The detection of (total and ccc) HBV DNA in liver transplant recipients with hepatitis B vaccine against HBV reinfection

Abstract

These authors equally contributed to the work.Keywords: ccc DNA, HBV reinfection, hepatitis B, liver transplantation, HBV DNA, vaccination Abbreviations: Abbreviations, Full names; HBV DNA, hepatitis B virus total DNA; ccc DNA, covalently closed circular DNA; PBMCs, peripheral blood mononuclear cells; PCR, polymerase chain reaction; anti-HBs, antibodies against hepatitis B surface antigen; HBIG, hepatitis B immunoglobulin; LT, liver transplantation; HBsAg, hepatitis B surface antigen; HBcAg, hepatitis B core antigen; HBsAb, hepatitis B surface antibody; HBeAg, hepatitis B e antigen; HBeAb, hepatitis B e antibody; HBcAb, hepatitis B core antibodyTo investigate the levels of hepatitis B virus total DNA (HBV DNA) and covalently closed circular (ccc) DNA in liver transplant recipients who received hepatitis B vaccination, including responders and non-responders, following liver transplantation due to hepatitis B-related diseases and to investigate the efficacy of hepatitis B immune reconstitution against HBV reinfection. Twenty responders and 34 non-responders were enrolled in the present study. The levels of HBV total DNA and ccc DNA in peripheral blood mononuclear cells (PBMCs) and the liver and plasma were detected by real-time polymerase chain reaction (PCR). Fifty-three blood samples and 38 liver allograft tissues were acquired. For the responders, the mean serum titer for anti-HBs (antibodies against hepatitis B surface antigen) was 289 (46.64-1000) IU/ml. Also for the responders, HBV total DNA was detected in PBMCs for one recipient and in the liver for another recipient, but ccc DNA was not detected in either of those 2 recipients. For the non-responders, HBV total DNA was detected in PBMCS for 2 recipients, neither of whom had ccc DNA. Also for the non-responders, HBV total DNA was detected in the livers of 3 recipients, 2 of whom also had ccc DNA. All responders had discontinued hepatitis B immunoglobulin (HBIG), and 13 responders had discontinued antiviral agents. One responder experienced HBV recurrence during the follow-up period. For the majority of liver transplant recipients, no HBV total DNA or ccc DNA was detected in the blood or liver. The lack of HBV total DNA and ccc DNA both in PBMCs and the liver in liver transplant recipients who received hepatitis B vaccination to prevent HBV reinfection should be a prerequisite for the withdrawal of HBIG and/or antiviral agents.

Long‐term consequences of stopping HBIG and/or nucleotide analogues in liver transplant recipients administered hepatitis B vaccination to prevent HBV reinfection

“…In the group stopping both HBIG and NAs, four recipients (4/36, 11.1%) presented with HBV reinfection with the reappearance of HBsAg and detectable HBV DNA. Levels of HBV total DNA and covalently closed circular DNA (cccDNA) in peripheral blood mononuclear cells (PBMCs) and liver were detected in 20 responders by real‐time polymerase chain reaction (PCR) . HBV was detected in two responders with HBV reinfection; for one recipient, total HBV DNA was found in PBMCs, but cccDNA was not detected.…”

“…Four recipients were lost in the follow-up, and one death occurred due to in peripheral blood mononuclear cells (PBMCs) and liver were detected in 20 responders by real-time polymerase chain reaction (PCR). 21 HBV was detected in two responders with HBV reinfection; for one recipient, total HBV DNA was found in PBMCs, but cccDNA was not detected. Intrahepatic total DNA was also detected in one responder without HBV recurrence.…”

“…However, it is very difficult to completely eradicate intrahepatic and extrahepatic HBV DNA and cccDNA in liver transplant recipients, and these represent potential sources of reinfection [22][23][24][25]. Even in recipients with successful HB vaccine responses, HBV DNA and cccDNA could be detected in PBMCs and/or livers in a previous study 21. In our study, however, HBV DNA and cccDNA in PBMCs or liver were not detected in recipients before stopping both HBIG and NAs because there is no standard detection procedure using PCR.…”

Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis

“…Written consent, approving the use of tissues for research purpose following surgery, was obtained from each patient included in the present study. (16). Optimal sensitivity was obtained by combining two forward primers with a reverse primer.…”

Hepatitis Vaccines

“…While patients with inflammatory bowel disease treated with immunosuppressants [ 42 ], on hemodialysis [ 43 ], or in renal failure [ 44 ] respond poorly to the HBV vaccine, kidney transplant recipients seem to respond well [ 45 ]. The current recommendation for patients who have undergone liver transplantation for HBV-related liver disease who have subsequently been vaccinated to prevent reinfection is to verify the absence of cccDNA in peripheral blood mononuclear cells and the liver prior to withdrawal and immunoprophylaxis with HBIG and/or antiviral agents [ 46 ]. Hepatitis D virus (HDV) vaccine attempts have been unsuccessful, unfortunately, since HIV and intravenous drug users (IDU) constitute a reservoir of HDV infection [ 47 ].…”