Hepatitis B Serological Changes In Allogeneic Hematopoietic Stem Cell Transplanted Children

Background and objectiveHemopoietic stem cell transplantation is the standard treatment of choice for most malignant hematopathy and tumour. Patients who have undergone allo-HSCT have a longlasting impaired immunologic function because of the previous chemotherapy conditioning regimens and immunosuppressive therapy, they are at high risk of various kinds of infections, and this may increase the mortality rate after HSCT. Infection is considered to be the main factor of dead after HSCT, and hepatitis B virus (HBV) infection is one of the common viral infections in allogeneic hematopoietic stem cell transplanted patients. HBV-related hepatitis is also a main complication in individuals being considered for hemopoietic stem cell transplantation, especially in areas where HBV infection is endemic.The prevalence of chronic HBV infection in China here HBV is endemic is about10%, most stem cells derive from HLA-identical sibling, and hepatitis B virus usually spread among individuals within the family, the recipients or their donors received allo-HSCT are likely to be chronic hepatitis B virus carriers, moreover, the conditioning regimens, immunosuppressive therapy and blood transfusion may cause HBV infection and HBV reactivation.Hepatitis B virus infection mainly leads to liver damage which is associative with HBV replication and the host immune response. During the intense chemotherapy and immunosuppressive therapy, the recipients have intense immune suppression for server moths to years, and T, B cells function reconstruction needs1-2years, during the immune suppression, there is a markedly enhanced viral replication resulting in a progressive decline in liver function due to the recovery of immune function, as reflected by increases in serum levels of ALT, TBIL, and liver failure or dead. Patients undergo allo-HSCT have a high risk of HBV reactivation, it had been reported the rate of HBV reactivation was about4%-50%, and it increases to70%at120months after HSCT, especially in patients whose hepatitis B virus surface antigen(HBsAg) is positive before transplantation. It is important to reduce the rate of HBV reactivation and infection during the longlasting immunosuppressed period.Previous data indicated that a clearance of chronic HBV infection in patient receiving bone marrow from an anti-HBs positive donor, it demonstrated that a transfer of specific memory cells of bone marrow origins which produce anti-body against HBV envelope and nucleocapsid by way of allo-HSCT. Onozawa et al suggested that progressive decreases in anti-HBs titer may indicate HBV reactivation and vaccination of recipients when immune rebuild successfully would be prophylactic for reactivation of HBV in anti-HBc positive recipients. Kaloyannidis et al indicated that the5-year probability of HBsAb disappearance was90%for HBsAb positive recipients before transplantation, and the donor’s active immunization significantly affected this loss. During the follow-up time after transplantation, it was found that hepatitis B vaccination can enhance the immunity against HBV infection; systematic re-immunization may be necessary following transplantation to maintain HBV immunity, particularly in6-9months post-transplant.The aim of this study was to evaluate the impact on the hepatitis B serological changes after allogeneic hematopoietic stem cell transplantation according to donors’ different immunity status, the incidence of HBV reactivation and risk factors, HBV-related hepatitis post-transplant after transplantation.MethodsWe performed a retrospective review of patients who undergone allo-HSCT at our center (department of pediatrics, NangFang Hospital, Guangzhou, China) between January2010and June2012. A total of130children and their donors were enrolled in this study. Of these patients,84were men and46were women, their median age was6years old, with a range from2y-16y. All of the patients were first-time transplantation, no second transplant cases. The median time of follow-up post-transplantation was18months, with a range from6month to36months. According to the recipient and donors’ HBsAg and HBsAb status, all patients were divided into6groups. Blood routine examination, liver function, serum markers of HBV, renal function, hepatitis A, hepatitis C, hepatitis D, syphilis and HIV were performed in all recipients and donors before and after transplantation. HBV-DNA quantitative detection was examined before and after allo-HSCT in recipients and their donors using when their HBsAg was positive. ALT, AST, TBIL were used to evaluate liver function and serum markers of HBV, HBV-DNA were used to evaluate changes of HBV serum markers. HBV reactivation was defined as hepatitis B virus DNA increased by10times or more, or it is absolute value increased to109copies/ml or more, or HBV-DNA seroconvert to positive. HBV infection group was defined as:recipient or donor for chronic HBV carriers (HBsAg+) or patients with resolved HBV infection before transplantation (HBsAb+/HBcAb+). Data were analyzed using SPSS13.0statistical software, measurement data using two independent samples t test analysis, count data using Chi-Square test, overall survival using Kaplan-Meier method analysis, P<0.05were considered to be statistically significant.Result130recipients received allo-HSCT,4patients were HBsAg positive before transplantation, and126patients were negative for HBsAg,92of the126were HBsAb positive before transplantation. Their donors,6were HBsAg positive and124were negative for HBsAg. None of the recipients and paired donors was positive for HBsAg at the same time. All patients were negative for HCV antibody. The changes of HBV serum markers were as follows:(1) Group1:recipients HBsAg-/HBsAb-, donor HBsAg-/HBsAb-There were12recipients in this group. All of them were negative for HBV serological markers before transplantation. The median follow-up time was25months,1recipient (8.3%) seroconverted to HBsAb and HBcAb positive after receiving stem cell transplantation from an HBsAb negative donor by the time of7months after transplantation, her liver function was normal, we considered that she potentially developed HBV infection post transplantation and had recovered spontaneously with an evidence of HBcAb, and HBsAb and HBcAb became negative1year after transplantation. There were no changes of HBV serum markers in the rest of the recipients.(2) Group2:recipients HBsAg-/HBsAb-, donor HBsAg-/HBsAb+There were21recipients in this group. All of them were negative for HBV serological markers before transplantation and their donors were HBsAb positive before transplantation. The median follow-up time was21months. Of these21recipients,15(71.4%)were seroconverted to HBsAb positive post transplantation with a mean HBsAb level of65.16mIU/ml, the rest of6recipients had no changes of HBV serum markers.(3) Group3:recipients HBsAg-/HBsAb+, donor HBsAg-/HBsAb-21recipients were positive for HBbAb and their donors were negative for both HBsAg and HBbAb before HSCT. The median follow-up time was17months,13(62%) recipients with a mean HBsAb level of139.65mIU/ml before HSCT lost their HBsAb, however,8recipients with a mean HBsAb level of343.01mIU/ml before HSCT still kept protective HBsAb levels above10mIU/ml with a mean value of169.78mIU/ml.(4) Group4:recipients HBsAg-/HBsAb+, donor HBsAg-/HBsAb+66recipients and their donors were positive for HBbAb before HSCT. The median follow-up time was17months,18(29%) recipients lost their HBsAb marker and47were still positive for HBsAb after transplantation,lrecipient whose HBsAb and HBcAb were positive before HSCT developed HBV reactivation by the time of252days post HSCT with HBV-DNA3.23×105copies/ml, ALT was422IU/L and TBIL was normal.(5) Group5:recipients HBsAg+, donor HBsAg-Of these4recipients in this group,3were positive for HBsAg, HBeAg and HBcAb and1were positive for HBsAg, HBeAb and HBcAb before HSCT. Lamivudine (0.1g, qd) was treated in all recipients before and after transplantation, and hepatitis B immune globulin was never used in these recipients. After transplantation, HBV reactivation was observed in1recipient, his HBV-DNA was increased to1.82×106copies/ml compared to3.16×105copies/ml before transplantation, ALT was increased to82.3U/L and TBIL was normal. The HBV-DNA levels did not changed after HSCT in another2recipients;1recipient had a decrease in HBV-DNA copy number, and seroconverted to HBeAb positivity after transplantation, during a follow-up of31months, there was no changes of HBV serum markers.(6) Group6:recipients HBsAg-, donor HBsAg+Of these6recipients in this group,4were positive for HBsAg, HBeAg and HBcAb and2were positive for HBsAg, HBeAb and HBcAb before HSCT. Lamivudine (0.1g, qd) was treated in all recipients before and after transplantation except1recipient, and hepatitis B immune globulins was used in1of the5recipients before and post HSCT.2recipients developed HBV infection after transplantation by the time of205days and475days. Their HBV-DNA were increased to5.34×107copies/ml and6.72×104copies/ml, the remaining recipients did not cause HBV infection during the follow-up time.(7) HBsAb acquisition after allo-HSCT between group1and group2The recipients of both group1and group2were negative for HBsAb before HSCT.8.3%of the recipients in group1seroconverted to anti-HBs positive, while71.4%of the recipients in group2seroconverted to anti-HBs positive, the difference between the two groups was statistically significant (P=0.001). Based on these results, the incidence of the seroconversion to HBsAb positive in recipients with HBsAb positive donors was higher than that of recipients, who had negative HBsAb before transplantation.(8) HBsAb loss after allo-HSCT between group3and group4The recipients of both group1and group2were positive for HBsAb before HSCT.61.9%of the recipients in group3lost their HBsAb with undetectable HBsAb levels (<10mIU/ml). on the contrary,28.8%of the recipients in group4lost their immunity to HBV(χ2=7.514,P=0.006). Therefore, the incidence of HBsAb disappears after transplantation in recipients with HBsAb positive donors was lower than that of recipients with HBsAb negative donors. Besides, the risk factors for HBsAb loss included CD34+≤7.24×106/kg and HBsAb level <257.47mIU/ml before HSCT.(9) HBV reactivation and infection after allo-HSCT19of130patients were positive for HBsAg or with evidence of past HBV infection. Of these19recipients,2patients developed HBV reactivation after transplantation,1were positive for HBsAg before transplantation and1was positive for HBsAb and HBcAb. The rate of HBV reactivation undergone HSCT was10.5%. Another2recipients without HBV infection developed HBV infection after receiving stem cell transplantation from HBsAg positive donors.(10) The survival in HBV infection group after HSCT29recipients and donors were the chronic hepatitis B carriers or had an evidence of past HBV infection before transplantation.2recipients died after HSCT, the overall survival rate was93.1%, the causes of death were hemorrhagic cystitis and the relapse of her leukemia; all patents achieved hematopoietic reconstruction. There was no significant difference on the overall survival rate compared with recipients and donors without HBV infection (P=0.465).ConclusionDonors and recipients infected with HBV were not contradictive to HSCT. Our finds support the notion that recipient can seroconvert to HBsAb positive receiving stem cells from an HBsAb positive donor after HSCT; recipients gradually lose either their previously acquired immunity or the adoptive immunity transferred from an immunized donor. Pre-HBbAb level, infusion of donor CD34+cell number and HBsAb positive donor significant affect the loss of their HBsAb. HBV-related hepatitis in one of most complication after HSCT, recipients or donors with HBV infection experience high risk of HBV reactivation, careful serial serologic monitoring in the early but also in the last post transplant period might be necessary for patients with HBV infection and low or decreasing HBsAb titers, and preemptive use of anti-HBV drugs may reduce the incidence of hepatitis due to HBV reactivation in HBsAg positive recipients. Therefore, vaccination of both recipients and donors before HSCT and re-immunization when immune rebuild successfully may play an important on reducing HBV reactivation and infection.