Letter to the Editor: Physical functioning as a neglected determinant of antiviral adherence in chronic hepatitis B

Abstract

As global strategies shift toward expanding treatment eligibility for chronic hepatitis B, ensuring long-term adherence is critical. Block et al recently published a study in World Journal of Virology, challenging the conventional focus on economic barriers and revealing that compromised physical functioning is a significantly more potent predictor of non-adherence than financial affordability. This finding exposes a profound “clinical discordance”: Patients may achieve viral suppression yet suffer from residual fatigue and functional impairment, potentially driven by immune exhaustion or metabolic comorbidities. We argue that this symptom burden serves as a functional blockade to daily persistence. Therefore, clinical care must evolve from “adherence policing” to active symptom management. Integrating patient-reported outcomes and addressing physical deficits are essential strategies to safeguard the efficacy of antiviral regimens in the elimination era.

Key Words: Chronic hepatitis B; Antiviral adherence; Physical functioning; Patient-reported outcomes; Symptom burden

Core Tip: New evidence indicates that physical functioning plays a more important role than affordability in shaping medication adherence among people with chronic hepatitis B. Addressing residual fatigue and related symptoms may be critical for sustaining long-term antiviral therapy.

TO THE EDITOR

Chronic hepatitis B (CHB) remains a formidable global health challenge, affecting over 250 million individuals and driving substantial mortality through cirrhosis and hepatocellular carcinoma. To accelerate elimination, the field is undergoing a decisive paradigm shift: The World Health Organization 2024 guidelines and the European Association for the Study of the Liver 2025 recommendations have both moved aggressively toward expanding antiviral access and simplifying treatment pathways[1]. Despite this regulatory momentum, concerns regarding long-term adherence to daily nucleos(t)ide analogues (NAs) remain a persistent barrier, frequently cited-explicitly or implicitly-as a rationale to defer treatment initiation or restrict eligibility. However, adherence is not an immutable patient trait; it is a dynamic outcome shaped by health systems, provider competence, and the lived burden of chronic illness. As treatment expansion accelerates, there is an urgent need for patient-centered evidence that distinguishes perceived adherence risks from real-world patterns, identifying actionable determinants that can be targeted in routine care[2].

In this context, Block et al[3] recently published a study in World Journal of Virology that provides timely and critical evidence. Through a global online survey of 614 adults receiving oral antiviral therapy, the authors report a robust overall adherence rate of approximately 81%, directly challenging the pervasive narrative that long-term oral therapy is broadly undermined by non-compliance[3]. Crucially, the study dismantles the “economics-first” assumption that has long dominated programme design. While financial affordability remains a structural necessity, the authors found that lower adherence clustered most significantly not with cost, but with modifiable barriers related to healthcare service acceptability and, most notably, patient-reported physical functioning challenges. This suggests that for a significant subset of patients, the primary obstacle to day-to-day persistence is not the price of the drug, but the persistent fatigue, exhaustion, and reduced productivity associated with the disease itself.

These finding matters because it reframes non-adherence from a purely access-mediated phenomenon to a functional and symptom-linked one. Consistent with contemporary behavioural models, even when medications are available, adherence can erode when therapy is experienced in the context of diminished physical capacity[4]. This interpretation is further corroborated by recent real-world analyses: United States claims-based data indicate that adherence varies with treatment context rather than just economic drivers[5], while cross-sectional evidence from lower-resource settings confirms that non-adherence is multi-determined by individual and care-delivery factors[6]. Collectively, these data argue for a “hierarchy-of-barriers” perspective: While affordability is necessary, it is insufficient. To ensure elimination-era durability, CHB programmes must evolve from treating adherence as a gatekeeping concern to actively addressing symptom burden and functional health as core clinical outcomes.

MECHANISMS OF RESIDUAL SYMPTOM BURDEN

A central implication of Block et al’s findings[3] is the distinct “clinical discordance” observed in treated patients: Virological control does not necessarily translate into perceived functional recovery. While long-term NA therapy is highly effective at suppressing hepatitis B virus (HBV) DNA and reducing liver disease progression, it rarely achieves hepatitis B surface antigen loss or eradicates the intrahepatic covalently closed circular DNA reservoir. Consequently, persistent low-level antigen exposure may sustain a state of immune dysregulation even during profound viral suppression, providing a biologically plausible basis for the ongoing fatigue and impaired physical functioning reported by adherent patients[7].

Contemporary immunological insights support this interpretation. Persistent antigenic stimulation is associated with T-cell exhaustion, altered cytokine profiles, and incomplete restoration of innate immune responses, creating a milieu of chronic low-grade inflammation[8]. Although modern NAs halt viral replication, they do not fully normalize this immunological landscape. This suggests that the “symptom burden” driving non-adherence is not merely psychosomatic but likely rooted in physiological pathways that standard antiviral regimens fail to address.

Compounding this biological reality is the rising syndemic of metabolic dysfunction-associated steatotic liver disease (MASLD). Metabolic comorbidities are increasingly prevalent among people living with CHB and are independent drivers of fatigue, mitochondrial dysfunction, and reduced health-related quality of life[9]. Because NA therapy does not target metabolic pathways, patients with overlapping MASLD may experience sustained functional impairment despite achieving perfect virological endpoints.

Therefore, physical functioning should not be viewed as a peripheral concern in CHB care. It represents a clinically meaningful dimension where biological immunity, metabolic health, and patient experience intersect. Recognizing that virological suppression without functional recovery is a distinct clinical entity is essential to understanding the root causes of non-adherence-and why symptom-informed care is a prerequisite for elimination-era success.

REFRAMING ADHERENCE AS AN ACTIVE CLINICAL OUTCOME

If physical functioning represents a meaningful determinant of long-term antiviral persistence, then hepatitis B care models must evolve accordingly. Historically, adherence has often been framed as a behavioral prerequisite for treatment eligibility-implicitly positioning non-compliance as a rationale to delay or withhold therapy. In the elimination era, this exclusionary framing is increasingly untenable. Instead, consistent with frameworks used in other chronic conditions requiring lifelong management, adherence should be conceptualised not as a gatekeeping criterion, but as a clinical outcome that must be actively cultivated and supported by the health system[10].

Operationalising this shift requires the integration of patient-reported outcomes (PROs) into routine serological monitoring. Recent real-world data demonstrate both the feasibility and clinical necessity of this approach. Analyses from the Global Liver Registry indicate that validated instruments-such as FACIT-fatigue or the chronic liver disease questionnaire capture dimensions of symptom burden and functional impairment that remain invisible to standard alanine aminotransferase or HBV DNA assays[11]. Furthermore, a 2025 systematic review confirms that chronic HBV infection can significantly impair health-related quality of life even in the absence of cirrhosis, reinforcing the imperative to move beyond the antiquated notion of CHB as a “clinically silent” disease until decompensation[12].

Equally critical is the implementation of shared decision-making (SDM) and longitudinal digital support. A 2025 cross-sectional study demonstrated a robust positive association between SDM and antiviral adherence, underscoring the therapeutic value of validating patient-reported symptoms, aligning expectations, and co-designing feasible daily routines[13]. Complementing this interpersonal approach, evidence from broader chronic disease management suggests that digital health interventions-such as automated reminder systems and medication-management applications-can serve as scalable adjuncts to sustain adherence in expanded treatment cohorts[14]. Ultimately, embedding PRO screening, systematic symptom management, and shared decision-making into routine practice ensures that adherence is no longer “policed,” but rather supported through a compassionate recognition of the functional realities of living with chronic hepatitis B.

CONCLUSION

The path to global hepatitis B elimination is paved not merely with potent antivirals, but with the sustained daily engagement of millions of patients. The pivotal data from Block, Ibrahim, and Cohen provide a necessary corrective to the field’s historical anxiety regarding non-compliance. By demonstrating that physical functioning-rather than financial capacity-is a primary driver of therapeutic persistence, this study exposes a critical blind spot in the current “virology-first” paradigm. It suggests that the “clinical discordance” between viral suppression and the patient’s lived experience of fatigue is not just a quality-of-life issue, but a structural threat to treatment success. Consequently, the mandate for the elimination era is clear: We must evolve from checking boxes on adherence to actively managing the symptom burden that erodes it. Integrating patient-reported outcomes into routine monitoring and restoring the patient's homeostatic energy are no longer optional adjuncts; they are strategic necessities. Ultimately, the most effective way to ensure patients adhere to life-saving therapy is to bridge the gap between laboratory success and functional recovery, ensuring that patients not only survive the virus but feel well enough to maintain the fight.