Abstract
BACKGROUND: Occult hepatitis B virus infection (OBI) is defined by the detection of replication-competent hepatitis B virus (HBV) DNA in the liver and/or blood despite the absence of detectable hepatitis B surface antigen (HBsAg) using conventional serological assays. Although OBI has been well-documented in individuals with resolved HBV infection or those receiving immunosuppressive therapy, reports of its occurrence during sequential antiviral treatment remain scarce. This report describes a case of chronic hepatitis B (CHB) transitioning through OBI during sequential combination therapy before ultimately achieving a functional cure. This case provides new insights into the emergence of OBI as a transitional phase during CHB treatment and emphasizes the importance of monitoring its clinical significance. CASE SUMMARY: A 33-year-old Chinese male was diagnosed with HBV infection in 2001. The patient first presented in 2012 with abnormal liver function tests and received initial treatment with conventional interferon therapy, which failed to achieve a virological response. Antiviral therapy was subsequently switched to entecavir monotherapy. By August 2019, the patient exhibited an HBsAg level of 29.93 IU/mL with undetectable HBV DNA (< 25 IU/mL). At this point, combination therapy with entecavir and pegylated interferon α (PEG-IFN α) was initiated. Remarkably, while HBsAg declined to 0.42 IU/mL by April 2020, a paradoxical HBV DNA rebound to 173 IU/mL was observed. The regimen was consequently modified to tenofovir alafenamide and PEG-IFN α. By October 2020, the patient achieved HBsAg seroconversion (HBsAg 0.01 IU/mL, hepatitis B surface antibody 52.18 mIU/mL) for the first time, while maintaining low-level viremia (37 IU/mL), consistent with transition to OBI. The patient was then switched to PEG-IFN α monotherapy. In November 2021, he discontinued PEG-IFN α therapy, and one month later, both HBV DNA (< 10 IU/mL) and HBsAg (< 0.05 IU/mL) were negative. This response has been sustained through follow-up. CONCLUSION: This case study illustrates the efficacy of sequential combination therapy in achieving functional cure in CHB patients, including those with a prolonged infection history. It highlights OBI as a transitional yet underrecognized phase during sequential antiviral therapy. While the patient ultimately achieved functional cure, the transient persistence of HBV DNA despite HBsAg clearance suggests the need for continued monitoring. This case provides new insights into OBI development during treatment and underscores the importance of further research into its long-term implications.