Hepatitis B: Comprehensive Management Approach

Screening and Initial Evaluation

All individuals at risk for hepatitis B should be screened with HBsAg, anti-HBc, and anti-HBs testing to determine infection status and immunity. 1

Who Should Be Screened:

All pregnant women during the first trimester of every pregnancy, regardless of prior vaccination or testing 2
Healthcare and public safety workers with occupational blood exposure risk 2
Persons born in endemic regions (Asia, Africa, Pacific Islands) 2
HIV-infected individuals, dialysis patients 2
Sexual partners of HBsAg-positive persons 1
Current or recent injection drug users 2
Persons with elevated liver enzymes of unknown cause 1

Initial Laboratory Assessment for HBsAg-Positive Patients:

HBV DNA quantification using real-time PCR (express in IU/mL) 1
HBeAg and anti-HBe to classify disease phase 2
ALT, AST, GGT, alkaline phosphatase, bilirubin, albumin, globulins 1
Complete blood count and prothrombin time 1
Hepatic ultrasound 1
Co-infection testing: HDV, HCV, HIV, and anti-HAV antibodies 1
HBV genotype in selected patients 1
Liver fibrosis assessment using transient elastography or biopsy 1, 2

Vaccination Strategy

Universal hepatitis B vaccination is the cornerstone of primary prevention and should be administered to all susceptible individuals. 1

Standard Vaccination Schedules:

Newborns: First dose within 24 hours of birth, then at 1-2 months and 6-18 months 2
Adults ≥20 years: Doses at 0,1, and 6 months 2
Adolescents 11-15 years: Two-dose series using adult 10 µg formulation is acceptable 2
Hemodialysis patients: Four-dose series of 40 µg at 0,1,2, and 6 months 2

Who Must Be Vaccinated:

All household and sexual contacts of HBsAg-positive persons who are negative for HBsAg, anti-HBc, and anti-HBs 1
Persons with diabetes aged 19-59 years (≥60 years at clinician discretion) 2
International travelers to endemic regions 2
Persons with chronic liver disease or hepatitis C 2

Additional Vaccination:

Hepatitis A vaccination for all anti-HAV negative chronic HBV patients 1

Treatment Indications: A Hierarchical Algorithm

The decision to treat depends on HBV DNA level, ALT elevation, presence of cirrhosis, and degree of liver fibrosis. 1, 2

Immediate Treatment Required (No Observation Period):

Any patient with decompensated cirrhosis and detectable HBV DNA 2
- Start entecavir or tenofovir immediately 2
- Evaluate for liver transplantation 2
- Pegylated interferon is absolutely contraindicated 2
Compensated cirrhosis with HBV DNA >2,000 IU/mL, regardless of ALT 2
Life-threatening acute hepatitis B (severe acute hepatitis or fulminant hepatitis) 2
- Start entecavir or tenofovir 2
HBV DNA ≥20,000 IU/mL with ALT ≥2× upper limit of normal (ULN), regardless of fibrosis 2
- No liver biopsy needed 2
Patients requiring immunosuppressive therapy or chemotherapy (including rituximab, anti-TNF agents) 2
- Prophylactic antiviral therapy mandatory to prevent reactivation 2

Treatment After Assessment:

HBV DNA ≥2,000 IU/mL with ALT >40 IU/L (>1× ULN) and moderate-to-severe necroinflammation or at least moderate fibrosis on biopsy or elastography 1, 2
HBV DNA ≥2,000 IU/mL with at least moderate fibrosis, even if ALT is normal 2

Observation Period Appropriate:

HBeAg-positive patients with HBV DNA >20,000 IU/mL but ALT 1-2× ULN or normal 2
- Observe for 3-6 months to assess for spontaneous HBeAg seroconversion 2
- If age >35-40 years, consider liver biopsy or elastography after observation 2
- Monitor ALT and HBV DNA every 3 months during first year 2

First-Line Treatment Options

Nucleos(t)ide analogues with high genetic barrier to resistance—entecavir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF)—are the preferred first-line treatments. 1, 2

Why These Agents:

Entecavir and TDF: No resistance after 8 years of TDF; <1% resistance after 5 years of entecavir 2
TAF: Less renal tubular dysfunction and bone mineral density loss compared to TDF through 96 weeks 2
First-generation NAs (lamivudine, adefovir, telbivudine) are not recommended due to low potency and high resistance rates 1, 2

Pegylated Interferon Alfa-2a:

Finite-duration therapy option with goal of inducing long-term immunological control 2
Variable response and significant side effects limit use 2
Absolutely contraindicated in decompensated cirrhosis and pregnancy 2

Special Populations

Pregnancy Management:

All HBsAg-positive pregnant women require quantitative HBV DNA testing to guide maternal antiviral therapy aimed at preventing perinatal transmission. 2

Maternal antiviral therapy indicated when HBV DNA >200,000 IU/mL 2
Start tenofovir DF between 24-32 weeks gestation 2
- TDF is the preferred agent due to high potency, low resistance, and favorable safety profile 2
Continue therapy up to 4 weeks postpartum with close monitoring for hepatic flares after discontinuation 2
Infant prophylaxis: Hepatitis B vaccine AND hepatitis B immune globulin (HBIG) within 12 hours of birth 2
Post-vaccination testing for all newborns of HBV-infected mothers at 9-18 months 2

HIV-HBV Coinfection:

All HIV-HBV coinfected patients should start antiretroviral therapy (ART) regardless of CD4 count 2
TDF- or TAF-based ART regimens are mandatory 2

Liver Transplant Candidates:

All candidates must receive NA therapy to achieve undetectable HBV DNA pre-transplant 2
Post-transplant: Combination of HBIG plus potent NA reduces graft infection to <5% 2

Healthcare Workers:

Healthcare workers with HBV DNA ≥2,000 IU/mL performing exposure-prone procedures should receive entecavir or tenofovir to reduce viral load to undetectable or <2,000 IU/mL 2

Monitoring During Treatment

Virological response is defined as undetectable HBV DNA by sensitive PCR assay; biochemical response is normalization of ALT levels. 1, 2

On-Treatment Monitoring:

Liver function tests every 3-6 months 2
HBV DNA levels every 3-6 months 2
HCC surveillance with ultrasound every 6 months for all cirrhotic patients and high-risk non-cirrhotic patients 2

Patients Not on Treatment:

ALT determinations at least every 3 months 2
HBV DNA every 6-12 months 2
Fibrosis assessment every 12 months 2

Specific Monitoring by Phase:

Immune-tolerant patients <30 years: ALT and HBV DNA every 6-12 months 2
Immune-tolerant patients ≥30 years: ALT and HBV DNA every 3-6 months 2
HBeAg-negative patients: ALT every 3 months during first year to confirm inactive-carrier status, then every 6-12 months with HBV DNA 2

Treatment Duration and Goals

Long-term, potentially indefinite treatment is typically required with nucleos(t)ide analogues. 1, 2

Treatment Goals:

Primary goal: Improve quality of life and survival by preventing progression to cirrhosis, decompensated cirrhosis, HCC, and death 1
Optimal endpoint: HBsAg loss (immunologic cure), but this is rarely achieved 1, 2
Sustained off-therapy virological response: HBV DNA <2,000 IU/mL for at least 12 months after therapy ends 2

Stopping Therapy Considerations:

HBeAg-positive patients: May consider stopping NA therapy after achieving HBeAg seroconversion with undetectable HBV DNA and completing at least 12 months of consolidation therapy 2
Lifelong treatment mandatory for all decompensated cirrhosis patients 2
Close monitoring required after discontinuation due to risk of hepatic flares 2

Hepatocellular Carcinoma Surveillance

HCC surveillance with ultrasound every 6 months is mandatory for high-risk patients, even during effective antiviral therapy. 2

Who Requires HCC Surveillance:

All patients with cirrhosis 2
Asian men >40 years and Asian women >50 years 2
First-generation African-American individuals >20 years 2
Any chronic carrier >40 years with persistent ALT elevation and/or HBV DNA >2,000 IU/mL 2
Persons with family history of HCC 2

Important Considerations:

Surveillance must continue even after HBsAg loss if patient is older than 40-50 years 2
Long-term nucleos(t)ide analogue therapy reduces but does not eliminate HCC risk 1
After 5 years of entecavir or TDF therapy, HCC incidence decreases further, with greater decrease in patients with baseline cirrhosis 1

Critical Clinical Pitfalls to Avoid

Do Not Assume Safety Based on Normal ALT:

Normal ALT by conventional criteria does not exclude significant liver disease 2
Traditional laboratory ALT cutoffs can miss necroinflammation and fibrosis 2

Do Not Delay Treatment in High-Risk Patients:

HBeAg-positive patients >40 years with persistently high HBV DNA have increased risk of cirrhosis and HCC and should be evaluated for treatment 2
Even "immune-tolerant" patients >40 years are not truly safe 2

Do Not Forget Lifestyle Counseling:

Counsel all patients to avoid or limit alcohol consumption (daily consumption of 40-80g accelerates disease progression) 3
Recommend smoking cessation (increases risk of cirrhosis and HCC) 3
Advise against regular marijuana use, particularly CBD-predominant products, due to documented hepatotoxicity risk 3
- If patient insists on use, monitor ALT/AST every 3 months initially, limit total CBD to <300 mg/day 3

Do Not Overlook Contacts:

All household and sexual contacts must be tested and vaccinated if susceptible 1

Do Not Use Pegylated Interferon in Contraindicated Patients:

Absolutely contraindicated in decompensated cirrhosis and pregnancy 2

Long-Term Outcomes and Prognosis

Antiviral treatment with potent nucleos(t)ide analogues improves natural history, prevents disease progression, and can reverse fibrosis. 1, 2

74% of cirrhotic patients show regression of fibrosis after 5 years of tenofovir 2
Chronic HBV infection cannot be completely eradicated due to persistence of covalently closed circular DNA (cccDNA) in hepatocyte nuclei 1
Up to 40% of untreated patients develop cirrhosis, liver failure, or HCC 4
600,000 people die annually worldwide from HBV-related liver disease or HCC 5

What is the recommended evaluation, vaccination, and treatment approach for hepatitis B infection, including indications for antiviral therapy and follow‑up?

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