---
title: "Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Heterogeneity of treatment effect"
description: "Formulary evidence on Hibsago (bepirovirsen, GSK3228836) in Chronic hepatitis B virus infection in adults without cirrhosis: Heterogeneity of treatment effect. Topics: Bepirovirsen: response by baseline HBsAg level in the pivotal trials; Bepirovirsen: subgroups with lower response, genotype, and early on-treatment predictor; Bepirovirsen: on-treatment ALT flares accompanying HBsAg decline; Bepirovirsen: baseline HBsAg threshold derived from the phase 2b trial; 5 further topics. 9 evidence topics quoted from 9 sources."
canonical: "https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/product-information-and-disease-description/heterogeneity-of-treatment-effect"
published: "2026-10-21T22:39:04-04:00"
modified: "2026-10-22T19:07:03-04:00"
---

# Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Heterogeneity of treatment effect

<a id="heading-2.2.2.3"></a>

## 2.2.2.3 Heterogeneity of Treatment Effect

<a id="topic-2.2.2.3-1"></a>

### Bepirovirsen: response by baseline HBsAg level in the pivotal trials

| Baseline HBsAg subgroup | B-Well 1, HIBSAGO n/N (%) | B-Well 1, placebo n/N (%) | B-Well 2, HIBSAGO n/N (%) | B-Well 2, placebo n/N (%) |
| --- | --- | --- | --- | --- |
| ≤3,000 IU/mL (primary endpoint) | “127/650 (20)” | “0/328 (0)” | “106/570 (19)” | “0/286 (0)” |
| ≤1,000 IU/mL (key secondary endpoint) | “105/426 (25)” | “0/214 (0)” | “95/342 (28)” | “0/179 (0)” |

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-2.2.2.3-2"></a>

### Bepirovirsen: subgroups with lower response, genotype, and early on-treatment predictor

> “The primary endpoint response rate was lower in participants with any of the following characteristics: higher HBsAg values at baseline, HBeAg positive at baseline, and age 65 years or older (see Figure 1).”
> “Overall response rates were 28% for genotype A, 21% for genotype B, 20% for genotype D, and 15% for genotype C. Response rates declined with increasing baseline HBsAg levels and fell below 10% for genotypes B and C at baseline HBsAg levels exceeding 1,000 IU/mL.”
> “Among participants with baseline HBsAg ≤3,000 IU/mL who met this criterion, 34% (203/601) had sustained suppression of HBV DNA and HBsAg not detected at 24 weeks after cessation of all chronic HBV treatment. Participants who did not meet this criterion (who had HBsAg ≥1 IU/mL at Week 12) had a 2% (9/498) probability of having sustained suppression of HBV DNA and HBsAg not detected at 24 weeks after cessation of all chronic HBV treatment.”
> “Among participants with baseline HBsAg ≤1,000 IU/mL who met this criterion, 42% (179/426) achieved this endpoint, and those who did not meet this criterion had a 2.5% (7/280) probability of achieving this endpoint.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-2.2.2.3-3"></a>

### Bepirovirsen: on-treatment ALT flares accompanying HBsAg decline

> “HIBSAGO may cause on-treatment hepatic flares with increases in ALT of >20-40x ULN associated with decline in HBsAg.”

Source: [Hibsago prescribing information (2026)](https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Hibsago/pdf/HIBSAGO-PI-MG-IFU.PDF)

<a id="topic-2.2.2.3-4"></a>

### Bepirovirsen: baseline HBsAg threshold derived from the phase 2b trial

> “In group 1, a total of 16% of the participants receiving NA therapy and 25% of those not receiving NA therapy with a low HBsAg level (≤3 log10 IU per milliliter) at baseline had a primary-outcome event, as compared with 6% and 7% of participants, respectively, with a high HBsAg level (>3 log10 IU per milliliter) at baseline (Fig. S3). A receiver-operating-characteristic analysis in group 1 indicated that an HBsAg level of approximately 3000 IU per milliliter (3.5 log10 IU per milliliter) at baseline may be an appropriate cutoff point for predicting response (Fig. S4).”

Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)

<a id="topic-2.2.2.3-5"></a>

### Nucleos(t)ide analogues and natural history: HBeAg status and baseline levels

> “A higher proportion of patients who tested negative for HBeAg at baseline had seroclearance (1.33%; 95% CI, 0.76-2.05) than those who tested positive for HBeAg (0.40%; 95% CI, 0.25-0.59) (P < .01).”
> “Having HBsAg seroclearance was also associated with a lower baseline HBV DNA level (6.61 log10 IU/mL; 95% CI, 5.94-7.27) vs not having HBsAg seroclearance (7.71 log10 IU/mL; 95% CI, 7.41-8.02) (P < .01) and with a lower level of HBsAg at baseline (2.74 log10 IU/mL; 95% CI, 1.88-3.60) vs not having HBsAg seroclearance (3.90 log10 IU/mL, 95% CI, 3.73-4.06) (P < .01).”

Source: [Yeo et al. (2019)](https://pubmed.ncbi.nlm.nih.gov/30342034/)

> “HBsAg loss was independently associated with older age and baseline HBeAg positivity.”

Source: [Papatheodoridis et al. (2026)](https://pubmed.ncbi.nlm.nih.gov/42409322/)

<a id="topic-2.2.2.3-6"></a>

### Peginterferon: genotype and baseline predictors in guidelines

> “HBV genotype: A and B genotypes are more likely to achieve HBeAg and HBsAg loss with peg-IFN than non-A or non-B genotypes.”
> “HBV genotyping can be useful in patients being considered for peg-IFN therapy, as genotypes A and B are associated with higher rates of HBeAg and/or HBsAg loss than genotype C and D, but it is not otherwise recommended for routine testing or follow-up of patients with CHB.”

Source: [Terrault et al. (2018)](https://pmc.ncbi.nlm.nih.gov/articles/PMC5975958/)

> “Baseline predictors of PEG-IFNα response in HBeAg-positive patients include a low viral load, elevated serum ALT (2-5× ULN), high histological inflammatory activity, younger age, female sex, and HBV genotypes A and B, which are associated with higher rates of HBeAg/anti-HBe seroconversion and HBsAg loss compared to genotypes D and C, respectively.”
> “Patients with low HBsAg levels (e.g. <1,500 IU/ml), HBeAg-negative status, and HBV DNA negativity may benefit from this therapy, regardless of prior IFNα treatment. Predictive factors for a positive treatment response include younger age (≤40 years) and low baseline or week 12 HBsAg levels.”

Source: [EASL (2025)](https://doi.org/10.1016/j.jhep.2025.03.018)

<a id="topic-2.2.2.3-7"></a>

### Peginterferon add-on: baseline HBsAg as the main predictor

> “In a multivariable logistic regression model, adjusting for HBeAg status and viral load at start of therapy, lower SOT HBsAg was the main predictor for HBsAg loss (adjusted odds ratio (aOR) 0.28; 95% CI 0.20 to 0.39, p<0.001; table 2). HBeAg status was not associated with HBsAg loss after adjusting for SOT HBsAg (aOR 1.19; 95% CI 0.51 to 2.76, p=0.68). In univariable analyses, ethnicity, age or ALT at baseline were not associated with HBsAg loss (p>0.05).”

Source: [Dongelmans et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC13638273/)

<a id="topic-2.2.2.3-8"></a>

### Nucleos(t)ide analogue withdrawal: end-of-treatment HBsAg level and ethnicity

> “HBsAg loss was higher among Whites (vs Asians: subdistribution hazard ratio, 6.8; 95% confidence interval, 2.7–16.8; P < .001) and among patients with HBsAg levels <100 IU/mL at end of therapy (vs ≥100 IU/mL: subdistribution hazard ratio, 22.5; 95% confidence interval, 13.1–38.7; P < .001).”
> “At 48 months of follow-up, the cumulative probability of HBsAg loss was higher among patients aged ≥50 years at end of therapy (16.8%; 95% CI, 12.9%–21.7%) compared with those aged <50 years (8.7%; 95% CI, 6.0%–12.5%) (Figure 3A), among Whites (36.5%; 95% CI, 26.0%–49.5%) compared with Asians (10.6%; 95% CI, 8.1%–13.7%) (Figure 3C), among patients treated with TDF before cessation (18.1%; 95% CI, 12.2%–26.5%) compared with ETV-treated patients (10.5%; 95% CI, 7.8%–14.2%) (Figure 3D), and among patients with HBsAg <100 IU/mL at end of therapy (43.0%; 95% CI, 34.4–52.7%) compared with patients with HBsAg levels between 100–1000 IU/mL at end of therapy (7.4%; 95% CI, 4.6–11.7%) or HBsAg >1000 IU/mL at end of therapy (1.1%; 95% CI, 0.3–3.5%; Figure 3F).”

Source: [Hirode et al. (2022)](https://doi.org/10.1053/j.gastro.2021.11.002)

> “It is noteworthy that the predictive thresholds for HBsAg levels are different for Asians and Caucasians: for Asians, an HBsAg value <100 IU/ml is associated with a favourable outcome, whereas for Caucasians, the threshold is <1,000 IU/ml.”

Source: [EASL (2025)](https://doi.org/10.1016/j.jhep.2025.03.018)

<a id="topic-2.2.2.3-9"></a>

### Peginterferon: HBsAg seroconversion by ethnicity in the HBeAg-positive pivotal trial

> “At week 72, HBsAg seroconversion was identified in eight patients receiving peginterferon alfa-2a monotherapy (three Asian and five white patients, five with HBV genotype A and three with genotype C) and in eight receiving peginterferon alfa-2a plus lamivudine (five Asian and three white patients; two with genotype A, one with genotype B, four with genotype C, and one with genotype H).”

Source: [Lau et al. (2005)](https://doi.org/10.1056/NEJMoa043470)

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