Can HBsAg Become Negative?
Yes, HBsAg can become negative through spontaneous clearance, occurring at approximately 0.5% per year in chronic carriers, representing "resolved hepatitis B" with sustained loss of HBsAg, undetectable HBV DNA, and absence of active viral infection. 1
Mechanisms and Rates of HBsAg Clearance
Spontaneous clearance occurs naturally but slowly:
- Approximately 0.5% of HBsAg carriers clear the antigen yearly 1
- Most patients who clear HBsAg will subsequently develop anti-HBs antibodies 1
- Clearance typically follows years of chronic infection, often after HBeAg seroconversion 1
Predictors of impending HBsAg clearance include:
- Decreasing HBsAg titers over time 2
- Persistent normalization of serum ALT levels 2
- Older age and prior HBeAg clearance 1
Clinical Phases Leading to HBsAg Loss
The pathway typically follows this sequence:
- Initial HBeAg clearance occurs at 8-12% per year in adults with elevated ALT 1
- After HBeAg seroconversion, 67-80% of carriers enter the "inactive carrier state" with low/undetectable HBV DNA and normal ALT 1
- From the inactive carrier state, approximately 0.5% annually progress to complete HBsAg clearance 1
Important caveat: HBsAg clearance may follow an acute ALT elevation, with HBsAg disappearing within 6 months (mean 70 days) after the flare 3, 2
Critical Post-Clearance Considerations
HBsAg negativity does NOT equal complete viral eradication:
- Low levels of HBV DNA remain detectable by PCR in up to 50% of patients after HBsAg disappearance 1
- Covalently closed circular DNA (cccDNA) persists in hepatocytes even after HBsAg clearance 4
- Patients remain at risk for HBV reactivation if subsequently immunosuppressed 1, 4
Long-term complications can still occur:
- Hepatocellular carcinoma can develop even after HBsAg clearance, particularly if HBV DNA persists 1, 3
- Active liver disease (chronic active hepatitis, cirrhosis) may progress despite HBsAg negativity 3
- The risk of hepatic decompensation decreases but is not eliminated 1
Treatment-Related HBsAg Loss
Antiviral therapy can accelerate HBsAg clearance:
- Nucleos(t)ide analogue (NA) therapy: HBsAg loss achieved in some patients, with medium HBsAg (MHBs) becoming undetectable approximately 12.8 months before total HBsAg loss 5
- Pegylated interferon therapy: HBsAg decline at week 12 predicts treatment response 6, 7
- HBsAg levels <100 IU/mL for six consecutive months may predict sustained response after treatment cessation 7
Monitoring After HBsAg Clearance
Continued surveillance remains essential:
- Monitor for HBV DNA by PCR, as low-level viremia may persist 1, 3
- Screen for hepatocellular carcinoma if prior cirrhosis or advanced fibrosis existed 1, 3
- Check anti-HBs development, though this does not guarantee complete protection against reactivation 1
- Before any immunosuppressive therapy, test HBV DNA even in HBsAg-negative/anti-HBc-positive patients 4
Common pitfall: Assuming HBsAg clearance means complete cure and discontinuing all monitoring—this can miss late complications including HCC and reactivation during immunosuppression 1, 3