The study by Kwo et al. addresses a still unresolved question: whether low-level viraemia (LLV) in chronic hepatitis B (HBV) is truly benign. Using a large U.S. claims database, authors demonstrate patients with LLV have significantly higher risks of cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC) compared with individuals without HBV infection 1. The cohort, with a mean age of 55 years, had a modest but not negligible emergence of liver related complications. The incidence of composite liver outcomes was 1.86 per 100 person-years in the LLV group compared with 0.39 in matched controls (205 vs. 43 events in 4236 individuals respectively). Small in absolute terms, yet individually clinically relevant. Low-level viraemia is not a benign state. This observation is supported by prior evidence. The REVEAL-HBV Study demonstrated a graded relationship between HBV DNA and HCC risk, without a safe lower threshold 2. Subsequent studies confirm that detectable HBV DNA—even at low levels—is associated with increased risks of cirrhosis and HCC 3. Persistent low-level replication likely sustains low-grade inflammation, fibrogenesis, and oncogenic signalling 4. Several limitations warrant consideration. Surveillance bias is likely, as patients with known HBV infection undergo more intensive monitoring than non-HBV controls. Given that outcomes such as HCC and cirrhosis are largely radiologically defined, earlier detection through surveillance may introduce lead-time bias. An important sensitivity analysis excluded patients who subsequently transition to higher viral loads and findings persist. The observation that approximately one-quarter of patients transitioned to higher viral loads during follow-up reinforces a more critical point: that HBV is dynamic. There is no set and forget for patients with low viral load, a risk if adherence with monitoring is poor. AASLD guidance recommends monitoring for LLV and stops short of mandating treatment in patients with HBV DNA > 2000 IU/mL and normal ALT, suggesting shared decision-making frameworks—such as consideration of AVT in those over 40 years of age 5. Monitoring is resource-intensive requiring twice-yearly viral load testing and clinical review which incur costs that might approximate those of antiviral therapy itself, in the era of low-cost generics. Monitoring carries a psychological burden. Patients with untreated viral infection may experience anxiety about progression when even unrelated symptoms occur. Further, patient expectations might be influenced by differing international guidelines—such as more treatment-expansive Chinese recommendations 6. Definitive trials to prove clinical benefit of antiviral therapy in LLV are unlikely to be performed despite evidence of oncologic benefit overall 7. Event rates are low, required sample sizes large, and follow-up would need to extend over many years. There is little commercial incentive to support such studies given the widespread availability of generic antivirals. Indeed, except for the lamivudine trial in advanced disease, modern HBV management already rests largely on laboratory outcomes rather than clinical evidence 8. This retrospective study supports the narrative that LLV carries some risk. How much risk should we expect our patients to carry for a treatable condition is the question. A more pragmatic, treatment-inclusive strategy—particularly in older patients with any level of viraemia—deserves serious consideration. Miriam T. Levy: conceptualization, writing – original draft. The author has nothing to report. This article is linked to Kwo et al. papers to view this article, visit https://doi.org/10.1111/apt.70613. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Miriam Levy (Thu,) studied this question.