Is Hepatitis B (HBV) reactivation a concern during Hepatitis C (HCV) treatment with Mavyret (glecaprevir/pibrentasvir) in a patient with Hepatitis B core and surface antibody positive, but surface antigen negative?

HBV Reactivation Risk with Mavyret in Resolved HBV Infection

Yes, HBV reactivation is a concern during Mavyret treatment in patients with positive hepatitis B core and surface antibodies but negative surface antigen, though the risk is low and can be managed with monitoring rather than prophylaxis. 1

FDA Black Box Warning and Manufacturer Guidance

The FDA has issued a black box warning for Mavyret (glecaprevir/pibrentasvir) specifically addressing HBV reactivation risk. 1 The warning mandates testing all patients for evidence of current or prior HBV infection before initiating treatment, as HBV reactivation has resulted in fulminant hepatitis, hepatic failure, and death in some cases. 1 Critically, the FDA label explicitly states that reactivation has been reported not only in HBsAg-positive patients but also in patients with serologic evidence of resolved HBV infection (HBsAg-negative and anti-HBc-positive). 1

Risk Stratification for Your Patient

Your patient's serologic profile (HBsAg-negative, anti-HBc-positive, anti-HBs-positive) indicates resolved HBV infection with protective immunity. 2 This places them in a low-risk category for HBV reactivation during DAA therapy:

• Reactivation rates in resolved HBV infection during DAA therapy range from 1-10%, significantly lower than in HBsAg-positive patients. 2
• The presence of anti-HBs provides additional protection, with reactivation rates of approximately 4.3% in anti-HBs-positive patients versus 14% in anti-HBs-negative patients. 3
• Research specifically examining DAA treatment in resolved HBV infection found that 6.3% of patients developed detectable HBV DNA during treatment, with only one case meeting criteria for true reactivation (HBV DNA 80 IU/mL), and none developed hepatic failure. 4

Recommended Management Strategy

For patients with resolved HBV infection (your patient's profile), the 2025 AGA guidelines recommend monitoring without antiviral prophylaxis. 2 This represents a conditional recommendation favoring monitoring alone for low-risk patients. 2

Monitoring Protocol

Implement the following surveillance schedule during and after Mavyret treatment:

• Baseline testing: HBV DNA, ALT, and confirm HBsAg status before starting Mavyret. 2, 1
• During treatment: Monitor HBsAg, ALT, and HBV DNA every 1-3 months throughout the treatment course. 2, 5
• Post-treatment: Continue monitoring for at least 6 months after completing Mavyret therapy. 2, 5
• Frequency: The AGA recommends 1-3 month intervals for monitoring, with more frequent monitoring (monthly) reasonable given the DAA context. 2, 6

Triggers for Intervention

Initiate antiviral therapy immediately if any of the following occur during monitoring:

• HBsAg becomes positive (seroreversion). 5, 1
• HBV DNA becomes detectable or quantifiable (>20 IU/mL). 5, 4
• ALT elevation >100 U/L and >3 times baseline in the context of detectable HBV DNA. 5, 1

Special Considerations and Pitfalls

When to Consider Prophylaxis Instead

While monitoring is the standard approach for your patient, prophylactic antiviral therapy should be considered if any of these high-risk features are present:

• Concomitant immunosuppressive therapy, particularly high-dose corticosteroids (>20 mg prednisone daily for >4 weeks). 2
• Isolated anti-HBc positivity without anti-HBs (not your patient's case, but important to distinguish). 5
• History of previous HBV reactivation. 5
• Advanced liver disease or cirrhosis, which increases both reactivation risk and severity of consequences. 1

Critical Timing Considerations

Research demonstrates that HBV reactivation during DAA therapy occurs early in the treatment course:

• The median time to reactivation with DAAs is approximately 4.2 months. 7
• Most cases occur within the first 4 weeks of treatment (median 27 days for hepatic decompensation events). 1
• This early timing underscores the importance of baseline testing before initiating Mavyret and frequent early monitoring. 1, 7

Anti-HBs Titer Dynamics

One important caveat: research shows that anti-HBs titers can decrease during DAA treatment, even in patients with initially protective levels. 4 Patients with very low baseline anti-HBs titers (<20 mIU/mL) are at higher risk for detectable HBV DNA during treatment. 4 If your patient's anti-HBs titer is borderline or low, consider more frequent monitoring.

Antiviral Selection if Prophylaxis Becomes Necessary

Should prophylaxis be required based on additional risk factors or if reactivation occurs during monitoring:

• Preferred agents: Entecavir or tenofovir (high barrier to resistance). 2, 5
• Avoid lamivudine due to high resistance rates. 3
• Duration: Start 2-4 weeks before Mavyret if prophylaxis is chosen, and continue for at least 6-12 months after completing HCV treatment. 2, 5

Clinical Bottom Line

Do not delay Mavyret treatment for HBV concerns in this patient. 1 The risk-benefit analysis strongly favors proceeding with HCV treatment using a monitoring strategy rather than prophylaxis, given the low reactivation risk in resolved HBV infection with protective antibodies. 2, 4 However, vigilant monitoring is non-negotiable given the FDA black box warning and documented cases of reactivation in this serologic profile. 1