Reactivation of Cured Hepatitis B Virus after Allogeneic Hematopoietic Stem Cell Transplantation and Its Asociation with Liver Graft Versus Host Disease.

Introduction: The prevalence of hepatitis B virus (HBV) in transplanted patients is not negligible and reactivation of latent HBV infection in the setting of allogeneic HSCT is a well-known complication. However, reverse seroconversion (RS) from positive hepatitis B surface antibody (HBsAb), positive hepatitis B core antibody (HBcAb) and negative hepatitis B surface antigen (HBsAg) to negative HBsAb and positive HBsAg has been less reported. The aims of our study were to describe the clinical characteristics of patients with cured hepatitis B and to identify associated conditions with RS after allogeneic HSCT. Secondarily, we have analyzed the behavior of patient’s serology for HBV after transplantation in relation with donors’ immunity.

Materials and methods: From April 1999 to April 2008, we evaluated the outcome regarding HBV serological status and liver function tests abnormalities of patients cured hepatitis B who received allogeneic HSCT. We assessed the presence of liver GVHD, sinusoidal obstruction syndrome, conditioning treatment, subjacent hematological disease and number of infused CD34+ cells as possible variables associated with RS. Data were analyzed with the statistical software SPSS15.0. Chi-Square test, Fisher’s exact test and Mann-Whitney test were used for statistical analysis.

Results: Of 107 transplanted patients, we found 24 patients (22.4%) with serology consistent with cured hepatitis B previous to transplant. Median age at transplant was 25 years (range, 16–49). The median follow-up time after transplant was 27 months (range. 2–76). The subjacent hematological disease was acute leukemia in 11 patients, lymphoma in 4, myeloproliferative syndromes in 3, myelodysplastic syndromes in 2, severe aplastic anemia in 2 and multiple myeloma in 2. All patients received myeloablative conditioning. Twenty patients were transplanted from siblings, 3 patients were transplanted from matched unrelated donors and 1 patient received umbilical cord blood progenitor cells. Nineteen patients received peripheral stem cells and 4 patients were infused with bone marrow. The mean number of infused CD34 was 5,18x10⁶/Kg. Eight patients developed liver GVHD confirmed by biopsy. Four patients had sinusoidal obstruction syndrome. Six of the 24 patients (25%) developed RS. All the patients with RS had liver GVHD and acute hepatitis appeared after a mean time of 13.5 months (range, 3–34) after immunosuppressive treatment for GVHD was stopped. The most prevalent hematological disease in patients with RS was acute leukemia (5 of the 6 patients with RS, not significant, p=0.2). Four of the 6 patients with RS died of liver failure. The remaining 2 patients are presently on treatment with entecavir. HBV RS was significantly associated with liver GVHD (p=0.007). No other significant association was found. Three donors were naturally immunized, 12 vaccinated, and 4 not-immunized. Data were missing in 5 donors. Loss of HBcAb and HBsAb was seen in all the three patients transplanted from naturally immunized donors within the year of transplantation. Five of twelve patients (41.6%) transplanted from vaccinated donors maintained immunization during a median follow up time of 40 months.

Conclusion: RS is a not minor complication after HSCT in patients with previously cured hepatitis B. To our knowledge, this is the first study that establishes an association between liver GVHD and RS. Immunosuppressive treatment for liver GVHD is possibly implicated in the pathophysiology