Dtsch Med Wochenschr 2009; 134(6): 255-258
DOI: 10.1055/s-0028-1123989
Übersicht | Review article
Gastroenterologie
© Georg Thieme Verlag KG Stuttgart · New York

Prophylaxe und Therapie der Reaktivierung einer Hepatitis B bei Immunsuppression

Prophylaxis and therapy of reactivation of hepatitis B in immunosuppressed patientsM. von Wagner1 , S. Zeuzem1
  • 1Medizinische Klinik I, Johann Wolfgang Goethe-Universität Frankfurt
Further Information

Publication History

eingereicht: 21.4.2008

akzeptiert: 6.11.2008

Publication Date:
29 January 2009 (online)

Zusammenfassung

Die chronische Hepatitis-B-Virus (HBV)-Infektion kann niedrig-replikativ mit günstiger Prognose oder hoch-replikativ mit dem Risiko einer Leberzirrhose und eines Leberzellkarzinoms verlaufen. Eine Immunsuppression im Rahmen einer lokalen oder systemischen Chemotherapie sowie einer autoimmunen Krankheit erhöht signifikant das Risiko der Reaktivierung einer HBV, zum Teil mit dem Bild einer akuten, selten fulminanten Hepatitis. Unter intensiver Immunsuppression z. B. im Rahmen einer Stammzelltransplantation kann eine Re-Serokonversion auftreten mit Verlust von anti-HBs +/– anti-HBc und erneutem Nachweis von HBsAg sowie HBV-DNA und dem Risiko einer akuten (fulminanten) Hepatitis. Bestimmte Chemotherapeutika und Immunsuppressiva begünstigen eine Reaktivierung. In Studien konnte gezeigt werden, dass die Reaktivierung einer Hepatitis B Virusinfektion erfolgreich mit dem Nukleosidanalogon Lamivudin behandelt werden kann, eine prophylaktische Gabe scheint der Therapie einer Re-Aktivierung überlegen zu sein. Für weitere Nukleosid- (Telbivudin, Entecavir) oder Nukleotidanloga (Adefovir, Tenofovir) liegen bislang keine größeren Erfahrungen in dieser Indikation vor. Bei allen Patienten vor einer immunsuppressiven Therapie muss daher der HBV Serostatus geprüft werden. Patienten ohne HBV Infektion und ohne ausreichenden anti-HBs-Titer müssen aktiv immunisiert werden. Bei Patienten mit chronischer HBV Infektion und hochdosierter Immunsuppression besteht gemäß der aktuellen Leitlinie der DGVS die Indikation zur antiviralen Therapie. Bei Nachweis einer durchgemachten Hepatitis B Virusinfektion (anti-HBc positiv, HBsAg negativ) muss eine Kontrolle vor und regelmäßig unter immunsuppressiver Therapie sowie im Fall der Reaktivierung eine Therapie mit Nukleos(t)idanaloga erfolgen. Bei Patienten vor Stammzelltransplantation muss bereits bei Nachweis einer durchgemachten HBV Infektion eine Prophylaxe mit einem Nukleos(t)idanalogon eingeleitet werden.

Abstract

Immunosuppression because of local or systemic chemotherapy or immunosuppressive therapy of autoimmune diseases is an increasing risk for reactivation of hepatitis B and may lead to acute hepatitis and rarely to fulminant hepatitis. Intensive immunosuppression, e. g. in advance of bone marrow transplantation, may lead to re-seroconversion with loss of anti-HBs and detection of HBsAg and HBV-DNA and a risk of (fulminant) hepatitis. Distinct chemotherapeutics and immunosuppressive medication promote reactivation or re-seroconversion of HBV infection. Several studies have shown a significant benefit by antiviral therapy with nucleosidanalogue lamivudine to avoid reactivation. For other nucleoside analogues (telbivudine, entecavir) or nucleotide analogues (adefovir dipivoxil, tenofovir) larger experiences are yet missing in this situation. Prophylaxis with antiviral agents may be superior to therapy of reactivation. Prior to onset of immunosuppressive treatment patients must be tested for HBV. Patients without detection of HBsAg and without sufficient anti-HBs-titer should receive active immunisation. In case of chronic HBV infection antiviral therapy should be initiated before intense immunosuppression. In case of HBV infection in medical history (anti-HBc positive, HBsAg negative) HBV serostatus should be tested frequently. In case of reactivation, therapy with nucleos(t)ide analogue should immediately be initiated. In case of bone marrow transplantation prophylaxis with nucleos(t)idanalogue has to be initiated before onset of treatment if anti-HBc is detectable, independent from HBsAg result.

Literatur

  • 1 Ahmed A, Keeffe E B. Lamivudine therapy for chemotherapy-induced reactivation of hepatitis B virus infection.  Am J Gastroenterol. 1999;  94 249-251
  • 2 Al Taie O H, Mork H, Gassel A M. et al . Prevention of hepatitis B flare-up during chemotherapy using lamivudine: case report and review of the literature.  Ann Hematol. 1999;  78 247-249
  • 3 Calabrese L H, Zein N N, Vassilopoulos D. Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies.  Ann Rheum Dis. 2006;  65 983-989
  • 4 Cheng A L, Hsiung C A, Su I J. et al . Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma.  Hepatology. 2003;  37 1320-1328
  • 5 Chisari F V, Ferrari C. Hepatitis B virus immunopathogenesis.  Annu Rev Immunol. 1995;  13 29-60
  • 6 Cornberg M, Protzer U, Dollinger M M. et al . Prophylaxe, Diagnotik und Therapie der Hepatitis-B-Virus-(HBV-) Infektion. AWMF-Register 021/011.  Z Gastroenterol. 2007;  45 525-574
  • 7 Dervite I, Hober D, Morel P. Acute hepatitis B in a patient with antibodies to hepatitis B surface antigen who was receiving rituximab.  N Engl J Med. 2001;  344 68-69
  • 8 Dhedin N, Douvin C, Kuentz M. et al . Reverse seroconversion of hepatitis B after allogeneic bone marrow transplantation: a retrospective study of 37 patients with pretransplant anti-HBs and anti-HBc.  Transplantation. 1998;  66 616-619
  • 9 Esteve M, Saro C, Gonzalez-Huix F. et al . Chronic hepatitis B reactivation following infliximab therapy in Crohn’s disease patients: need for primary prophylaxis.  Gut. 2004;  53 1363-1365
  • 10 Floreani A, Boninsegna S, Lobello S. et al . Fatal hepatic decompensation in a bone marrow transplant recipient with HBV-related cirrhosis following lamivudine withdrawal.  Gastroenterol Clin Biol. 2006;  30 307-309
  • 11 Fontaine H, Vallet-Pichard A, Chaix M L. et al . Efficacy and safety of adefovir dipivoxil in kidney recipients, hemodialysis patients, and patients with renal insufficiency.  Transplantation. 2005;  80 1086-1092
  • 12 Gartner B C, Jung W, Welsch C. et al . Permanent loss of anti-HBc after reactivation of hepatitis B virus infection in an anti-HBs and anti-HBc-positive patient after allogeneic stem cell transplantation.  J Clin Virol. 2007;  38 146-148
  • 13 Guidelines for the management of rheumatoid arthritis: 2002 Update.  Arthritis Rheum. 2002;  46 328-346
  • 14 Hui C K, Cheung W W, Zhang H Y. et al . Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy.  Gastroenterology. 2006;  131 59-68
  • 15 Iwai K, Tashima M, Itoh M. et al . Fulminant hepatitis B following bone marrow transplantation in an HBsAg-negative, HBsAb-positive recipient; reactivation of dormant virus during the immunosuppressive period.  Bone Marrow Transplant. 2000;  25 105-108
  • 16 Jang J W, Choi J Y, Bae S H. et al . Transarterial chemo-lipiodolization can reactivate hepatitis B virus replication in patients with hepatocellular carcinoma.  J Hepatol. 2004;  41 427-435
  • 17 Jang J W, Choi J Y, Bae S H. et al . A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization.  Hepatology. 2006;  43 233-240
  • 18 Knoll A, Boehm S, Hahn J. et al . Reactivation of resolved hepatitis B virus infection after allogeneic haematopoietic stem cell transplantation.  Bone Marrow Transplant. 2004;  33 925-929
  • 19 Kumagai K, Takagi T, Nakamura S. et al . Hepatitis B virus carriers in the treatment of malignant lymphoma: an epidemiological study in Japan.  Ann Oncol. 1997;  8 Suppl 1 107-109
  • 20 Lai C L, Dienstag J, Schiff E. et al . Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B.  Clin Infect Dis. 2003;  36 687-696
  • 21 Lau G K, He M L, Fong D Y. et al . Preemptive use of lamivudine reduces hepatitis B exacerbation after allogeneic hematopoietic cell transplantation.  Hepatology. 2002;  36 702-709
  • 22 Lau G K, Lok A S, Liang R H. et al . Clearance of hepatitis B surface antigen after bone marrow transplantation: role of adoptive immunity transfer.  Hepatology. 1997;  25 1497-1501
  • 23 Lau G K, Suri D, Liang R. et al . Resolution of chronic hepatitis B and anti-HBs seroconversion in humans by adoptive transfer of immunity to hepatitis B core antigen.  Gastroenterology. 2002;  122 614-624
  • 24 Lau G K, Yiu H H, Fong D Y. et al . Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy.  Gastroenterology. 2003;  125 1742-1749
  • 25 Law J K, Ho J K, Hoskins P. et al . Fatal reactivation of hepatitis B post-chemotherapy for lymphoma in a hepatitis B surface antigen-negative, hepatitis B core antibody-positive patient: potential implications for future prophylaxis recommendations.  Leuk Lymphoma. 2005;  46 1085-1089
  • 26 Liao C A, Lee C M, Wu H C. et al . Lamivudine for the treatment of hepatitis B virus reactivation following chemotherapy for non-Hodgkin’s lymphoma.  Br J Haematol. 2002;  116 166-169
  • 27 Liaw Y F. Hepatitis viruses under immunosuppressive agents.  J Gastroenterol Hepatol. 1998;  13 14-20
  • 28 Lok A S, Liang R H, Chiu E K. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study.  Gastroenterology. 1991;  100 182-188
  • 29 Meuleman P, Libbrecht L, Wieland S. et al . Immune suppression uncovers endogenous cytopathic effects of the hepatitis B virus.  J Virol. 2006;  80 2797-2807
  • 30 Onozawa M, Hashino S, Izumiyama K. et al . Progressive disappearance of anti-hepatitis B surface antigen antibody and reverse seroconversion after allogeneic hematopoietic stem cell transplantation in patients with previous hepatitis B virus infection.  Transplantation. 2005;  79 616-619
  • 31 Ostuni P, Botsios C, Punzi L. et al . Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate.  Ann Rheum Dis. 2003;  62 686-687
  • 32 Ozgonenel B, Moonka D, Savasan S. Fulminant hepatitis B following rituximab therapy in a patient with Evans syndrome and large B-cell lymphoma.  Am J Hematol. 2006;  81 302
  • 33 Perceau G, Diris N, Estines O. et al . Late lethal hepatitis B virus reactivation after rituximab treatment of low-grade cutaneous B-cell lymphoma.  Br J Dermatol. 2006;  155 1053-1056
  • 34 Shibolet O, Ilan Y, Gillis S. et al . Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers.  Blood. 2002;  100 391-396
  • 35 Tamori A, Nishiguchi S, Tanaka M. et al . Lamivudine therapy for hepatitis B virus reactivation in a patient receiving intra-arterial chemotherapy for advanced hepatocellular carcinoma.  Hepatol Res. 2003;  26 77-80
  • 36 Tsutsumi Y, Tanaka J, Kawamura T. et al . Possible efficacy of lamivudine treatment to prevent hepatitis B virus reactivation due to rituximab therapy in a patient with non-Hodgkin’s lymphoma.  Ann Hematol. 2004;  83 58-60
  • 37 Vizzini G B, Luca A, Marino I R. Hepatitis B virus reactivation after a single session of transarterial chemoembolization in patients with hepatocellular carcinoma.  Ann Intern Med. 2003;  138 691-692
  • 38 Wands J R, Chura C M, Roll F J, Maddrey W C. Serial studies of hepatitis-associated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders.  Gastroenterology. 1975;  68 105-112
  • 39 Westhoff T H, Jochimsen F, Schmittel A. et al . Fatal hepatitis B virus reactivation by an escape mutant following rituximab therapy.  Blood. 2003;  102 1930
  • 40 Yamagata M, Murohisa T, Tsuchida K. et al . Fulminant B hepatitis in a surface antigen and hepatitis B DNA-negative patient with diffuse large B-cell lymphoma after CHOP chemotherapy plus rituximab.  Leuk Lymphoma. 2007;  48 431-433
  • 41 Yeo W, Chan P K, Ho W M. et al . Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy.  J Clin Oncol. 2004;  22 927-934
  • 42 Yeo W, Chan P K, Zhong S. et al . Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors.  J Med Virol. 2000;  62 299-307
  • 43 Yeo W, Ho W M, Hui P. et al . Use of lamivudine to prevent hepatitis B virus reactivation during chemotherapy in breast cancer patients.  Breast Cancer Res Treat. 2004;  88 209-215
  • 44 Yeo W, Johnson P J. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy.  Hepatology. 2006;  43 209-220
  • 45 Yeo W, Steinberg J L, Tam J S. et al . Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy.  J Med Virol. 1999;  59 263-269
  • 46 Yeo W, Zee B, Zhong S. et al . Comprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy.  Br J Cancer. 2004;  90 1306-1311

Prof. Dr. Stefan Zeuzem

Klinikum der J.W. Goethe-Universität

Theodor-Stern-Kai 7

60590 Frankfurt a.M.

Phone: 069/6301-4544

Fax: 069/6301-6448

Email: zeuzem@em.uni-frankfurt.de

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