Brief communication
Reactivation of Hepatitis B With Reappearance of Hepatitis B Surface Antigen After Chemotherapy and Immunosuppression

https://doi.org/10.1016/j.cgh.2009.06.027Get rights and content

Background & Aims

HBV infection may reactivate in the setting of immunosuppression, although the frequency and consequences of HBV reactivation are not well known. We report 6 patients who experienced loss of serologic markers of hepatitis B immunity and reappearance of HBsAg in the serum as a result of a variety of acquired immune deficiencies.

Methods

Between 2000 and 2005, six patients with reactivation of hepatitis B were seen in consultation by the Liver Diseases Branch at the Clinical Center, National Institutes of Health. The course and outcome of these 6 patients were reviewed.

Results

All 6 patients developed reappearance of HBsAg and evidence of active liver disease after stem cell transplantation (n = 4), immunosuppressive therapy (n = 1), or change in human immunodeficiency virus antiretroviral regimen (n = 1), despite having antibody to HBsAg (anti-HBs) or antibody to hepatitis B core antigen (anti-HBc) without HBsAg before. All 6 patients developed chronic hepatitis B, 2 patients transmitted hepatitis B to their spouses, and 1 patient developed cirrhosis. The diagnosis of hepatitis B reactivation was frequently missed or delayed and often required interruption of the therapy for the underlying condition. None of the patients received antiviral prophylaxis against HBV reactivation.

Conclusions

Serologic evidence of recovery from hepatitis B infection does not preclude its reactivation after immunosuppression. Screening for serologic evidence of hepatitis B and prophylaxis of those with positive results by using nucleoside analogue antiviral therapy should be provided to individuals in whom immunosuppressive therapy is planned.

Section snippets

Case 1

A 45-year-old Ethiopian-born physician with chronic myelogenous leukemia (CML) for 12 years was evaluated for allogeneic stem cell transplantation. His serum was HBsAg negative, but positive for both anti-HBs and anti-HBc. He denied a history of jaundice or hepatitis, blood transfusions, alcohol, or drug use. He had received hepatitis B vaccine during medical school.

He underwent a T-cell–depleted, myeloablative stem cell transplantation in June 2001 from his sister, a 6/6 HLA match who tested

Discussion

The host immune response plays a major role in the course and outcome of acute HBV infection. Thus, most adults with acute HBV infection recover uneventfully, and probably fewer than 5% fail to clear HBsAg and develop chronic hepatitis B.11 In contrast, newborns and immunocompromised adults usually do not recover, but they develop chronic infection with variable degrees of chronic inflammation and injury.12 Persons with acute HBV infection who recover often have symptomatic and icteric disease,

Conclusion

We present 6 cases of HBV reactivation in patients at a single institution seen during a 5-year period. Five patients experienced reverse seroconversion after immunosuppressive therapy, and one experienced reactivation after withdrawal of nucleoside analogue therapy. These cases exemplify the need to provide prophylaxis against hepatitis B reactivation in immunocompromised patients. They illustrate the importance of proper screening of transplant recipients and donors and others who face a

Acknowledgments

The authors thank their patients for their ability to teach and humble them. In memory of patients 1 and 6.

Drs Palmore and Shah contributed equally to this work.

References (66)

  • O. Shibolet et al.

    Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers

    Blood

    (2002)
  • J.R. Wands et al.

    Serial studies of hepatitis-associated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders

    Gastroenterology

    (1975)
  • A.L. Mindikoglu et al.

    Hepatitis B virus reactivation after cytotoxic chemotherapy: the disease and its prevention

    Clin Gastroenterol Hepatol

    (2006)
  • J.E. Uhm et al.

    Changes in serologic markers of hepatitis B following autologous hematopoietic stem cell transplantation

    Biol Blood Marrow Transplant

    (2007)
  • A. Berger et al.

    HBV reactivation after kidney transplantation

    J Clin Virol

    (2005)
  • S. Awerkiew et al.

    Reactivation of an occult hepatitis B virus escape mutant in an anti-HBs positive, anti-HBc negative lymphoma patient

    J Clin Virol

    (2007)
  • B.J. McMahon

    Epidemiology and natural history of hepatitis B

    Semin Liver Dis

    (2005)

  • Hepatitis B, 2004

    (2004)
  • L. Xunrong et al.

    Hepatitis B virus (HBV) reactivation after cytotoxic or immunosuppressive therapy: pathogenesis and management

    Rev Med Virol

    (2001)
  • P.M. Chen et al.

    Reactivation of hepatitis B virus in two chronic GVHD patients after transplant

    Int J Hematol

    (1993)
  • U. Laukamm-Josten et al.

    Decline of naturally acquired antibodies to hepatitis B surface antigen in HIV-1 infected homosexual men

    AIDS

    (1988)
  • F. Romand et al.

    [Hepatitis B virus reactivation after allogeneic bone marrow transplantation in a patient previously cured of hepatitis B]

    Gastroenterol Clin Biol

    (1999)
  • J. Waite et al.

    Hepatitis B virus reactivation or reinfection associated with HIV-1 infection

    AIDS

    (1988)
  • J.H. Hoofnagle et al.

    Reactivation of chronic hepatitis B virus infection by cancer chemotherapy

    Ann Intern Med

    (1982)
  • D. Ganem et al.

    Hepatitis B virus infection: natural history and clinical consequences

    N Engl J Med

    (2004)
  • R. Perillo et al.

    Hepatitis B and D

  • B. Rehermann et al.

    The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response

    Nat Med

    (1996)
  • C. Brechot et al.

    Hepatitis B virus DNA in patients with chronic liver disease and negative tests for hepatitis B surface antigen

    N Engl J Med

    (1985)
  • H. Iizuka et al.

    Correlation between anti-HBc titers and HBV DNA in blood units without detectable HBsAg

    Vox Sang

    (1992)
  • J.H. Hoofnagle et al.

    Antibody to hepatitis B core antigen: a sensitive indicator of hepatitis B virus replication

    N Engl J Med

    (1974)
  • T.J. Liang et al.

    Hepatitis B virus infection in patients with idiopathic liver disease

    Hepatology

    (1991)
  • M.E. Wachs et al.

    The risk of transmission of hepatitis B from HBsAg(−), HBcAb(+), HBIgM(−) organ donors

    Transplantation

    (1995)
  • G.E. Loss et al.

    Transplantation of livers from hbc Ab positive donors into HBc Ab negative recipients: a strategy and preliminary results

    Clin Transplant

    (2001)

    • Cited by (56)

    • Risk of hepatitis B surface antigen seroreversion after corticosteroid treatment in patients with previous hepatitis B virus exposure

      2020, Journal of Hepatology

    • Antiviral strategies to eliminate hepatitis B virus covalently closed circular DNA (cccDNA)

      2016, Current Opinion in Pharmacology
      Citation Excerpt :

      The continual presence of cccDNA in the hepatocyte nucleus is a major impediment to HBV treatment and cure, as it is not directly targeted by current treatments and is a continual source of the pgRNA transcriptional template and additional viral mRNAs. Although a proportion of cccDNA molecules are removed during resolution of acute (transient) HBV infection, most likely due to immune-mediated clearance of HBV infected cells during hepatocyte turnover [9,10,11,12,13,14,15] or noncytolytic clearance [16], re-activation of HBV infection in immunosuppressed patients that may have previously resolved their acute infection [17,18,19,20,21] shows that cccDNA is not completely cleared during disease resolution in all patients. Hence the removal of cccDNA, or the suppression of its transcriptional activity, is a desired aim for treatment and cure regimens.

    • Irbesartan, an FDA approved drug for hypertension and diabetic nephropathy, is a potent inhibitor for hepatitis B virus entry by disturbing Na<sup>+</sup>-dependent taurocholate cotransporting polypeptide activity

      2015, Antiviral Research
      Citation Excerpt :

      Using the HepG2.N9 cell line, 2 small molecules, cyclosporin A (Nkongolo et al., 2014; Watashi et al., 2013) and ezetimide (Lucifora et al., 2013) reported recently as HBV infection inhibitors, were independently validated in this study, and irbesartan was demonstrated as a new inhibitor of HBV entry. Cyclosporin A is an immunosuppressive drug which may restrict its application for HBV therapy in future (Palmore et al., 2009). Ezetimibe is an inhibitor of intestinal cholesterol absorption and is widely used for the therapy of hypercholesterolemia (Ballantyne et al., 2003).

    • Prevalence and chemotherapy-induced reactivation of occult hepatitis B virus among hepatitis B surface antigen negative patients with diffuse large B-cell lymphoma: Significance of hepatitis B core antibodies screening

      2015, Journal of the Egyptian National Cancer Institute
      Citation Excerpt :

      Anti-HBc IgM may help in the diagnosis of the acute HBV and also during flares [6]. HBV reactivation in patients under immunosuppressive treatment is life-threatening occurring in both overt and occult HBV infection [7,8]. The risk of HBV reactivation is high with marked immunosuppression, especially in hematological malignancies chemotherapy (21–67%), bone marrow transplantation and monoclonal antibody therapy [9,10].

    • Using the AS04C-adjuvanted hepatitis B vaccine in patients classified as non-responders

      2024, Transactions of the Royal Society of Tropical Medicine and Hygiene

    • Hepatitis B virus infection and its determinants among HIV positive pregnant women: Multicenter unmatched case-control study

      2021, PLoS ONE
    View all citing articles on Scopus

    Conflicts of interest The authors disclose the following: Dr Uri Lopatin runs the HBV translational medicine program at Roche Pharmaceuticals. He made his contributions to the manuscript 3 years ago, when he was an NIH fellow. The remaining authors disclose no conflicts.

    Funding This research was supported by the Intramural Research Programs of the NIDDK (Z01 DK054514-02), NIAID, NHLBI, and NCI, NIH.

    View full text
    Copyright © 2009 AGA Institute. Published by Elsevier Ltd. All rights reserved.