 3
• HBV DNA ≥2,000 IU/mL AND liver stiffness ≥9 kPa with normal ALT or ≥12 kPa with ALT <5× ULN 3
• HBV DNA ≥2,000 IU/mL AND at least moderate fibrosis demonstrated by biopsy or non-invasive markers, even with normal ALT 1, 3
• HBeAg-positive patients over age 30 with persistently normal ALT and HBV DNA >1,000 IU/mL 4
• Family history of cirrhosis and/or hepatocellular carcinoma (HCC) with HBV DNA ≥2,000 IU/mL 3

Critical pitfall: Do not rely on traditional laboratory ALT cutoffs to exclude necroinflammation—normal ALT by conventional criteria does not exclude significant liver disease. 2

Patients With Cirrhosis

All patients with cirrhosis and any detectable HBV DNA must be treated immediately, regardless of ALT levels. 1, 2, 3

• For decompensated cirrhosis, initiate ETV or TDF urgently and simultaneously evaluate for liver transplantation 1, 2
• Pegylated interferon alfa is absolutely contraindicated in decompensated disease 2
• Lifelong treatment is mandatory for all decompensated patients 2

Special Populations

Pregnancy

Use tenofovir DF as the preferred agent during pregnancy, starting prophylactic therapy at 24-32 weeks of gestation for women with HBV DNA >200,000 IU/mL to prevent mother-to-child transmission. 2, 3

• Breastfeeding is not contraindicated even while on tenofovir DF 3
• Post-vaccination testing should be performed for all newborns of HBV-infected mothers at 9-18 months 2

Immunosuppression/Chemotherapy

All HBsAg-positive patients undergoing chemotherapy or immunosuppressive therapy must receive ETV, TDF, or TAF as prophylaxis. 1

For HBsAg-negative, anti-HBc positive patients:

• High-risk groups (>10% reactivation risk, including rituximab-based regimens or stem cell transplantation) require antiviral prophylaxis 1
• Continue prophylaxis through treatment and for at least 12 months (18 months for rituximab-based regimens) after cessation of immunosuppression 1
• Monitor liver function tests and HBV DNA every 3-6 months during prophylaxis and for at least 12 months after discontinuation 1

HIV-HBV Coinfection

All HIV-HBV coinfected patients should start antiretroviral therapy (ART) with TDF- or TAF-based regimens immediately, regardless of CD4 count. 2, 3

Renal Dysfunction

For patients with renal impairment or bone disease, prefer entecavir, TAF, or besifovir over TDF. 4

• Monitor renal function in all patients on TDF or adefovir 4
• Tenofovir DF may cause new or worsening kidney problems, including kidney failure 5

Monitoring During Treatment

Initial Phase

• HBV DNA every 3 months until undetectable, then every 6 months 2, 3
• Liver function tests (ALT/AST) every 3-6 months 2, 3
• For patients not on treatment: ALT every 3 months, HBV DNA every 6-12 months, fibrosis assessment every 12 months 2

Long-Term Monitoring

• Annual quantitative HBsAg testing to assess for potential HBsAg loss 3
• Renal function monitoring if on tenofovir 3
• Ultrasound examination every 6 months for HCC surveillance in high-risk patients (Asian men >40 years, Asian women >50 years, any patient with cirrhosis, family history of HCC) 2, 3

HCC surveillance is mandatory for all cirrhotic patients and those with moderate-to-high HCC risk scores, even under effective NA therapy. 2

Treatment Response Definitions

• Virological response: Undetectable HBV DNA by sensitive PCR assay during NA therapy 1, 2
• Biochemical response: Normalization of ALT levels 1
• Sustained off-therapy virological response: Serum HBV DNA <2,000 IU/mL for at least 12 months after therapy ends 2

Treatment Duration and Discontinuation

Long-term, potentially indefinite treatment is typically required with nucleos(t)ide analogues, with HBsAg loss (functional cure) as the optimal endpoint, though this is rarely achieved. 2, 4

Stopping NA therapy may be considered in:

• HBeAg-positive patients who achieve HBeAg seroconversion with undetectable HBV DNA and have completed at least 12 months of consolidation therapy 2, 3
• Close monitoring is essential after discontinuation, as severe acute exacerbations can occur 6

Alternative Treatment Option

Pegylated interferon alfa can be considered for finite-duration therapy (48 weeks) in selected patients with mild to moderate disease who desire time-limited treatment, though response is variable and side effects limit its use. 2, 3

Additional Preventive Measures

• Hepatitis A vaccination if anti-HAV negative, as coinfection increases mortality 5.6- to 29-fold 3
• Counsel on complete alcohol abstinence, as even limited consumption worsens outcomes 3
• Screen for coinfections: anti-HCV, anti-HDV (if injection drug use history), anti-HIV 3

Critical Safety Warnings

• Lactic acidosis and severe hepatomegaly with steatosis: Suspend treatment if suspected 6, 5
• Severe acute exacerbations after discontinuation: Monitor hepatic function closely for at least several months after stopping therapy 6
• HIV coinfection: Entecavir is not recommended unless the patient is also receiving highly active antiretroviral therapy (HAART) 6