Why is it necessary to test for both Hepatitis B surface antigen (HBsAg) and Hepatitis B core antibody (AntiHBc) before starting direct-acting antiviral (DAA) therapy in patients with confirmed Hepatitis C virus (HCV) infection, rather than testing for HBsAg alone?

Why Both HBsAg and Anti-HBc Testing Are Required Before HCV Treatment

Testing for both HBsAg and anti-HBc before starting HCV direct-acting antiviral (DAA) therapy is mandatory because HBsAg alone misses patients with resolved HBV infection (HBsAg-negative/anti-HBc-positive) who remain at risk for HBV reactivation during or after HCV treatment. 1, 2

The Critical Gap: What HBsAg Alone Misses

Resolved HBV Infection Carries Reactivation Risk

• Patients who are HBsAg-negative but anti-HBc-positive have resolved (past) HBV infection, and approximately 20% of HCV patients fall into this category. 3
• While the reactivation rate in this population is very low (0-0.1% to 1.4%), it is not zero, and reactivation can occur during DAA therapy. 1, 4
• Testing HBsAg alone would completely miss this population, leaving them unmonitored for a preventable complication. 1, 2

Occult HBV Infection

• Some patients with resolved HBV infection have occult hepatitis B (HBsAg-negative, anti-HBc-positive, with detectable HBV DNA), occurring in approximately 0.48% of HCV patients. 1, 3
• These patients have a higher risk of reactivation and may require prophylactic antiviral therapy. 1
• Without anti-HBc testing, occult HBV infection cannot be identified. 2

The Evidence for HBV Reactivation During DAA Therapy

Active HBV Infection (HBsAg-Positive)

• In HBsAg-positive patients receiving DAA therapy, HBV reactivation occurs in 24% of cases, with HBV-related hepatitis developing in 9%. 4
• A meta-analysis showed that HBV DNA became newly detected or increased in 14.1% of patients within 4-12 weeks of DAA administration, with active hepatitis (ALT elevation) in 12.2%. 1
• Three major clinical events have been reported: one liver decompensation, two liver failures (one requiring transplantation). 4

Resolved HBV Infection (HBsAg-Negative/Anti-HBc-Positive)

• While the reactivation rate is much lower (0.16-1.4%), cases have been documented. 4, 3
• In one study, 6.3% of patients with resolved HBV infection had detectable HBV DNA during DAA treatment, particularly those with negative or very low anti-HBs titers (<20 mIU/mL). 5
• Reactivation risk increases in immunocompromised patients or those receiving immunosuppressive therapy. 1, 3

Clinical Management Algorithm Based on Testing Results

If HBsAg-Positive

• Start nucleos(t)ide analogue (NA) therapy (entecavir, tenofovir disoproxil, or tenofovir alafenamide) before or concurrent with DAA therapy. 1, 2
• Monitor ALT and HBV DNA levels during and after DAA therapy. 1
• In patients with cirrhosis or HCC history, simultaneous NA therapy is strongly recommended to prevent liver failure. 1

If HBsAg-Negative but Anti-HBc-Positive

• No prophylactic antiviral therapy is required before starting DAA therapy. 1, 2
• Monitor ALT levels monthly during DAA treatment. 2
• If ALT elevation occurs, immediately test HBsAg and HBV DNA to check for reactivation. 1
• If HBV reactivation is confirmed (HBsAg becomes positive or HBV DNA detectable), start NA therapy immediately. 1, 2

If Both HBsAg and Anti-HBc Are Negative

• No specific HBV monitoring is required during DAA therapy. 2
• The patient has no prior HBV exposure and is not at risk for reactivation. 6

Common Pitfalls to Avoid

Testing Only HBsAg

• This is the single most important pitfall—it misses 20% of patients with resolved HBV infection who need monitoring. 3
• Without anti-HBc testing, you cannot stratify reactivation risk or implement appropriate monitoring. 1, 2

Assuming Low Risk Means No Risk

• Even though reactivation rates are low in HBsAg-negative/anti-HBc-positive patients, the consequences of missed reactivation can be severe. 2
• The cost of monthly ALT monitoring is minimal compared to the risk of acute liver failure. 1

Not Checking Anti-HBs Levels

• Patients with resolved HBV infection who have negative or very low anti-HBs titers (<20 mIU/mL) are at higher risk for detectable HBV DNA during treatment. 5
• Consider more frequent monitoring in this subgroup. 5

Guideline Consensus

All major hepatology societies mandate dual testing:

• The Korean Association for the Study of the Liver (KASL) 2022 guidelines explicitly recommend testing both HBsAg and anti-HBc before DAA therapy. 1
• The KDIGO 2022 guidelines state that all CKD patients with HCV should undergo testing for HBV infection (including both markers) prior to DAA therapy. 1
• The European Association for the Study of the Liver recommends testing HBsAg, anti-HBc, and anti-HBs before initiating HCV treatment. 2

The rationale is clear: comprehensive HBV screening identifies all patients at risk—both those with active infection requiring prophylaxis and those with resolved infection requiring monitoring—thereby preventing potentially fatal HBV reactivation during HCV treatment. 1, 2, 4