What is the diagnosis and treatment for a patient with reactive Hepatitis B surface antigen (HBsAg) and nonreactive Hepatitis B surface antibody (anti-HBs)?

Diagnosis: Chronic Hepatitis B Infection

A patient with reactive HBsAg and nonreactive anti-HBs has chronic hepatitis B infection, requiring further characterization of disease phase and assessment for treatment eligibility. 1

Confirming Chronic HBV Infection

• HBsAg positivity for ≥6 months defines chronic hepatitis B (CHB), distinguishing it from acute infection 1
• The absence of anti-HBs (surface antibody) confirms ongoing infection without immune clearance 2
• If this is the first positive HBsAg test, repeat testing in 6 months is necessary to confirm chronicity 1

Essential Diagnostic Workup to Characterize Disease Phase

The following tests are mandatory to determine treatment eligibility and prognosis:

Viral Replication Status

• HBV DNA quantification using real-time PCR (required for all CHB patients) 1, 3
• HBeAg and anti-HBe testing to distinguish HBeAg-positive from HBeAg-negative disease 1, 4

Liver Disease Activity and Severity

• ALT and AST levels to assess hepatic inflammation 1, 4
• Liver function tests including bilirubin, albumin, and prothrombin time 4
• Abdominal ultrasound to evaluate for cirrhosis and exclude hepatocellular carcinoma 4
• Non-invasive fibrosis assessment (transient elastography) or liver biopsy if ALT is elevated and HBV DNA >2,000 IU/mL 1

Coinfection Screening

• Anti-HCV, anti-HDV, and HIV testing in at-risk individuals, as coinfections accelerate liver disease 5, 4
• Hepatitis A serology with vaccination if non-immune 5

Disease Phase Classification

Based on the AASLD 2018 guidelines, chronic HBV infection is categorized into distinct phases that determine treatment decisions 1:

HBeAg-Positive Disease

• Immune-tolerant phase: HBV DNA >1 million IU/mL, normal/minimally elevated ALT, no significant fibrosis—generally do not treat, monitor every 3-6 months 1
• Immune-active phase: HBV DNA >20,000 IU/mL, ALT ≥2× ULN—treat immediately 1
• Immune-active phase with ALT >ULN but <2× ULN: Assess fibrosis; if ≥F2 or ≥A3, treat 1

HBeAg-Negative Disease

• Inactive carrier: HBV DNA <2,000 IU/mL, persistently normal ALT—do not treat, monitor ALT and HBV DNA every 3-6 months for first year, then every 6 months 1
• HBeAg-negative CHB: HBV DNA >2,000 IU/mL with elevated ALT—exclude other causes of ALT elevation, assess fibrosis; if ≥F2 or ≥A3, treat 1
• Age >40 years with persistent ALT >ULN and HBV DNA >20,000 IU/mL—treat regardless of fibrosis stage 1

Treatment Recommendations

First-Line Antiviral Agents

• Entecavir 0.5 mg daily or tenofovir disoproxil fumarate (TDF) are preferred oral antivirals due to high barrier to resistance 1
• Tenofovir alafenamide (TAF) is an alternative with improved renal and bone safety profile 1
• Peginterferon alfa-2a 180 mcg weekly for 48 weeks may be considered in select patients (younger age, high ALT, low HBV DNA, no cirrhosis) 1

Treatment Endpoints

• Optimal endpoint: HBsAg loss with or without anti-HBs seroconversion 1
• Satisfactory endpoint for HBeAg-positive patients: HBeAg seroconversion (loss of HBeAg with development of anti-HBe) followed by 12 months of consolidation therapy 1
• For HBeAg-negative patients: Indefinite treatment is typically required, as stopping therapy leads to virological relapse in most cases 1

Critical Monitoring During Treatment

• HBV DNA and ALT every 3-6 months to assess virological response and detect breakthrough 1, 3
• HBeAg and anti-HBe every 6-12 months in HBeAg-positive patients 1
• HBsAg annually to monitor for functional cure 1, 3
• Assess for HBV DNA at weeks 12 and 24 to predict sustained response and resistance risk 3

Hepatocellular Carcinoma Surveillance

• All patients with chronic HBV require HCC surveillance regardless of cirrhosis status, as HCC can develop even after HBsAg clearance 6
• Ultrasound with or without AFP every 6 months for all CHB patients 1

Common Pitfalls and Caveats

• Do not rely on ALT alone: Normal ALT does not exclude significant liver disease; up to 20-30% of patients with normal ALT have significant fibrosis 1
• HBV DNA levels fluctuate: A single low HBV DNA measurement does not confirm inactive disease; serial measurements over 12 months are required 1
• Reactivation risk: Even patients with resolved infection (HBsAg-negative, anti-HBc-positive) can reactivate with immunosuppression and require prophylaxis 7, 5
• Contact screening and vaccination: Test all household and sexual contacts for HBsAg and anti-HBs; vaccinate all seronegative contacts 5