Outcome and Risk Factors of de novo HBV Infection in Pediatric Liver Transplant Recipients with Non-HBV Related Liver Diseases
Date Issued
2008
Date
2008
Author(s)
Su, Wei-Ju
Abstract
De novo hepatitis B virus (HBV) infection is defined as HBV surface antigen (HBsAg)-negative patients become HBsAg-positive following organ transplantation. The long-term clinical outcome of de novo HBV infection after orthotopic liver transplantation (OLT) is not understood well. We aimed to assess the incidence, risk factors, and clinical outcome and its relating factors of de novo HBV infection in pediatric liver transplant recipients. From 1996 to 2006, 71 Taiwanese children with non-HBV-related liver diseases underwent OLT at the National Taiwan University Hospital. All surviving recipients were tested regularly for liver function, serum levels of immunosuppressant, HBsAg, titers of antibodies to hepatitis B surface antigen (anti-HBs), antibodies to hepatitis B core antigen (anti-HBc), and antibodies to hepatitis C virus (anti-HCV). HBV vaccination histories and the anti-HBs titers before OLT were recorded. Children waiting for OLT received the primary universal HBV immunization during their infancy. However, there was no prophylaxis for de novo HBV infection before OLT. When patients acquired de novo HBV infection, drug levels of immunosuppressant, alanine aminotransferase (ALT), and HBV serum markers, including HBsAg, anti-HBs, anti-HBc, and hepatitis B e antigen (HBeAg) and its antibody (anti-HBe) were closely monitored. Lamivudine was administrated when ALT > 80 U/L was noticed and rejection was excluded by histology examination. Meanwhile, immunosuppressant consisted of tacrolimus or cyclosporine tapered to a minimal level without the influence of the graft survival. HBV viral load and genotype were checked by real-time PCR when HBsAg was detected. Furthermore, sequencing was performed to detect any special mutants accounting for de novo HBV infection. Fifty-nine patients (33 females and 26 males) were followed-up for a median of 4.6 years (range, 1.2-10.2 yr). Of these, 36 (61.0%) received allografts from anti-HBc-positive and HBsAg-negative donors. De novo HBV infection was found in nine (15.3%) subjects after OLT, eight of whom received allografts from HBsAg-negative and anti-HBc-positive donors. Forty-eight (81.4%) subjects received three or more doses of HBV vaccine before OLT. Pre-OLT anti-HBs titers were available for 49 recipients. In the group of de novo HBV-infected recipients (n=9), one patients had an anti-HBs antibody titer >200 mIU/ml. In the group of recipients who did not have de novo HBV infection (n=40), twenty-two patients had anti-HB antibody titers >200 mIU/ml (P=0.02). No graft loss or fulminant hepatitis occurred and all were anti-HCV-negative. Five de novo HBV infection recipients underwent HBsAg clearance and the other four were still HBsAg-positive after 2.3 years (range 2.3~2.9 years) of follow-up. Eight of the nine de novo hepatitis B patients had or have taken lamivudine and five of them underwent HBsAg seroclearance. Three of the five had HBsAg seroconversion. For the four patients with HBsAg persistence, two patients were double positive for HBsAg and anti-HBs. HBV DNA sequence was available in 8/9 patients. Seventy-five percent (6/8) of de novo HBV infection children were inoculated by surface mutants. No mutations within “a” determinant were noticed in patients recovered from de novo hepatitis B. In the median of 1.3 months (0.0~4.3 months) after diagnosis of de novo HBV infection, HBV viral loads were ranged from 104 to 106 copies/ml, 108 copies/ml, and 105 to 109 copies/ml for patients with HBsAg seroconversion (n=3), HBsAg seroclerance only (n=2), and HBsAg persistence (n=4), respectively. Seven of the nine patients were infected by genotype B and the other two patients were infected by genotype C. By statistical analysis, we defined that high titers of anti-HBs (>200 mIU/ml) before OLT prevent de novo hepatitis B infection in HBsAg-negative recipients through HBV vaccination. Anti-HBs titers may decline rapidly and become undetectable in a significant proportion of patients post-transplantation. Regardless of whether the anti-HBs titers wax and wane, regular monitoring of anti-HBs titers and HBV serum markers after OLT is essential. The major route of de novo HBV infection is through the allografts from anti-HBc-positive donors. The protective titers of anti-HBs in recipients before OLT play an important role in determining the transmission of de novo HBV to recipients. After adjustment of the variable of donors with anti-HBc, the protective titer of >200 mIU/ml anti-HBs remained significant (P=0.03). We speculated that two factors signaling a better outcome for de novo HBV infection could be the absence of HBsAg variants and lower viral loads (<105 copies/ml) in the early phases of infection. No mutations within “a” determinant were found in patients who recovered from de novo hepatitis B. In contrast to those who could not undergo HBsAg seroconversion, mutations within “a” determinant did exist at aa 126, 127, 129, 142, 143, and 145. Levels of HBV DNA seemed to be lower in patients who ran a resolving course. In conclusion, the incidence of de novo HBV infection in pediatric OLT recipients is 15.3% in the absence of adequate prophylaxis. An anti-HBs titer of >200 mIU/ml before OLT may be sufficient to prevent de novo HBV infection in HBsAg-negative recipients. The incidence of “a” determinant mutants in de novo HBV infection OLT recipients was up to 75%. Absence of HBsAg mutants might be a good prognosis factor. With the help of lamivudine, and possible decreasing the dose of calcineurin inhibitors, the outcome of de novo HBV infection might run a successful HBsAg seroclearance clinical course.
Subjects
de novo HBV infection
Anti-HBs titer
Liver transplantation
Outcome
HBsAg mutans
SDGs
File(s)![Thumbnail Image]()
Loading...
Name
ntu-97-P95421020-1.pdf
Size
23.32 KB
Format
Adobe PDF
Checksum
(MD5):f91aeb5de94ef457f310cb2cc1acac3c