In this study, we conducted a comprehensive bibliometric analysis of global research on interferon therapy for CHB, identifying 2,035 publications from 2004 to 2025. Publication trends revealed a consistent upward trajectory. Geographical analysis identified China, the USA, and Japan as the leading contributors to CHB research, with China demonstrating the highest research output and citation impact. This dominance reflects not only the country’s substantial disease burden but also its strong investment in hepatitis B research. For instance, a meta-analysis of 3,740 studies involving over 231 million individuals documented China’s long-term reduction in HBV prevalence and regional disease heterogeneity, underscoring the country’s capacity to generate large-scale epidemiological evidence. The high research output from China correlates with its substantial national disease burden, as China still accounted for an estimated 43.3 million chronic HBV infections in 2021(3.0% prevalence), with notable variation across age groups and regions [24]. Additionally, a national economic evaluation showed that China has actively applied research insights to policy by identifying cost-effective universal screening strategies aimed at accelerating hepatitis B elimination [25]. Notably, the top three most productive institutions—Capital Medical University, Fudan University, and National Taiwan University—are all based in China, further underscoring its pivotal role in advancing the field. Key journals such as Hepatology, Journal of Hepatology, and Journal of Viral Hepatitis dominated the publication landscape. Notable publications include the widely cited “EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection,” which has accumulated 4,040 citations and remains a cornerstone in standardizing CHB care [21]. Prominent authors such as Harry L. A. Janssen, Bettina E. Hansen, and Patrick Marcellin made substantial contributions, ranking highest in productivity and citation impact. Dr. Harry L. A. Janssen, in particular, has significantly influenced the field with groundbreaking research on immune-mediated responses [26] and functional cures in CHB [27]. His work has advanced the understanding of interferon therapy’s role in achieving hepatitis B surface antigen (HBsAg) loss [28] and improving long-term clinical outcomes [29].
The top 2 cited articles in this field, both published in the Journal of Hepatology (IF = 26.8), outline key guidelines for managing hepatitis B. The 2017 article, with 4,040 citations [21], provides updated recommendations on long-term HBV suppression, treatment criteria, nucleos(t)ide analogs as first-line therapy, and the importance of ongoing monitoring to prevent disease progression and hepatocellular carcinoma. The 2012 article, which has received 2,579 citations [22], presents an earlier version of these guidelines, forming the foundation for the later updates. Together, these publications reflect the evolving clinical management strategies for chronic hepatitis B virus infection. The third most cited article, published in the New England Journal of Medicine (IF = 96.2) in 2004, has garnered 1,835 citations [23]. It highlights the efficacy of continuous lamivudine treatment in delaying disease progression, reducing hepatic decompensation and hepatocellular carcinoma risk in patients with advanced fibrosis or cirrhosis, while also addressing concerns about resistance mutations.
Research hotspots
The keyword co-occurrence analysis identified four primary research clusters in interferon therapy for CHB, each representing a distinct research focus.
Cluster 1 (Red): Immune and Molecular Mechanisms.
This cluster explores how interferon therapy modulates immune responses and influences molecular pathways. For example, studies have identified alpha-enolase as a critical regulator that suppresses interferon signaling, contributing to HBV persistence [30]. In addition, research on Schisandrin C demonstrated its ability to enhance cGAS-STING pathway activation, stimulate interferon β production, and inhibit HBV replication [31]. These findings suggest its potential as an antiviral agent [31] and provide valuable insights into the molecular underpinnings of interferon therapy.
Cluster 2 (Green): Clinical Management and Disease Progression.
This cluster focuses on the clinical application of interferon therapy, particularly in achieving sustained virological response and mitigating disease progression. Studies have shown that in HBeAg-negative CHB patients, sustained biochemical remission induced by interferon-alpha significantly improves long-term outcomes, including in individuals with cirrhosis or advanced age [32]. Moreover, IFN-α has been linked to reduced late recurrence of hepatocellular carcinoma in HCV-pure patients who adhere to treatment. However, it does not significantly prevent overall recurrence following liver resection in HCV-related cirrhosis [33].
Cluster 3 (Yellow): Combination Therapies and Treatment Strategies.
This cluster examines approaches to enhance interferon therapy effectiveness by combining it with other antiviral agents. Research has demonstrated that in NA-experienced CHB patients, combining PEG-IFN-α with NA therapy significantly enhances CD56bright natural killer cell activity. This leads to greater HBsAg reduction and improves the chance of clearance compared to NA monotherapy [34]. Additionally, sequential therapy approaches—such as bepirovirsen followed by PEG-IFN—have been shown to reduce relapse rates, particularly in patients with baseline HBsAg < 3,000 IU/mL [35]. These results underscore the potential of combination regimens to optimize treatment outcomes.
Cluster 4 (Blue): Pharmacological Advancements and Long-term Outcomes.
This cluster addresses the development of improved interferon formulations and their long-term impact on CHB management. Long-term follow-up studies suggest that PEG-IFN therapy results in favorable outcomes, with 43.4% of patients achieving a sustained off-therapy response, increased HBsAg loss rates, and no disease progression [36]. Combination therapy involving PEG-IFN-α2b and adefovir dipivoxil has shown improved virological response, though its effects on HBeAg seroconversion are limited and it is associated with increased thyroid dysfunction [37]. Further, studies reveal that PEG-IFN-α2b responders exhibit enhanced NKp30 + natural killer cell activity, which correlates with stronger antiviral cytokine production and lower HBV viral loads. Conversely, non-responders display dysfunctional NKp30 + NK cells due to elevated NKG2A expression, shedding light on variability in treatment efficacy [38].
Collectively, these research hotspots reflect a concerted effort to advance the understanding, clinical utility, and pharmacological development of interferon therapy for CHB.
Emerging topics
An analysis of citation bursts reveals a distinct progression in research priorities, transitioning from foundational studies to optimizing clinical strategies and, more recently, focusing on achieving functional cures.
From 2004 to 2013, research primarily centered on understanding the mechanisms of interferon therapy and its early clinical applications. Keywords such as “e antigen” (2004–2012), “adefovir dipivoxil” (2004–2009), and “alpha interferon” (2004–2007) highlight investigations into virological markers [39] and immune pathways [40] influenced by interferon. Concurrently, studies on “mutations” (2004–2007) and “pegylated interferon alpha-2b” (2005–2013) focused on factors affecting treatment response and improving interferon formulations [41, 42]. These early studies laid the groundwork for subsequent advancements in interferon-based CHB therapy.
Between 2014 and 2020, research priorities shifted toward optimizing interferon therapy to achieve sustained virological control. Keywords such as “virological response” (2010–2016) and “natural history” (2010–2017) illustrate efforts to understand the long-term effects of interferon treatment on disease progression [43]. The emphasis on “sustained response” (2011–2017) underscores the importance of achieving durable antiviral effects to minimize relapse [44]. Additionally, the emergence of “guidelines” (2017–2024) during this period reflects efforts to standardize evidence-based clinical practices for interferon therapy, ensuring its effective and consistent use in CHB management [45, 46].
From 2021 to 2024, research has increasingly focused on achieving a functional cure through interferon-based treatment strategies. Unlike traditional approaches aimed at viral suppression, the concept of a functional cure is defined by the sustained loss of HBsAg and undetectable HBV DNA without ongoing therapy [47]. Keywords such as “functional cure” (2021–2024), “HBsAg loss” (2021–2024), and “entecavir” (2019–2024) highlight efforts to enhance therapeutic outcomes by combining interferon with NAs such as entecavir and tenofovir [48, 49]. The emphasis on “HBsAg loss” reflects its importance as a key therapeutic milestone, as achieving this outcome is associated with long-term immune control and a reduced risk of cirrhosis and HCC [50].
Future trends
The growing focus on functional cure marks a shift in CHB treatment, aiming beyond viral suppression to sustained HBsAg loss and undetectable HBV DNA without continuous therapy. Research highlights the combination of interferon with nucleos(t)ide analogs like entecavir and tenofovir to enhance antiviral efficacy. Future efforts will refine treatment regimens by optimizing interferon dosages, timing, and combination strategies to expand the functional cure potential for a broader patient population.
These trends have clear implications for future funding priorities and clinical trial design. As “HBsAg loss” becomes a key therapeutic endpoint [50], research funding should support studies that investigate immune mechanisms underlying antigen clearance, including the roles of interferon-stimulated genes (ISGs) and cytokine pathways [51, 52, 53],. Simultaneously, predictive biomarkers are being developed to identify likely responders to interferon-based regimens [54, 55], which could inform patient stratification in future trials and improve efficiency. Clinical trials should consider adaptive designs or biomarker-guided inclusion criteria to enhance precision and reduce heterogeneity in treatment response. For instance, recent findings suggest that patients with lower baseline HBsAg levels (< 3000 IU/mL) may benefit more from sequential or combination therapies [35], indicating the importance of individualized trial arms.
The increasing interest in “entecavir” highlights its potential in combination therapies to enhance immune-mediated viral clearance. Studies have shown that adding interferon to entecavir regimens may improve sustained virological response and increase HBsAg loss, particularly in patients with high baseline antigen levels [56, 57]. Ongoing research will aim to identify optimal patient subgroups and assess long-term benefits, such as fibrosis reduction and hepatocellular carcinoma prevention.
The continuous refinement of “guidelines” from 2017 to 2024 highlights the evolving understanding and standardization of interferon therapy for CHB, closely linked to updates from major hepatology organizations, particularly the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD). The 2017 EASL guidelines introduced functional cure as a treatment goal, defined by HBsAg loss with undetectable HBV DNA, while also establishing criteria for finite nucleos(t)ide analog (NA) therapy and reaffirming interferon-based regimens as a treatment option for selected patients [21]. Subsequently, the 2018 AASLD guidelines emphasized long-term suppression of HBV DNA, advocated for careful patient selection for interferon therapy, and encouraged more individualized treatment approaches to optimize therapeutic outcomes [58].
Recent updates, particularly the 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference, have further refined treatment endpoints, reinforcing interferon’s role as a potential functional cure strategy [50]. Emerging clinical trial data suggest that interferon-based combination therapies, especially when paired with antiviral agents, could enhance treatment efficacy, influencing the direction of future guideline revisions. Additionally, real-world evidence (RWE) is expected to be incorporated into upcoming guidelines, refining patient eligibility criteria, treatment duration, and combination regimens to ensure more personalized and effective therapeutic strategies. Addressing global equity and accessibility is also a growing priority, ensuring that both interferon and antiviral therapies remain available in resource-limited settings. Furthermore, advances in biomarkers and host immune response assessments are paving the way for more precision-based treatment decisions. As interest in interferon-based combination strategies continues to grow, future guidelines may undergo further adaptations to integrate novel therapeutic insights. These continuous updates reflect a dynamic research landscape and an ongoing commitment to optimizing CHB management, ensuring that interferon therapy remains a viable and strategically positioned option for selected patient populations.
Strengths and limitations
This bibliometric analysis provides a comprehensive overview of global research trends, key contributing countries, and thematic focuses in interferon therapy for chronic hepatitis B (CHB) from 2004 to 2025. By leveraging analytical tools such as VOSviewer, CiteSpace, and R-bibliometrix, the study identifies historical trajectories and emerging directions in immune mechanisms, therapeutic strategies, and pharmacological innovations.
Several limitations, however, should be acknowledged:
First, citation-based metrics may not accurately capture the clinical significance or translational impact of research. Highly cited studies are not necessarily those with the greatest real-world applicability or influence on clinical practice.
Second, the analysis was restricted to publications indexed in the Web of Science Core Collection, which predominantly includes English-language journals. While this enhances consistency and data quality, it may introduce language and regional bias by excluding relevant studies published in non-English languages or local journals. This is particularly important in the context of CHB, which has high prevalence in regions such as Asia and Africa, where impactful research may appear in local-language publications.
Third, reliance on a single bibliographic database may limit the breadth and diversity of the dataset. Different databases—such as Scopus, PubMed, and Embase—offer varying coverage of journals and document types. As a result, some relevant literature not indexed in Web of Science may have been omitted. Future bibliometric studies could improve coverage and inclusiveness by integrating multiple, multilingual databases.
Fourth, citation counts were not normalized by publication age. Older articles naturally accumulate more citations over time, which may bias the identification of “highly influential” publications toward earlier studies. Future work may consider applying age-normalized citation metrics (e.g., citations per year) or field-weighted indicators to more accurately assess comparative impact across time.
Fifth, this study did not explore potential authorship biases related to gender, institutional affiliation, or regional origin. Such dimensions are increasingly recognized as important factors influencing scholarly visibility, resource distribution, and collaborative networks. For instance, researchers from high-income countries or prestigious institutions may have greater access to funding, networks, and publication opportunities, which can skew citation and authorship patterns. Similarly, underrepresentation of women or scholars from low- and middle-income regions in leading authorship roles may reflect broader systemic inequities. Future bibliometric studies should incorporate author-level metadata where available and consider equity-focused indicators to better understand and address such disparities.
Sixth, the study period was limited to publications from January 1, 2004, to January 8, 2025. This time frame was selected to capture developments following the introduction and widespread clinical adoption of pegylated interferon, which marked a significant therapeutic shift in CHB management. However, we acknowledge that interferon therapy has been used and studied since the early 1980s, and foundational research from earlier decades played a critical role in shaping current understanding and treatment paradigms. Due to database limitations and to maintain relevance to modern clinical practice, earlier literature was not included in the present analysis. Future bibliometric studies aiming for a more historical perspective may benefit from extending the time frame to encompass these seminal contributions.
Finally, while bibliometric indicators offer quantitative insights into research productivity and collaboration, they do not fully reflect clinical outcomes or societal impact. Incorporating alternative metrics—such as expert evaluations, implementation outcomes, and health system impact—would provide a more comprehensive understanding of the influence and utility of interferon therapy research. Future work that combines bibliometric data with clinical effectiveness studies may offer a more holistic assessment of progress in CHB management.