Peg-IFNα-2b Drives HBsAg Loss, Outperforms NAs in High-Risk Hep B

A functional cure, or sustained hepatitis B surface antigen (HBsAg) loss off all therapy, remains the primary goal of chronic hepatitis B (CHB) management and is associated with meaningful reductions in hepatocellular carcinoma (HCC) risk. Although nucleos(t)ide analogues (NAs) suppress viral replication reliably, their HBsAg clearance rates remain limited at 2% to 11%.¹ Pegylated interferon alfa (Peg-IFNα-2b), which exerts both antiviral and immunomodulatory effects, can achieve substantially higher functional cure rates in selected populations, but optimal patient selection and treatment strategy remain areas of active investigation.

Two prospective multicenter studies from China presented at the European Association for the Study of the Liver (EASL) Congress 2026 provide new real-world guidance.

Adding NAs to Peg-IFNα-2b Does Not Improve HBsAg Loss

The multicenter, prospective VISION study enrolled patients with CHB across 20 hospitals in China beginning in May 2024.² The 48-week analysis compared Peg-IFNα-2b monotherapy with Peg-IFNα-2b plus NAs in 798 propensity score–matched patients (399 per arm), with primary endpoints of HBsAg loss rate, hepatitis B (HBV) DNA suppression, and alanine aminotransferas (ALT) normalization.

After matching, the 2 cohorts were well balanced across all key variables: sex, age, hepatitis B e-antigen (HBeAg) positivity, baseline HBsAg, HBV DNA, and ALT levels showed no significant differences between arms (all P > .05).

The defining finding was the absence of any difference in HBsAg loss. At week 48, loss rates were 30.1% in the monotherapy group and 29.3% in the combination group (P = .816), with ALT levels likewise comparable between arms. The one significant difference was modestly lower HBV DNA in the combination arm (1.2 vs 1.6 log IU/mL; P = .029), consistent with the additive antiviral effect of NAs, but this did not translate into greater antigen clearance.

Subgroup analysis by baseline HBsAg stratum confirmed consistency across all antigen levels. HBsAg loss rates in the monotherapy and combination groups, respectively, were 55.9% vs 56.3% at baseline below 100 IU/mL, 27.9% vs 27.8% at 100 to less than 500 IU/mL, 12.3% vs 10.0% at 500 to less than 1500 IU/mL, and 6.8% vs 7.2% at or above 1500 IU/mL, with no significant difference at any level (all P > .05). Both groups were well tolerated with no serious adverse events reported.

The investigators concluded that for patients with low baseline HBsAg and HBV DNA, Peg-IFNα-2b monotherapy and combination therapy produced comparable outcomes at 48 weeks, with no short-term advantage of adding NAs. Long-term follow-up is ongoing.

Peg-IFNα-2b Drives HBsAg Loss Where NAs Cannot

This prospective multicenter cohort study (ChiCTR2200066281) enrolled 538 high-risk patients with CHB from 21 hospitals, defined by family history of cirrhosis or HCC, abnormal HCC biomarkers, imaging-confirmed hepatic nodules, or HBV-related compensated cirrhosis.³ Patients received Peg-IFNα-2b–based therapy (n = 447) or NA monotherapy (n = 91) for at least 48 weeks, with 4-year HCC surveillance planned.

The contrast between the 2 strategies was stark. At week 48, patients who received Peg-IFNα-2b therapy showed a median HBsAg decline of 0.57 log_₁₀ IU/mL vs 0.06 log₁₀ IU/mL with NAs. Rates of HBsAg decline of at least 1.0 log₁₀ were 38.5% vs 1.1%, and HBsAg loss was achieved in 18.1% vs 0% (all P < .001). These differences appeared as early as week 24, when HBsAg loss was already 13.4% with Peg-IFNα-2b and 0% with NAs.

Notably, complete virological response rates were comparable between arms (58.5% vs 47.8%, P = .170), reinforcing that the serological advantage reflects Peg-IFNα-2b's immune-activating properties rather than differential effects on viral replication alone. Superior serological responses were consistent across all high-risk subgroups (all P < .01). One HCC case occurred within 48 weeks in a Peg-IFNα-2b–treated patient who had multiple baseline risk factors; the impact on longer-term HCC incidence will be reported as follow-up matures.

The authors concluded that Peg-IFNα-2b therapy achieved significantly higher HBsAg loss in high-risk CHB patients than NA monotherapy, with long-term HCC data forthcoming.

Putting the Data Together

These 2 studies address complementary clinical questions. VISION establishes that the interferon immune axis, not additional NA-driven viral suppression, is the primary driver of HBsAg loss with Peg-IFNα-2b and that the added complexity of combination therapy may not be warranted when antigen clearance is the goal. The high-risk cohort makes a clear case for prioritizing interferon-based strategies in patients where functional cure matters most: those facing elevated HCC risk, in whom NA monotherapy delivered zero HBsAg loss at 48 weeks.

Both datasets reinforce baseline HBsAg as the dominant predictor of response, and both contribute prospective, real-world evidence to a field historically reliant on smaller controlled trials. The 4-year HCC follow-up from the high-risk cohort will be the critical readout in determining whether the serological advantage demonstrated here translates into the outcome data needed to meaningfully shift treatment guidelines.

References

1. Dong M, Peng Y, Liu X, et al. Functional cure of chronic hepatitis B virus infection: current therapeutic regimens. Hepatol Int. 2025. doi:10.1007/s12072-025-10101

2. Zeng QL, Liu Y, Li G, et al. Effect of peginterferon alfa-2b with or without nucleos(t)ide analogues on long-term outcomes in chronic hepatitis B: 48-week results from the VISION study. Presented at: EASL Congress; May 27-30, 2026; Barcelona, Spain.

3. Li Y, Cao H, Wang Q, et al. Peginterferon alfa-2b–based therapy achieves higher HBsAg loss in high-risk chronic hepatitis B patients: a prospective multicenter cohort study. Presented at: EASL Congress; May 27-30, 2026; Barcelona, Spain.