Reduction in Intrahepatic cccDNA and Integration of HBV in Chronic Hepatitis B Patients with a Functional Cure

Abstract

Background and Aims: Functional cure (FC) is characterized by the clearance of the hepatitis B surface antigen from the serum of patients with chronic hepatitis B (CHB). However, the level of intrahepatic covalently closed circular DNA (cccDNA) and hepatitis B virus (HBV) integration remains unclear. We conducted this study to determine them and reveal their value in the treatment of CHB. Methods: There were two sessions to elucidate the changes in intrahepatic cccDNA and HBV integration after antiviral therapy. In the first session, 116 patients were enrolled and divided into FC, non-functional cure (NFC), and CHB groups, including 48 patients with functionally cured CHB, 27 with CHB without functional cure after antiviral treatment, and 41 with treatment-naïve CHB. Patients were tested for both intrahepatic cccDNA and other viral markers. All patients in the FC group were followed up for at least 24 weeks to observe relapse. In the second session, another ten patients were included for in-depth whole-genome sequencing to analyze HBV integration. Results: Thirteen patients in the FC group were negative for intrahepatic cccDNA. Intrahepatic cccDNA was much higher in the CHB group compared with the FC group. Seven patients had HBsAg seroreversion, including two with virological relapse. Integration of HBV was detected in one (33.3%) functionally cured patients and in seven (100%) with CHB. 28.0% of the HBV breakpoints were assigned in the 1,500 nt to 1,900 nt range of the HBV genome. Conclusions: After achieving an FC, the rate of intrahepatic

Editorial:HBsAgseroclearance after pegylated interferon treatment—The beginning of the end. Authors' reply

“…Our prior studies reported that the levels of intrahepatic covalently closed circular DNA (cccDNA) are associated with HBV relapse. 3 Positive serum HBV RNA and high level of hepatitis B core-related antigen (HBcrAg) at the end of treatment, reflect active transcription from cccDNA and are potential predictors of HBsAg reversion in patients with functional cure after interferon-based therapy. 4,5 In addition to viral replication factors, lasting cellular and humoral immune responses to HBV are vital for sustaining a loss of serum hepatitis B surface antigen (HBsAg).…”

Integrated HBV DNA and cccDNA maintain transcriptional activity in intrahepatic HBsAg‐positive patients with functional cure following PEG‐IFN‐based therapy

“…Although, more than 20% of patients who achieved functional cure following interferon‐based therapy may experience hepatitis B virus (HBV) relapse, the mechanisms causing the relapse are not fully understood 6 . Our previous research linked virological relapse to the high level of intrahepatic covalently closed circular DNA (cccDNA), but we also discovered the limitations of cccDNA in predicting virological relapse, as it could only explain the virological relapse in some patients 7 …”

“…Up to now, no studies have reported whether the transcription of intrahepatic HBV is indeed completely silenced in patients who have achieved functional cure via pegylated‐interferon (PEG‐IFN)‐based therapy. Furthermore, our previous results showed that intrahepatic HBsAg remains positive in patients with PEG‐IFN‐induced HBsAg seroclearance 7 . This suggests that intrahepatic HBV RNA is still being transcribed in these patients, but it is unclear whether it originates from cccDNA or integrated HBV DNA.…”

“…6 Our previous research linked virological relapse to the high level of intrahepatic covalently closed circular DNA (cccDNA), but we also discovered the limitations of cccDNA in predicting virological relapse, as it could only explain the virological relapse in some patients. 7 Elimination of intrahepatic cccDNA and HBV integration is considered a conceptual endpoint, which is hardly to achieve. Transcriptional silencing of cccDNA and HBV integration are more likely to be achieved by current therapies.…”

“…Furthermore, our previous results showed that intrahepatic HBsAg remains positive in patients with PEG-IFN-induced HBsAg seroclearance. 7 This suggests that intrahepatic HBV RNA is still being transcribed in these patients, but it is unclear whether it originates from cccDNA or integrated HBV DNA.…”