Which baseline characteristics—such as younger age, non‑cirrhotic status, stable nucleos(t)ide analogue therapy, low hepatitis B surface antigen level (<1000 IU/mL, especially <500 IU/mL), low HBV DNA, HBeAg‑negative status, and elevated pretreatment alanine aminotransferase—were common among the approximately 20 % of patients who achieved a functional cure with bepirovirsen (antisense oligonucleotide)?

Baseline Characteristics Associated with Functional Cure in Bepirovirsen-Treated Patients

Among the approximately 20% of patients who achieved functional cure with bepirovirsen, the most common baseline characteristics were: low HBsAg levels (<1000 IU/mL, particularly <500 IU/mL), stable nucleos(t)ide analogue (NA) therapy, HBeAg-negative status, non-cirrhotic disease, younger age, and low HBV DNA levels.

Key Predictive Factors for Functional Cure

HBsAg Levels: The Strongest Predictor

The most critical baseline characteristic was low HBsAg concentration. The phase 3 B-Well trials specifically enrolled patients with HBsAg levels between 100-3000 IU/mL, recognizing this as the optimal treatment window 1. Within this range, patients with HBsAg <1000 IU/mL had substantially higher success rates. The STOP-NUC study demonstrated that patients with HBsAg <1000 IU/mL at treatment discontinuation achieved HBsAg loss rates of 28% compared to only 10% overall 2. This threshold represents a critical inflection point—patients above 1000 IU/mL are unlikely to achieve spontaneous HBsAg seroclearance and show suboptimal responses to novel antivirals 3.

Stable NA Therapy Status

All patients achieving functional cure in the B-Well trials were receiving stable nucleos(t)ide analogue therapy at baseline 1. This is not coincidental—NA therapy suppresses viral replication and reduces subclinical liver inflammation, which can otherwise suppress HBV-specific T cell function 4. The combination of NA-induced viral suppression with bepirovirsen's mechanism of targeting HBV transcripts creates a synergistic effect that enhances the likelihood of functional cure.

HBeAg-Negative Status

HBeAg-negative patients were more likely to achieve sustained remission. The evidence shows that HBeAg positivity is an independent negative predictor of achieving low HBsAg levels (OR 0.264-0.349) 3. In studies of NA discontinuation, HBeAg-negative patients maintained sustained off-therapy remission in 71.4% of cases compared to only 33.3% in HBeAg-positive patients (p = 0.049) 5. This reflects the more advanced immune control phase of infection in HBeAg-negative disease.

Non-Cirrhotic Disease

The B-Well trials specifically enrolled non-cirrhotic patients 1. This exclusion of cirrhosis is critical for safety—patients with cirrhosis face significantly higher risks of severe hepatitis flares (3.63%) and flare-related death or liver transplantation (0.37%) after NA discontinuation 2. Non-cirrhotic patients have preserved hepatic reserve to tolerate the immune-mediated ALT flares that commonly occur during bepirovirsen treatment (grade 3 ALT elevations in 6% of patients) 1.

Younger Age

Younger age (<40 years) was identified as an independent predictor of sustained virological remission after NA discontinuation 2. Younger patients with HBeAg-positive chronic infection demonstrate broader and more functional anti-HBV T cell responses compared to older patients with advanced disease 4. Additionally, HBsAg loss before age 50 is associated with lower HCC risk, emphasizing the importance of achieving functional cure at younger ages 2.

Low HBV DNA Levels

Low baseline HBV DNA (<200,000 IU/mL) was associated with increased likelihood of persistent virological remission 2. This reflects better baseline viral control and is an independent determinant of achieving low HBsAg levels (OR 0.675-0.832) 3. Patients on stable NA therapy typically have undetectable HBV DNA, which was a prerequisite for the B-Well trials.

Clinical Context and Mechanism

The convergence of these factors creates an optimal immunological and virological environment for functional cure. Low HBsAg levels indicate reduced cccDNA transcriptional activity and lower integrated HBV DNA burden. In younger HBeAg-negative patients on NA therapy, circulating HBsAg more reliably reflects cccDNA activity rather than integrated DNA, making them more responsive to therapies targeting viral transcripts 4. The non-cirrhotic liver retains sufficient immune competence to mount effective responses when viral antigens are reduced.

Important Caveats

• Female sex was also identified as a predictor of sustained remission in some studies 2, though this was not specifically reported in the bepirovirsen trials
• Elevated pretreatment ALT mentioned in the expanded question is somewhat paradoxical—while it may indicate immune activity, the B-Well trials enrolled patients on stable NA therapy who typically have normalized ALT
• The 20% functional cure rate represents a highly selected population; broader real-world application will likely yield lower rates
• Single nucleotide polymorphisms in the bepirovirsen binding site were present in only 7% of participants and had limited impact on response, though participants with SNPs showed numerically smaller HBsAg reductions 6