When patients with HBeAg-positive CHB achieve a satisfactory antiviral treatment endpoint (e.g., HBeAg seroconversion), the clinical recurrence is 20–40%, and the virological recurrence can be as high as 80–90% after drug withdrawal [
28,
29]. Because the safety of drug withdrawal is uncertain, HBsAg clearance is recommended as the ideal treatment endpoint for CHB patients. The accessibility and rate of HBsAg clearance was mentioned above, but the durability of HBsAg clearance after treatment cessation remains controversial.
There is no unified definition of recurrence after HBsAg clearance or conversion, and most studies defined recurrence as the reappearance of HBsAg or HBV DNA. One study recently [
30] reported that the recurrence type was defined as the reappearance of HBsAg, HBV DNA, or both during follow-up after treatment cessation. Wu et al. [
30] investigated 238 CHB patients who achieved HBsAg clearance after Peg-IFN treatment. Eighteen recurrence cases were observed during a median 160-week follow-up time after treatment cessation. The cumulative recurrence rates were 0.84%, 6.29%, 6.88%, 8.18%, and 9.66% at 26 weeks, 52 weeks, 78 weeks, 104 weeks, and 597 weeks, respectively. Patients with HBV S-region variation and drug resistance had a higher recurrence rate, and high levels of anti-HBs were a protective factor against recurrence. High-risk populations for recurrence should receive follow-up and monitoring after treatment discontinuation. Li et al. [
31] also performed a study with 176 HBeAg-negative CHB patients with HBsAg clearance after IFN/Peg-IFN treatment. They found that the cumulative rates of HBsAg reversion and HBV DNA reversion were 12.79% and 2.33%, respectively, after treatment cessation at a 48-week follow-up. Patients with consolidation treatment ≥ 12 weeks and high anti-HBs levels were associated with a significantly higher rate of sustained functional cure. Kim et al. [
11] included 110 CHB patients who achieved HBsAg clearance after NA treatment. The recurrence rates were 7.6% and 11.9% at 12 months and 36 months, respectively. Alawad et al. [
32] included 65 patients who achieved HBsAg clearance spontaneously or after NA/Peg-IFN treatment and found that 3 patients had HBsAg reversion after a 115-month follow-up. These patients all received NA or Peg-IFN treatment, and the recurrence rate was 7% in post-treated patients. The overall cumulative recurrence rates were 1.6% and 5.4% at 1 year and 5 years, respectively. The recurrence rate after HBsAg clearance varied from 1.7 to 23.8% in these and other related studies because of the different regions, characteristics and follow-up times of patients and the different clearance methods. There was no significant difference in the recurrence rate between different HBsAg clearance methods [
33‐
36]. Most studies showed that HBsAg clearance was durable and safe during long-term follow-up after treatment discontinuation, and it was the optimal treatment endpoint for CHB patients. However, HBsAg clearance does not indicate virus eradication [
37,
38]. Due to the presence of cccDNA, HBV reactivation is possible. Several studies provided explanations for cases of recurrence, including patients who received immunosuppressive or hormone therapy and the detection of drug resistance sites during NA treatment before HBsAg seroclearance [
30,
39,
40]. Patients with S region mutations may develop an intracellular retention of HBsAg proteins [
41]. These conditions increase the risk of recurrence in patients with HBsAg seroclearance and require surveillance.