HBV Reverse Seroconversion and Intervention with Vaccination after Allogeneic HSCT in Patients with Previous HBV Infection.
Authors: Onozawa Masahiro , Kanamori Hiroe , Kahata Kaoru , Kondo Takeshi , Ota Shuichi , Hashino Satoshi , Tanaka Junji , Imamura Masahiro , Asaka Masahiro 
Published: October 2019

Abstract
Appearance of anti-hepatitis B surface antigen antibody (anti-HBs) and clearance of hepatitis B virus (HBV) from serum usually indicates resolution of hepatitis in patients infected with HBV. However, in most patients in whom HBV has been eliminated from serum, HBV DNA is still detectable in the liver using polymerase chain reaction. Reactivation of this dormant HBV in the liver is known as reverse seroconversion (RS). Previously, we reported that HBV-RS after allogeneic hematopoietic stem cell transplantation (allo-HSCT) was a frequent late-onset complication that can be predicted by careful monitoring of progressive disappearance of anti-HBs. RS hepatitis after allo-HSCT is thought to be a phenomenon caused by naive donor immunity after loss of recipient-oriented immunity against HBV. We speculated that vaccination could prevent reactivation of HBV in allo-HSCT recipients. Safety and efficacy of recombinant HBV vaccine in allo-HSCT recipients have already been confirmed. We studied HBV serological markers in 23 patients with anti-HBs and/or anti-HBc before allo-HSCT who were followed for more than 1 year. Patients’ characters are following; Age at HSCT 22 to 65 (median, 38) years; M:F ratio 14:9; Hematological disorders CML 6, AML 1, ALL 4, MDS 4, SAA 2, NHL 4, MM 1 and CAEBV 1; Serological markers anti-HBc(+) and anti-HBs(+) 17, anti-HBc(+) and anti-HBs(−) 3, anti-HBc(−) and anti-HBs(+) 3. No patients had a prior history of vaccination or HBV-specific immunoglobulin usage. All patients were negative for hepatitis B surface antigen (HBsAg) and were considered to have previous HBV infection. The follow-up period varied from 12 to 116 (median, 36) months. Eighteen patients were followed without intervention. Five patients were vaccinated with recombinant HBV vaccine by the standard three-dose protocol after cessation of immunosuppressant administration. RS was defined as disappearance of anti-HBs and appearance of HBsAg and HBV-DNA with or without clinical hepatitis. Progressive decreases in anti-HBs titer were observed in all pre-HSCT anti-HBs-positive recipients. In 18 of the 20 patients with pre-HSCT anti-HBs, anti-HBs titer decreased to less than the protective value (<10.0 mIU/ml) at 4 to 38 (median, 12) months after HSCT. RS occurred in 11 of the 18 patients without intervention (61%) at 12 to 51 (median, 20) months after HSCT. Timing of onset and severity of hepatitis were not correlated. In patients with RS, anti-HBs had disappeared 0 to 26 (median, 8) months prior to RS. Although re-seroconversion occurred in 7 patients, the remaining 4 patients remained in HBV carrier status after resolution of transient hepatitis. In the 7 patients with re-seroconversion, hepatitis subsided and HBsAg disappeared with acquisition of anti-HBe shortly after RS. On the other hand, reappearance of anti-HBs was delayed by 6 to 51 (median, 32) months after onset of RS. Four of the 5 patients with intervention were successfully immunized by HBV vaccine (80%), and none of those 5 patients had RS during the follow-up period (12–40 months; median, 20 months). In conclusion, all patients with previous HBV infection are considered to be at high risk for RS after allo-HSCT. Recombinant HBV vaccines effectively immunize allo-HSCT recipients and are protective against HBV-RS.