--- title: "Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Limitations of current therapies" description: "Formulary evidence on Hibsago (bepirovirsen, GSK3228836) in Chronic hepatitis B virus infection in adults without cirrhosis: Limitations of current therapies. Topics: Summary: limitations of current therapies, Indefinite duration of nucleos(t)ide analogue therapy, Current therapies are not curative, Low HBsAg loss on nucleos(t)ide analogues: pivotal and long-term trial data, and 4 further topics. 8 evidence topics quoted from 14 sources." canonical: "https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/product-information-and-disease-description/limitations-of-current-therapies" 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: Limitations of current therapies ## 2.2.2.1.4 Limitations of Current Therapies ### Summary: limitations of current therapies Guideline-preferred nucleos(t)ide analogues suppress HBV DNA but are given long term: the AASLD 2018 guidance suggests “indefinite antiviral therapy for adults with HBeAg-negative, immune-active CHB”, and the WHO 2024 guideline states that “Antiviral therapy is lifelong.” A meta-analysis of 34 studies reported a pooled annual HBsAg seroclearance rate of 1.02%, and 8-year tenofovir alafenamide data show HBsAg loss in 2% to 3% of participants. In the PAGE-B cohort of 1,644 Caucasian patients treated with entecavir or tenofovir, the 10- and 15-year cumulative incidences of HCC were 10.9% and 13.2%. In a cohort of 6696 patients receiving long-term nucleos(t)ide analogue therapy, the discontinuation probability was 29.4% at 12 months and 55.6% at 5 years. Peginterferon is a finite alternative with higher HBsAg loss than nucleos(t)ide analogues, but the AASLD/IDSA guideline states that it “is rarely used, given its limitations of applicability, safety and tolerability”. Source: [Terrault et al. (2018)](https://pmc.ncbi.nlm.nih.gov/articles/PMC5975958/); [WHO hepatitis B guidelines (2024)](https://iris.who.int/server/api/core/bitstreams/34470cc8-af90-4d7b-a949-ef27e5d0726f/content); [Yeo et al. (2019)](https://pubmed.ncbi.nlm.nih.gov/30342034/); [Buti et al. (2024)](https://pmc.ncbi.nlm.nih.gov/articles/PMC11599788/); [Papatheodoridis et al. (2026)](https://pubmed.ncbi.nlm.nih.gov/42409322/); [Anderson et al. (2025)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12265875/); [EASL (2025)](https://doi.org/10.1016/j.jhep.2025.03.018); [Ghany et al. (2026)](https://doi.org/10.1097/HEP.0000000000001549) ### Indefinite duration of nucleos(t)ide analogue therapy > “The AASLD suggests indefinite antiviral therapy for adults with HBeAg-negative, immune-active CHB unless there is a compelling rationale for treatment discontinuation” > “A decision to discontinue therapy for HBeAg-negative adults without cirrhosis requires careful consideration of risks and benefits for health outcomes, including the following: (i) risk for virological relapse, hepatic decompensation, liver cancer, and death; (ii) burden of continued antiviral therapy, financial concerns associated with medication costs and long-term monitoring, adherence, and potential for drug resistance with treatment interruptions; and (iii) patient and provider preferences.” Source: [Terrault et al. (2018)](https://pmc.ncbi.nlm.nih.gov/articles/PMC5975958/) > “Available treatments for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are associated with poor sustained responses. As a result, nucleoside and nucleotide analogues are typically continued indefinitely, a strategy associated with the risk of resistance and unknown long-term safety implications.” Source: [Marcellin et al. (2004)](https://pubmed.ncbi.nlm.nih.gov/15371578/) ### Current therapies are not curative > “Current therapies (pegylated interferon alfa [pegIFNa] and nucleos(t)ide analogues [NAs]) are not curative due to persistence of covalently closed circular DNA (cccDNA), a stable, non-integrated form of viral DNA located in the hepatocyte nucleus, as well as HBV DNA that is directly integrated into the host genome.” Source: [Ghany et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12373085/) > “Although treatment is not considered curative, antiviral treatment, monitoring, and liver cancer surveillance can reduce morbidity and mortality.” Source: [Conners et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9997714/) ### Low HBsAg loss on nucleos(t)ide analogues: pivotal and long-term trial data | Regimen and duration | HBeAg-positive | HBeAg-negative | | --- | --- | --- | | Entecavir, 48 weeks | “HBsAg loss: 2%” | “HBsAg loss: <1%” | | Tenofovir disoproxil fumarate, 96 weeks | “HBsAg loss: 1%” | “HBsAg loss:0%” | | Tenofovir alafenamide, 96 weeks | “HBsAg loss: 1%” | “HBsAg loss:<1%” | | Tenofovir alafenamide, 5 years | “HBsAg loss: 0.8%” | “HBsAg loss:1.2%” | Source: [EASL (2025)](https://doi.org/10.1016/j.jhep.2025.03.018) > “Low rates of HBsAg loss on NA treatment are ascribed to the limited effect of NAs on the cccDNA template and to the significant contribution of HBV integration to HBsAg production, especially in HBeAg-negative individuals.” > “Achieving functional cure (HBsAg loss) remains rare with current therapies. The prospect of effective finite treatments is highly appealing, particularly given the challenges associated with the strict adherence required for prolonged NA therapy, especially for young patients. Thus, there is an unmet need for curative therapies.” Source: [EASL (2025)](https://doi.org/10.1016/j.jhep.2025.03.018) > “Annual rates of spontaneous and on-treatment NA-related HBsAg loss remain very low (~0.5-1%).” > “Increasingly, there is emphasis on the achievement of HBsAg loss as the desired endpoint for treatment (functional cure), because of its association with reduction in clinical outcomes and long-term durability, though it is recognized that functional cure is infrequent with current approved therapies, albeit higher with peginterferon than for NAs.” Source: [Ghany et al. (2026)](https://doi.org/10.1097/HEP.0000000000001549) ### Residual hepatocellular carcinoma risk during long-term nucleos(t)ide analogue therapy > “Of 1,644 patients, 903 were followed beyond year 10 (mean:14 ± 2 years). The 10- and 15-year cumulative incidences of HCC were 10.9% and 13.2%, respectively. The HCC IR was 1.25 before year 10 and 0.55/100 PYs after year 10 (p <0.001), with similar findings after inverse probability weighting.” > “Despite >10 years of NA therapy, patients with CHB remain at risk of HCC, although the incidence rate declines significantly. HCC remains the main determinant of mortality.” Source: [Papatheodoridis et al. (2026)](https://pubmed.ncbi.nlm.nih.gov/42409322/) > “Nevertheless, a risk of adverse liver-related outcomes remains despite HBV DNA suppression, and this risk can be mitigated by achieving HBsAg loss.” Source: [Dongelmans et al. (2026)](https://pmc.ncbi.nlm.nih.gov/articles/PMC13638273/) ### Persistence and adherence with long-term nucleos(t)ide analogue therapy: U.S. claims data > “In total, 6696 patients met the study eligibility criteria.” > “Overall, 40.6% of patients discontinued treatment; discontinuation probability was 29.4% at 12 months and 55.6% at 5 years. Of those who discontinued, 45.7% restarted during the study period. Mean adherence (proportion of days covered [PDC]) was 0.91, and 86.5% of participants had a PDC ≥ 80%.” Source: [Anderson et al. (2025)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12265875/) > “An inception cohort of 564 patients (24%), without a NA prescription in the 6 months pre-index period and at least 2 years of follow-up, was created. Persistence among the inception cohort was 29% for first year and 14% for first 2 years.” Source: [Sbarigia et al. (2020)](https://pmc.ncbi.nlm.nih.gov/articles/PMC7089729/) ### Peginterferon tolerability and response variability > “The variable response rates and unfavourable safety profile of PEG-IFNα treatment are major drawbacks that limit patients' eligibility or prompt patients to decline this treatment option.” > “Despite the slightly higher HBeAg/anti-HBe seroconversion rates, the overall rate of HBsAg loss after PEG-IFNα therapy is still low.” Source: [EASL (2025)](https://doi.org/10.1016/j.jhep.2025.03.018) ### Relapse risk with finite nucleos(t)ide analogue therapy > “Discontinuation increases HBsAg loss but carries a substantial risk of virological relapse and clinical flares.” Source: [Pan et al. 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