This research indicates that antiviral therapy can effectively suppress replication of the HBV virus in HBeAg-negative patients with normal or mildly elevated ALT. The decline in HBV DNA and HBsAg levels between the two groups was comparable in this study. Liver stiffness significantly improved after antiviral therapy, which may prevent deterioration of liver histology.
The HBV DNA level in patients with mildly elevated ALT was higher than those in patients with normal ALT in our study, which was in line with the natural history of chronic HBV infection that patients in the phase of HBeAg-negative chronic HBV infection have relatively low HBV DNA levels accompanied by persistently normal ALT; while, patients in the phase of HBeAg-negative chronic hepatitis B have persistent or fluctuating moderate to high levels of serum HBV DNA as well as fluctuating or persistently elevated ALT values .
Virologic response may be important when assessing antiviral efficacy of NAs in patients. Sustained suppression of HBV replication has been shown to have a protective effect against liver fibrosis progression and related clinical outcomes [18, 19]. The low incidence of a VR to antiviral treatment was one of the reasons for therapy deferment in HBeAg-negative patients with ALT < ULN. In our study, however, the VR rate at week 96 in the normal ALT group was parallel to the mildly elevated ALT group. In a previous study of HBeAg-negative patients without significantly elevated ALT by Zhao et al. , it was found that patients with normal ALT can achieve a VR rate similar to that of participants with a mild elevation in ALT. In addition, compared with the reported rates of VR to NAs in HBeAg-negative patients with ALT > 2 ULN (range: 88.0– 96.6% at 24 months) [20–23], our data demonstrated that the VR rate of patients with normal ALT and mildly elevated ALT who received antiviral treatment may be comparable to that of patients with ALT > 2 ULN.
Baseline serum HBV DNA levels have been found to correlate with an increased risk of liver necroinflammation and fibrosis in HBeAg-negative individuals [24, 25]. In our current study, HBV viral load in the two groups decreased notably after antiviral treatment. These observations provide further evidence that HBeAg-negative patients without significantly elevated ALT could benefit from antiviral therapy.
Furthermore, the factors associated with 96-week VR in HBeAg-negative patients with normal or mildly elevated ALT and ROC curve analyses were evaluated in this study. Our results indicate that when evaluating these patients based on the areas under the ROC curves for HBV DNA and HBsAg levels during treatment, the HBV viral load at week 12 is a more accurate predictor of 96-week VR than HBsAg levels at week 24. HBV viral load < 1.56 log10 IU/mL at week 12 had favourable virological outcomes. In this study, however, the serum ALT levels failed to predict VR, which supports the conclusion that there is a need to initiate antiviral therapy for these patients, regardless of ALT level.
The low rate of HBsAg loss and depressed HBsAg reductions during treatment with NAs remain a noteworthy issue [26, 27]. Previous studies have demonstrated that the cumulative rate of HBsAg clearance in HBeAg-negative patients was 2.2% at year 5 , that the median annual decline of HBsAg levels over 5 years was 0.098 log IU/ml/year and the decline amplitude of HBsAg level was 5.9% at year 2 under treatment with low-genetic barrier NAs . In the current study, no patients achieved HBsAg loss, and the decline amplitude of HBsAg level at week 96 was 6.2% in the total HBeAg-negative patients, which was similar to the result in the study mentioned above.
Another favourable finding in our study was the histological amelioration compared with baseline measurements that was observed in patients following antiviral therapy. Paired FibroScan measurements exhibited obvious changes in liver stiffness at the 48- and 96-week time points. Du et al  and Yan et al  reported that fibrosis scores decrease significantly after long-term therapy in HBeAg-negative patients with either normal or elevated ALT. These similar outcomes indicate that antiviral treatment for such patients could achieve histological improvement.
First, one limitation of the present study is its retrospective design. Nevertheless, this study included patients in two teaching hospitals in China, and the sample size was large. Consequently, the data was representative and reliable. Second, the liver biopsy had not been performed on patients. However, LSM was used as a non-invasive method for the evaluation of liver fibrosis in the study. Third, the follow-up time of antiviral treatment only lasted 96 weeks. More abundant data about the efficacy of antiviral treatment and the loss of HBsAg will be explored in future studies. Despite these limitations, our current findings provide a novel strategy for managing CHB with ALT < 2 ULN.