HBV Genotype and Biomarkers Predict Severe Flares After NA Cessation

The study highlights the significant role of HBV genotype and end-of-treatment (EOT) biomarkers in predicting severe virologic relapses (SVRel) and severe biochemical flares (SBF) after nucleos(t)ide analogue (NA) cessation in patients with chronic hepatitis B virus (HBV) infection. Here's a detailed breakdown of the findings:

### HBV Genotype and Treatment Response:

1. **Genotype Influence**:

• Different HBV genotypes were associated with varying risks of SVRel and SBF.
• Genotypes C, D, and E were linked to higher rates of relapse and flares.
• Notably, none of the patients with genotype A developed severe biochemical flares (SBF), indicating a potentially protective role of genotype A against severe post-cessation events.

2. **Genotype as a Predictive Marker**:

• Non-A genotypes were significantly associated with a higher risk of severe biochemical flares (SBF) after NA cessation. This was supported by a multivariate analysis, where non-A genotype had an adjusted odds ratio (aOR) of 19.03 (p=0.018) for predicting SBF.

### Biomarkers and Predictive Value:

1. **Key Biomarkers**:

• HBcrAg (Hepatitis B core-related antigen): Detectable levels at the end of treatment were strongly associated with severe virologic relapses (SVRel). The adjusted odds ratio (aOR) for SVRel was 3.93 (p=0.01).
• HBV RNA: Detectable HBV RNA was independently predictive of severe biochemical flares (SBF) with an aOR of 7.84 (p=0.005).
• Anti-HBc IgG: Lower levels of anti-HBc IgG were associated with a higher risk of SBF (aOR 0.31, p=0.016).

2. **COBRA Score**:

• A risk stratification tool, called the COBRA score, was developed using three biomarkers: HBcrAg, HBV RNA, and anti-HBc IgG.
• A COBRA score ≥2 was effective in identifying patients at increased risk for severe biochemical flares (SBF), with a sensitivity of 80.0% and a negative predictive value (NPV) of 90.7%.

### Conclusion of the Study:

• The study concludes that both HBV genotype and EOT biomarkers (HBcrAg, HBV RNA, and anti-HBc IgG) are valuable predictors of severe virologic relapses (SVRel) and severe biochemical flares (SBF) after NA cessation in patients with chronic HBV infections.
• Among the genotypes, non-A genotypes (C, D, and E) were associated with higher risks of severe events, whereas genotype A appeared to confer a lower risk of SBF.
• The COBRA score provides a practical tool for individualized risk stratification, enabling clinicians to identify patients at the highest risk and tailor post-cessation monitoring and management strategies accordingly.

These findings underscore the importance of incorporating genotype and biomarker assessments into clinical decision-making to improve patient outcomes when discontinuing NA therapy in chronic HBV management.