Tenofovir Alafenamide in the Treatment of Chronic Hepatitis B Virus Infection in the High‐Replicative Low‐Inflammatory Phase: A 48‐Week Randomized Controlled Trial

Antiviral treatment for chronic HBV infection in the "high-replicative low-inflammatory" phase has not been widely recommended. This study aimed to evaluate the safety and efficacy of antiviral therapy in this patient population and analyze peripheral immunological characteristics in relation to treatment response. In this randomized controlled trial, HBeAg-positive patients with normal ALT and elevated HBV DNA were randomly allocated 1: 1 to receive TAF 25 mg/day or observation. The primary endpoint was the decline from baseline in HBsAg at Week 48. Secondary endpoints included HBV DNA response rates and the magnitude of HBV DNA reduction. The treatment group was further divided into virological response (VR) and low-level viremia (LLV) subgroups based on HBV DNA response at Week 48. PBMCs from VR (n = 3) and LLV (n = 3) patients underwent scRNA-seq for comparative immunological analysis. A total of 59 patients were allocated to the treatment (n = 30) and control (n = 29) groups. No serious adverse events occurred, except for one control patient who developed an ALT flare and required antiviral initiation. At Week 48, the treatment group demonstrated significantly greater reductions in HBsAg (0. 19 vs. 0 log10 IU/mL, p = 0. 005) and HBV DNA (6. 32 vs. 0. 19 log10 IU/mL, p < 0. 001) compared to controls. In the treatment group, 20% achieved HBV DNA < 20 IU/mL and 3. 3% achieved HBeAg seroconversion, while none occurred in the untreated patients. PBMCs scRNA-seq revealed dominant distributions of NKFCER1G, NKKLRF1, NKXCL1, and NKTFCGR3A subclusters in the VR group, with upregulated expression of genes such as SLC27A4 and PTMA. Taken together, our findings revealed that TAF demonstrates favorable safety and antiviral efficacy in patients with high-replicative, low-inflammatory HBV infection during the 48-week follow-up period, although complete virological suppression rates remain suboptimal. NK-mediated mechanisms may contribute to antiviral success. Trial Registration: The trial was registered on ClinicalTrials. gov (NCT04231565).