The response of ADV monotherapy for HBeAg positive CHB patients is less satisfying comparing with that of other oral NAs, but in many Asian countries like China, tenofovir is unavailable, ADV is still the only nucleotide analogue without cross resistance to other NAs to date [
12‐
14]. The optimization of ADV therapy according to patients' baseline and on-treatment parameters may be a feasible strategy to increase the response. It was ever reported that ADV might provide additional benefits for HBeAg seroconversion in patients with pre-treatment HBV DNA levels between 10
7 and 10
8 copies/ml [
15]. Subgroup analysis of GLOBE Study with telbivudine revealed that patients with ALT≥2 × ULN and HBV DNA < 10
9 copies/ml had more chance of VR, HBeAg seroconversion and ALT nomalization at year 2 [
16]. There were also similar reports about long term LAM therapy [
10]. In our study baseline factors such as ALT predicted long term response to ADV therapy. Patients with higher baseline ALT (≥5 × ULN) had more chance of optimal outcomes, and lower levels of HBeAg (< 800 s/co) and HBsAg(< 5000 IU/ml) also predicted HBeAg loss. In addition, there was a trend that patients with lower HBV DNA level might have higher rates of VR, HBeAg loss and HBeAg seroconversion although no statistical significance was observed in our study. Our findings may be limited by the relatively small sample size. When we combined baseline ALT and HBV DNA, we found that patients with baseline HBV DNA < 10
9 copies/ml and ALT ≥3 × ULN had more favorable outcomes. An elevated ALT level indicates increased clearance to HBV infected hepatocytes. It was reported that Chinese patients with ALT > 5 × ULN had high rate of spontaneous HBeAg seroconversion even without treatment [
17], but treatment with anti-virus medicaments can improve the chance of HBeAg seroconversion and decrease the disease progression which has been proved in many clinical studies [
2,
18‐
20]. Similarly, HBeAg level may reflect the clearance capability of a HBV infected body to HBV infected hepatocytes [
21,
22]. The significance of HBsAg in treatment of patients with CHB is being paid close attention to recently. HBsAg may reflect the level of cccDNA in liver and the decrease during treatment with pegylated interferon alfa-2a may predict the sustained viral response [
23,
24]. More studies are needed to elucidate HBsAg variations during treament with NAs. In our study patients with lower level of baseline HBeAg and HBsAg had more chance of HBeAg loss which indicaties that baseline HBeAg and HBsAg may be regarded as subsidiary parameters in pretreatment evaluation.
Early HBV DNA reduction may also contribute to VR and HBeAg seroconversion in some studies [
11,
15,
25]. It's generally accepted that therapy can be optimized by monitoring of serum HBV DNA levels during treatment with oral NAs and week 24 is the most important time point recommended to assess efficacy in LAM and telbivudine therapy [
26], but whether it's reasonable in treatment of suboptimal antiviral drug like ADV remains controversial. We selected week 4, 12, 24 and 52 as time points in our study and found that serum HBV DNA < 4 log
10 copies/ml at week 24 was predictive for VR, HBeAg loss and HBeAg seroconversion after 5-year treatment, The drop of HBV DNA from baseline ≥3 log
10 copies/ml at week 4, ≥ 4 log
10 copies/ml at week 12 and HBV DNA turning negative at week 52 can also predict favorable outcomes although not as optimal as HBV DNA < 4 log
10 copies/ml at week 24. None of the patients who achieved HBV DNA < 4 log
10 copies/ml at week 24 experienced viral breakthrough. Accordingly we recommend serum HBV DNA level < 4 log
10copies/ml at week 24 as one of the major predictors for long term outcomes in patients with ADV therapy.
Our study has some limitations because of its small sample size and lack of a control group. However, in our study most patients completed 5 years' follow-up, and the detection method was advanced. The findings may give some evidence to manage HBeAg positive patients who intend to accept or have already accepted ADV therapy.