Challenges and Controversies

I would choose option A: Recommend initiating HBV antiviral therapy using shared decision-making. This patient has HBeAg-negative, "indeterminate" phase, chronic HBV infection, characterized by persistent HBV DNA ≥2,000 IU/mL without ALT ≥2× the upper limit of normal or significant fibrosis. The most recent 2025 AASLD/IDSA guideline specifically suggests antiviral therapy for noncirrhotic, HBeAg-negative adults in the indeterminate phase, after a discussion of its benefits and risks (conditional recommendation, very-low-certainty evidence). [1] Factors favoring treatment include age >40 years, male sex, and platelet count <180,000/mm³. [1] This patient has two of these factors—age 45 and male sex—although his normal platelets and F0–1 fibrosis indicate a relatively low short-term risk. The WHO 2024 guideline also supports treatment because his HBV DNA exceeds 2,000 IU/mL and ALT of 35 U/L exceeds the WHO male ULN of 30 U/L.[2] The APASL 2026 guideline recommends treatment for patients with detectable HBV DNA and ALT above the ULN (e.g., ≥40 U/L) and prioritizes those with additional risk factors. However, it also endorses a broader “treat-all” approach where resources permit. As noted above, contemporary guidance generally favors earlier treatment. A recent meta-analysis associated antiviral therapy in people with indeterminate-phase HBV with lower HCC incidence, although the evidence was heterogeneous and mainly observational.[4] Given his persistent viremia, age, male sex, and the long-term safety and efficacy of entecavir, TAF, and TDF, initiation of antiviral therapy will be the most reasonable choice in my opinion.

In this setting, clinically I would recommend shared decision making. The patient is in the "indeterminate" zone for treatment. Although his HBV DNA is ≥ 2000, his ALT is not ≥ 2x ULN. As such, he does not meet classic treatment criteria for immune-active HBV. That being said, he has some additional risk factors that can guide decision making. He is over age 40 and male, both of which are considered risk factors for HCC. As such, this can inform your discussion with the patient to potentially guide HBV treatment initiation. Choosing the second choice would also be appropriate as it is similarly in line with the guidelines.