Hepatitis B Virus Reactivation After Cytotoxic Chemotherapy: The Disease and Its Prevention
2006; Elsevier BV; Volume: 4; Issue: 9 Linguagem: Inglês
10.1016/j.cgh.2006.05.027
ISSN1542-7714
AutoresAyse L. Mindikoglu, Arie Regev, Eugene R. Schiff,
Tópico(s)Liver Disease Diagnosis and Treatment
ResumoReactivation of hepatitis B virus (HBV) is a well-recognized complication in patients with chronic HBV infection who receive cytotoxic or immunosuppressive therapy. In most cases, reactivations occur in patients who are carriers of HBV infection showing positive hepatitis B surface antigen (HBsAg). Reactivation also may occur in patients with resolved infection who are HBsAg negative, anti–HBs positive, and anti–hepatitis B core positive. HBV reactivations can lead to severe flares that may be life-threatening unless recognized and treated promptly. Physician awareness is essential because prophylactic antiviral treatment can diminish the occurrence and improve the outcome of such episodes. Patients undergoing cytotoxic therapy should be checked routinely for HBV serologic markers and serum HBV DNA levels. Patients who are HBV carriers or anti–hepatitis B core positive should be monitored closely during and after the administration of cytotoxic chemotherapy. Prophylactic treatment with a nucleoside or nucleotide analogue should be considered strongly to prevent HBV reactivation in these patients. Reactivation of hepatitis B virus (HBV) is a well-recognized complication in patients with chronic HBV infection who receive cytotoxic or immunosuppressive therapy. In most cases, reactivations occur in patients who are carriers of HBV infection showing positive hepatitis B surface antigen (HBsAg). Reactivation also may occur in patients with resolved infection who are HBsAg negative, anti–HBs positive, and anti–hepatitis B core positive. HBV reactivations can lead to severe flares that may be life-threatening unless recognized and treated promptly. Physician awareness is essential because prophylactic antiviral treatment can diminish the occurrence and improve the outcome of such episodes. Patients undergoing cytotoxic therapy should be checked routinely for HBV serologic markers and serum HBV DNA levels. Patients who are HBV carriers or anti–hepatitis B core positive should be monitored closely during and after the administration of cytotoxic chemotherapy. Prophylactic treatment with a nucleoside or nucleotide analogue should be considered strongly to prevent HBV reactivation in these patients. See CME exam on page 1074. See CME exam on page 1074. Hepatitis B remains one of the major causes of acute and chronic liver disease. It is estimated that 350–400 million people have chronic hepatitis B virus (HBV) infection worldwide. HBV reactivation in patients who receive cytotoxic or immunosuppressive therapy is well documented. It generally is characterized by the reappearance of HBV DNA or hepatitis B e antigen (HBeAg) in a person who is an inactive HBV carrier or has resolved HBV infection.1Keeffe E.B. Dietrich D.T. Han S.B. et al.A treatment algorithm for the management of chronic hepatitis B virus infection in the United States.Clin Gastroenterol Hepatol. 2004; 2: 87-106Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 2Keeffe E.B. Hepatitis B virus reactivation with chemotherapy: diagnosis and prevention with antiviral prophylaxis.Rev Gastroenterol Disord. 2004; 4: 46-48PubMed Google Scholar, 3Lok AS, McMahon BJ. AASLD Practice Guidelines. Chronic hepatitis B. Available: www.aasld.org. Accessed: November 20, 2005.Google Scholar The reappearance of markers of activity may be asymptomatic but often is followed by a clinical flare characterized by a substantial increase of serum transaminase levels and histologic evidence of active inflammation. Occasionally, such flares may lead to fatal hepatic failure.4Hoofnagle J.H. Dusheiko G.M. Schafer D.F. et al.Reactivation of chronic hepatitis B virus infection by cancer chemotherapy.Ann Intern Med. 1982; 96: 447-449Crossref PubMed Scopus (363) Google Scholar, 5Lok A.S.F. Liang R.S. Chiu E.K.W. et al.Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy Report of a prospective study.Gastroenterology. 1991; 100: 182-188Abstract PubMed Google Scholar According to current guidelines and treatment algorithms, the different phases and activity states of chronic HBV infection are largely defined based on 5 serologic tests and serum levels of HBV DNA determined by polymerase chain reaction (PCR) (Table 1). Case series and studies vary in the definition of HBV reactivation. Early case reports were published before testing for HBV DNA was available. As a result, HBV reactivation and flare were defined based on clinical features such as jaundice and increasing serum levels of transaminases in the absence of other causes,6Galbraith R.M. Eddleston A.L. Williams R. et al.Fulminant hepatic failure in leukaemia and choriocarcinoma related to withdrawal of cytotoxic drug therapy.Lancet. 1975; 2: 528-530Abstract PubMed Scopus (218) Google Scholar, 7Thung S.N. Gerber M.A. Klion F. et al.Massive hepatic necrosis after chemotherapy withdrawal in a hepatitis B virus carrier.Arch Intern Med. 1985; 145: 1313-1314Crossref PubMed Scopus (89) Google Scholar or the reappearance or increase of serum levels of hepatitis B surface antigen (HBsAg) in patients with previously undetected or low levels.8Wands J.R. Chura C.M. Roll F.J. et al.Serial studies of hepatitis-associated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders.Gastroenterology. 1975; 68: 105-112Abstract Full Text PDF PubMed Scopus (238) Google Scholar, 9Alexopoulos C.G. Vaslamatzis M. Hatzidimitriou G. Prevalence of hepatitis B virus marker positivity and evolution of hepatitis B virus profile, during chemotherapy, in patients with solid tumors.Br J Cancer. 1999; 81: 69-74Crossref PubMed Scopus (93) Google Scholar Subsequent publications defined HBV reactivation based on the earlier-described criteria with the addition of the appearance or a marked increase in serum HBV DNA levels.4Hoofnagle J.H. Dusheiko G.M. Schafer D.F. et al.Reactivation of chronic hepatitis B virus infection by cancer chemotherapy.Ann Intern Med. 1982; 96: 447-449Crossref PubMed Scopus (363) Google Scholar, 5Lok A.S.F. Liang R.S. Chiu E.K.W. et al.Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy Report of a prospective study.Gastroenterology. 1991; 100: 182-188Abstract PubMed Google Scholar, 10Lau J.Y.N. Lai C.L. Lin H.J. et al.Fatal reactivation of chronic hepatitis B virus infection following withdrawal of chemotherapy in lymphoma patients.QJM. 1989; 73: 911-917PubMed Google Scholar, 11Lau G.K.K. Leung Y.H. Fong D.Y.T. et al.High hepatitis B virus (HBV) DNA viral load as the most important risk factor for HBV reactivation in patients positive for HBV surface antigen undergoing autologous hematopoietic cell transplantation.Blood. 2002; 99: 2324-2330Crossref PubMed Scopus (185) Google Scholar When present, seroconversion from anti-HBe to HBeAg positivity or the reappearance of anti–hepatitis B core (HBc) immunoglobulin M is considered strong evidence for reactivation.10Lau J.Y.N. Lai C.L. Lin H.J. et al.Fatal reactivation of chronic hepatitis B virus infection following withdrawal of chemotherapy in lymphoma patients.QJM. 1989; 73: 911-917PubMed Google Scholar, 11Lau G.K.K. Leung Y.H. Fong D.Y.T. et al.High hepatitis B virus (HBV) DNA viral load as the most important risk factor for HBV reactivation in patients positive for HBV surface antigen undergoing autologous hematopoietic cell transplantation.Blood. 2002; 99: 2324-2330Crossref PubMed Scopus (185) Google Scholar, 12Shibolet 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: 391-396Crossref PubMed Scopus (139) Google Scholar In recent studies, HBV reactivation was defined as a 10-fold or greater increase in HBV DNA level compared with the prereactivation level or the reappearance of a previously negative HBsAg on 2 consecutive tests.11Lau G.K.K. Leung Y.H. Fong D.Y.T. et al.High hepatitis B virus (HBV) DNA viral load as the most important risk factor for HBV reactivation in patients positive for HBV surface antigen undergoing autologous hematopoietic cell transplantation.Blood. 2002; 99: 2324-2330Crossref PubMed Scopus (185) Google Scholar, 13Yeo W. Chan P.K.S. Chan H.L.Y. et al.Hepatitis B virus reactivation during cytotoxic chemotherapy-enhanced viral replication precedes overt hepatitis.J Med Virol. 2001; 65: 473-477Crossref PubMed Scopus (57) Google ScholarTable 1Terminology Used for Different Phases and Activity States of Chronic HBV InfectionHBsAgAnti-HBsHBeAgAnti-HBeAnti-HBcTypical HBV DNA level by PCR (copies/mL)Resolved infection−+−++UndetectableInactive carrier state+−−++ 105Replicative phase (HBeAg − chronic hepatitis)+−−++>104HBsAg, hepatitis B surface antigen; Anti-HBs, anti–hepatitis B surface; anti-HBe, anti–hepatitis B e; anti-HBc, anti–hepatitis B core; HBV DNA, hepatitis B virus deoxyribonucleic acid; PCR, polymerase chain reaction. Open table in a new tab HBsAg, hepatitis B surface antigen; Anti-HBs, anti–hepatitis B surface; anti-HBe, anti–hepatitis B e; anti-HBc, anti–hepatitis B core; HBV DNA, hepatitis B virus deoxyribonucleic acid; PCR, polymerase chain reaction. There is limited information regarding the effect of prophylactic treatment on the risk of HBV reactivation in patients treated with anticancer chemotherapy. Furthermore, studies addressing this question include different patient populations consisting of inactive chronic carriers, patients with resolved HBV infection, and patients with chronic hepatitis B in the replicative state (Table 1). The outcome and survival rates are therefore reported based on mixed groups of patients. This review focuses on the cumulative experience with incidence, clinical manifestations, and prophylaxis for HBV reactivation after immunosuppressive therapy. The risk for HBV reactivation after cytotoxic chemotherapy varies greatly in different case series. The frequency of reactivation in HBV carriers has been reported in the range of 14%–72%.5Lok A.S.F. Liang R.S. Chiu E.K.W. et al.Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy Report of a prospective study.Gastroenterology. 1991; 100: 182-188Abstract PubMed Google Scholar, 14Liang R.H.S. Lok A.S.F. Lai C.L. et al.Hepatitis B infection in patients with lymphomas.Hematol Oncol. 1990; 8: 261-270Crossref PubMed Scopus (96) Google Scholar, 15Yeo W. Chan P.K. Hui P. et al.Hepatitis B virus reactivation in breast cancer patients receiving cytotoxic chemotherapy: a prospective study.J Med Virol. 2003; 70: 553-561Crossref PubMed Scopus (182) Google Scholar, 16Zhong S. Yeo W. Schroder C. et al.High hepatitis B virus (HBV) DNA viral load is an important risk factor for HBV reactivation in breast cancer patients undergoing cytotoxic chemotherapy.J Viral Hepat. 2004; 11: 55-59Crossref PubMed Scopus (90) Google Scholar, 17Yeo W. Chan P.K.S. 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: 299-307Crossref PubMed Scopus (566) Google Scholar, 18Perrillo R.P. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.Gastroenterology. 2001; 120: 1009-1022Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar This variation may be related to differences in study designs, HBV DNA assays, definitions of HBV reactivation, types of malignancy, regimens of chemotherapy, and patient populations consisting of not only inactive carriers or those with resolved hepatitis B but also patients with chronic HBV infection in the replicative phase (Table 1).16Zhong S. Yeo W. Schroder C. et al.High hepatitis B virus (HBV) DNA viral load is an important risk factor for HBV reactivation in breast cancer patients undergoing cytotoxic chemotherapy.J Viral Hepat. 2004; 11: 55-59Crossref PubMed Scopus (90) Google Scholar, 17Yeo W. Chan P.K.S. 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: 299-307Crossref PubMed Scopus (566) Google Scholar, 18Perrillo R.P. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.Gastroenterology. 2001; 120: 1009-1022Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar, 19Markovic S. Drozina G. Vovk M. et al.Reactivation of hepatitis B but not hepatitis C in patients with malignant lymphoma and immunosuppressive therapy A prospective study in 305 patients.Hepatogastroenterology. 1999; 46: 2925-2930PubMed Google Scholar Although the frequency of HBV and reactivation varies considerably between published reports, it is clear that chemotherapy administered to cancer patients who have chronic HBV infection leads to an increased risk for liver-related morbidity and mortality.20Liang R. Lau G.K.K. Kwong Y.L. Chemotherapy and bone marrow transplantation for cancer patients who are also chronic hepatitis B carriers: a review of the problem.J Clin Oncol. 1999; 17: 394-398PubMed Google Scholar Patients with resolved HBV infection (HBsAg negative, anti–HBs positive, anti–HBc positive) are also at risk for HBV reactivation during cytotoxic chemotherapy. It is well established that individuals who cleared the surface antigen and have serologic evidence of immunity (anti-HBs) after HBV infection, still may harbor and transmit the virus.21Hoofnagle J.H. Seeff L.B. Bales Z.B. et al.Type B hepatitis after transfusion with blood containing antibody to hepatitis B core antigen.N Engl J Med. 1978; 298: 1379-1383Crossref PubMed Scopus (372) Google Scholar Contrary to what is expected, the presence of anti-HBs, which generally is considered a protective antibody, does not eliminate the possibility of reactivation during immunosuppression. Although HBV reactivation seems to occur significantly less commonly in HBsAg-negative patients, it has been described in about 14%–20% of anti–HBc-positive anti–HBs-positive individuals who received chemotherapy for lymphoma.5Lok A.S.F. Liang R.S. Chiu E.K.W. et al.Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy Report of a prospective study.Gastroenterology. 1991; 100: 182-188Abstract PubMed Google Scholar, 18Perrillo R.P. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.Gastroenterology. 2001; 120: 1009-1022Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar The chemotherapy-induced reactivation inHBsAg-negative patients with detectable anti-HBc and anti-HBs appears to be associated with an ongoing HBV replication by the episomal form of the virus.22Marusawa H. Imoto S. Yoshihide U. et al.Reactivation of latently infected hepatitis B virus in a leukemia patient with antibodies to hepatitis B core antigen.J Gastroenterol. 2001; 36: 633-636Crossref PubMed Scopus (30) Google Scholar Fulminant hepatitis also may develop in HBsAg-negative and anti–HBs-positive patients secondary to HBV reactivation.23Kawatani T. Suou T. Tajima F. et al.Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for hematologic malignancies.Eur J Haematol. 2001; 67: 45-50Crossref PubMed Scopus (103) Google Scholar A third important population at risk for flare is patients with chronic HBV infection in the replicative phase (Table 1). This has been shown in both HBeAg-positive patients16Zhong S. Yeo W. Schroder C. et al.High hepatitis B virus (HBV) DNA viral load is an important risk factor for HBV reactivation in breast cancer patients undergoing cytotoxic chemotherapy.J Viral Hepat. 2004; 11: 55-59Crossref PubMed Scopus (90) Google Scholar and HBeAg-negative patients (precore or core-promoter mutations).24Dai M.S. Lu J.J. Chen Y.C. et al.Reactivation of precore mutant hepatitis B virus in chemotherapy-treated patients.Cancer. 2001; 92: 2927-2932Crossref PubMed Scopus (49) Google Scholar, 25Kosaka Y. Takase K. Kojima M. et al.Fulminant hepatitis B: induction by hepatitis B virus mutants defective in the precore region and incapable of encoding e antigen.Gastroenterology. 1991; 100: 1087-1094PubMed Google Scholar In the latter group, chemotherapy-induced reactivation seems to carry a higher risk for fulminant hepatitis and liver failure.24Dai M.S. Lu J.J. Chen Y.C. et al.Reactivation of precore mutant hepatitis B virus in chemotherapy-treated patients.Cancer. 2001; 92: 2927-2932Crossref PubMed Scopus (49) Google Scholar, 25Kosaka Y. Takase K. Kojima M. et al.Fulminant hepatitis B: induction by hepatitis B virus mutants defective in the precore region and incapable of encoding e antigen.Gastroenterology. 1991; 100: 1087-1094PubMed Google Scholar Several factors are associated with an increased risk for HBV reactivation among HBV carriers. These include a diagnosis of lymphoma or breast cancer, male sex, young age, pre-existing hepatitis, certain cytotoxic drugs (anthracyclines or vincristine), and higher HBV DNA levels based on real-time PCR measurement.5Lok A.S.F. Liang R.S. Chiu E.K.W. et al.Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy Report of a prospective study.Gastroenterology. 1991; 100: 182-188Abstract PubMed Google Scholar, 16Zhong S. Yeo W. Schroder C. et al.High hepatitis B virus (HBV) DNA viral load is an important risk factor for HBV reactivation in breast cancer patients undergoing cytotoxic chemotherapy.J Viral Hepat. 2004; 11: 55-59Crossref PubMed Scopus (90) Google Scholar, 26Yeo 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: 1306-1311Crossref PubMed Scopus (275) Google Scholar, 27Rossi G. Prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HbsAg carriers with hemato-oncological neoplasias treated with chemotherapy.Leuk Lymphoma. 2003; 44: 759-766Crossref PubMed Scopus (43) Google Scholar The baseline hepatic biochemical tests including alanine transaminase, total bilirubin, and albumin levels were not associated with a higher risk for HBV reactivation. A high HBV DNA level (>105 copies/mL) before administration of chemotherapy was reported as the most important risk factor for HBV reactivation.11Lau G.K.K. Leung Y.H. Fong D.Y.T. et al.High hepatitis B virus (HBV) DNA viral load as the most important risk factor for HBV reactivation in patients positive for HBV surface antigen undergoing autologous hematopoietic cell transplantation.Blood. 2002; 99: 2324-2330Crossref PubMed Scopus (185) Google Scholar, 16Zhong S. Yeo W. Schroder C. et al.High hepatitis B virus (HBV) DNA viral load is an important risk factor for HBV reactivation in breast cancer patients undergoing cytotoxic chemotherapy.J Viral Hepat. 2004; 11: 55-59Crossref PubMed Scopus (90) Google Scholar Whether steroid-free chemotherapy decreases the incidence of HBV reactivation needs to be investigated further because of conflicting reports in the literature.28Cheng A.L. Hsiung C.A. Su I.J. et al.Lymphoma Committee of Taiwan Cooperative Oncology GroupSteroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma.Hepatology. 2003; 37: 1320-1328Crossref PubMed Scopus (254) Google Scholar, 29Shimizu D. Nomura K. Matsumoto Y. et al.Hepatitis B virus reactivation in a patient undergoing steroid-free chemotherapy.World J Gastroenterol. 2004; 10: 2301-2302PubMed Google Scholar In addition, transarterial chemolipiodolization is an important risk factor for HBV reactivation. In 1 study, 33.7% of hepatocellular carcinoma patients undergoing transarterial chemolipiodolization were reported to have HBV reactivation.30Jang 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: 427-435Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar It is important to note that half of the patients who were reported to have HBV reactivation already were HBeAg positive before the chemotherapy, indicating an active HBV replication at least in some of these patients. HBV patients who were co-infected with hepatitis C virus also were found to be at higher risk for severe liver dysfunction during cytotoxic chemotherapy.23Kawatani T. Suou T. Tajima F. et al.Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for hematologic malignancies.Eur J Haematol. 2001; 67: 45-50Crossref PubMed Scopus (103) Google Scholar Most episodes of chemotherapy-induced HBV reactivation are caused by a change in the balance between the immunologic response to HBV and the extent of viral proliferation. Cytotoxic therapy may suppress the normal immune function, enhance the viral replication, and, eventually, result in increased HBV DNA polymerase activity and HBV DNA and HBeAg levels, reappearance of HBsAg, and decreased HBsAb titers.18Perrillo R.P. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.Gastroenterology. 2001; 120: 1009-1022Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar, 27Rossi G. Prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HbsAg carriers with hemato-oncological neoplasias treated with chemotherapy.Leuk Lymphoma. 2003; 44: 759-766Crossref PubMed Scopus (43) Google Scholar, 31Lau 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: 1742-1749Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar, 32Wands J.R. Chura C.M. Roll F.J. et al.Serial studies of hepatitis-associated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders.Gastroenterology. 1975; 68: 105-112Abstract Full Text PDF PubMed Google Scholar Subsequent discontinuation of chemotherapy, which leads to restoration of the immune system, results in immune-mediated destruction of hepatocytes infected with HBV.33Lau G.K.K. He M.L. Fong D.Y.T. et al.Preemptive use of lamivudine reduces hepatitis B exacerbation after allogenic hematopoietic cell transplantation.Hepatology. 2002; 36: 702-709Crossref PubMed Scopus (161) Google Scholar, 34Idilman R. Arat M. Soydan E. et al.Lamivudine prophylaxis for prevention of chemotherapy-induced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies.J Viral Hepat. 2004; 11: 141-147Crossref PubMed Scopus (89) Google Scholar The severity of the viral replication during cytotoxic therapy and the liver damage on withdrawal of therapy seems to be associated directly with the potency of the immunosuppressive or cytotoxic therapy.18Perrillo R.P. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.Gastroenterology. 2001; 120: 1009-1022Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar HBV reactivation occurs not only on withdrawal of immunosuppressive therapy, but also during persistent immunosuppression, suggesting that a direct cytopathic effect of the virus may play a role in the mechanism of HBV reactivation.27Rossi G. Prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HbsAg carriers with hemato-oncological neoplasias treated with chemotherapy.Leuk Lymphoma. 2003; 44: 759-766Crossref PubMed Scopus (43) Google Scholar In addition, the glucocorticoid-responsive element of HBV that is stimulated by glucocorticoids may be important in HBV reactivation.18Perrillo R.P. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.Gastroenterology. 2001; 120: 1009-1022Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar, 34Idilman R. Arat M. Soydan E. et al.Lamivudine prophylaxis for prevention of chemotherapy-induced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies.J Viral Hepat. 2004; 11: 141-147Crossref PubMed Scopus (89) Google Scholar It has been shown that the glucocorticoid-responsive element induces replication and transcription of hepatitis HBV.18Perrillo R.P. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.Gastroenterology. 2001; 120: 1009-1022Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar Clinical manifestations of chemotherapy-induced HBV reactivation range from asymptomatic increase of serum transaminase levels to acute liver failure and death.24Dai M.S. Lu J.J. Chen Y.C. et al.Reactivation of precore mutant hepatitis B virus in chemotherapy-treated patients.Cancer. 2001; 92: 2927-2932Crossref PubMed Scopus (49) Google Scholar, 27Rossi G. Prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HbsAg carriers with hemato-oncological neoplasias treated with chemotherapy.Leuk Lymphoma. 2003; 44: 759-766Crossref PubMed Scopus (43) Google Scholar Serologic evidence for HBV reactivation was reported as early as 4 weeks and the median onset at 16 weeks after the first course of chemotherapy.31Lau 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: 1742-1749Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar Severely affected patients may present with jaundice and can develop ascites and hepatic encephalopathy rapidly. In a prospective study, 50% of patients who developed HBV reactivation were icteric.5Lok A.S.F. Liang R.S. Chiu E.K.W. et al.Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy Report of a prospective study.Gastroenterology. 1991; 100: 182-188Abstract PubMed Google Scholar The incidence of ascites and encephalopathy was reported as 7% and 4% for HBsAg-positive and HBsAg-negative patients, respectively.5Lok A.S.F. Liang R.S. Chiu E.K.W. et al.Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy Report of a prospective study.Gastroenterology. 1991; 100: 182-188Abstract PubMed Google Scholar Liver-related mortality ranges from 5% to 22%.5Lok A.S.F. Liang R.S. Chiu E.K.W. et al.Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy Report of a prospective study.Gastroenterology. 1991; 100: 182-188Abstract PubMed Google Scholar, 19Markovic S. Drozina G. Vovk M. et al.Reactivation of hepatitis B but not hepatitis C in patients with malignant lymphoma and immunosuppressive therapy A prospective study in 305 patients.Hepatogastroenterology. 1999; 46: 2925-2930PubMed Google Scholar, 35Liang R. Lok A.S.F. Lai C.L. et al.Hepatitis B infection in patients with lymphomas.Hematol Oncol. 1990; 8: 261-270Crossref PubMed Scopus (130) Google Scholar Since 1992, 5 medications have been approved for treatment of chronic HBV infection. These include interferon alfa-2b, lamivudine, adefovir, entecavir, and pegylated interferon alfa-2a.1Keeffe E.B. Dietrich D.T. Han S.B. et al.A treatment algorithm for the management of chronic hepatitis B virus infection in the United States.Clin Gastroenterol Hepatol. 2004; 2: 87-106Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 36Lok A.S.F. The maze of treatments for hepatitis B.N Engl J Med. 2005; 352: 2743-2746Crossref PubMed Scopus (79) Google Scholar, 37Lok A.S. McMahon B.J. Chronic hepatitis B: update of recommendations.Hepatology. 2004; 39: 857-861Crossref PubMed Scopus (494) Google Scholar So far, lamivudine has been used almost exclusively in clinical studies as prophylactic therapy to prevent HBV reactivation caused by immunosuppressive treatment. In most of these studies, prophylactic lamivudine administration has proven effective for the primary prevention of HBV reactivation (Table 2). In 1 nonrandomized study, a daily dose of 100 mg of lamivudine was used as a prophylactic regimen in 65 HBsAg-positive patients receiving cytotoxic chemotherapy. This group was compared to a historical control group. Twenty percent of the patients in the prophylactic lamivudine group and 19% of patients in the control group had detectable HBV DNA before the chemotherapy.38Yeo W. Chan P.K.S. 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: 927-934Crossref PubMed Scopus (225) Google Scholar Lamivudine was started within 7 days before the initiation of chemotherapy and discontinued 8 weeks after the completion of chemotherapy. In the prophylactic lamivudine group, HBV reactivation was significantly less frequent in the group who received prophylactic lamivudine compared with historical controls (4.6% vs 24.4%). In a recent randomized trial, a 100-mg daily dose of lamivudine was given to 30 HBsAg-positive lymphoma patients preemptively starting 1 week before chemotherapy or only when there was serologic evidence of HBV reactivation.31Lau 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: 1742-1749Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar Twenty percent of the patients in the early preemptive lamivudine group and 33% of patients in the control group had detectable HBV DNA before chemotherapy. In the absence of HBV reactivation, the early preemptive treatment was discontinued 6 weeks or later after the completion of chemotherapy. There was no HBV reactivation in the early preemptive lamivudine group, whereas 53% of the patients who did not receive early preemptive lamivudine had HBV reactivation. HBV reactivation–free survival in patients who received early pre-emptive lamivudine therapy was reported as significantly longer than in patients who were treated only after reactivation.Table 2Prophylactic/Preemptive Therapy for the Prevention of Chemotherapy-Induced HBV ReactivationStudyYearNo. of patients and medications in prophylactic/preemptive groupSerology before chemotherapyTumor typesType of chemotherapyTime to initiation of prophylactic/preemptive therapyDuration of prophylactic/preemptive therapyDose of lamivudine/interferonOutcomeLau et al31Lau 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: 1742-1749Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar200315 lamivudine15 HBsAg+, 4 HBeAg+, 3 HBV DNA+12 NHL, 3 HLCEOP/ABVD/CHOP/COPP/others1 week before chemotherapyContinued minimum 6 weeks after completion of chemotherapy and until white blood cell count normalized100 mg/dayNo HBV reactivation in lamivudine groupIdilman et al34Idilman R. Arat M. Soydan E. et al.Lamivudine prophylaxis for prevention of chemotherapy-induced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies.J Viral Hepat. 2004; 11: 141-147Crossref PubMed Scopus (89) Google Scholar20048 lamivudine8 HBsAg+, 8 HBeAg−, 8 HBeAb+,1 AML, 1 HL, 3 NHL, 1 ALL, 1 CLL, 1 MMCHOP, IDA + ARA-C, ABVD, 2-CdA, hyper-CVAD, fludurabine, VADAt the initiation of chemotherapyContinued 1 year after discontinuation of chemotherapy100 mg/dayNo HBV reactivation in lamivudine group, 50% survival in lamivudine group without HBV reactivationYeo et al38Yeo W. Chan P.K.S. 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: 927-934Crossref PubMed Scopus (225) Google Scholar200465 lamivudine65 HBsAg+, 7 HBeAg+, 13 HBV DNA+17 NHL, 19 breast, 4 lung, 18 gastrointestinal, 4 gynecologic malignancies, 3 other cancersSteroids/anthracycline and vinca alkaloid–containing regimenWithin 7 days before the initiation of chemotherapyContinued 8 weeks after completion of chemotherapy100 mg/dayHBV reactivation in 4.6% of patients in lamivudine groupDai et al42Dai M.S. Chao T.Y. Kao W.Y. Delayed hepatitis B reactivation after cessation of preemptive lamivudine in lymphoma patients treated with rituximab plus CHOP.Ann Hematol. 2004; 83: 769-774Crossref PubMed Scopus (122) Google Scholar20044 lamivudine3 HBsAg+, 3 HBeAg−, 3 HBeAb+, 3 HBV DNA+, 1 with unknown serology4 diffuse large B-cell NHLRituximab + CHOP1 week before chemotherapyContinued 4 weeks after completion of chemotherapy100 mg/dayDelayed HBV reactivation in all patientsLeaw et al45Leaw S.J. Yen C.J. Huang W.T. et al.Preemptive use of interferon or lamivudine for hepatitis B reactivation in patients with aggressive lymphoma receiving chemotherapy.Ann Hematol. 2004; 83: 270-275Crossref PubMed Scopus (69) Google Scholar200413 interferon, 11 lamivudine24 HBsAg+24 aggressive lymphomaCEOP, BACOP, ACVB, m-BACOD, BACOP-B, PACEBOMAt the initiation of chemotherapyContinued 4–8 weeks after completion of chemotherapy13 received SC alfa-interferon 3 × 10/U 3 times wk, 11 received lamivudine 100 mg/dayNo clinical hepatitis, 100% survival in lamivudine group, 54% survival in interferon group without reactivationNagamatsu et al46Nagamatsu H. Itano S. Nagaoka S. et al.Prophylactic lamivudine administration prevents exacerbation of liver damage in HBe antigen positive patients with hepatocellular carcinoma undergoing transhepatic arterial infusion chemotherapy.Am J Gastroenterol. 2004; 99: 2369-2375Crossref PubMed Scopus (45) Google Scholar20048 lamivudine8 HBsAg+, 8 HBeAg+Hepatocellular carcinomaTranshepatic arterial infusion chemotherapy with FEM or FP regimenAverage period was 28 days before chemotherapyThroughout chemotherapy100 mg/dayNo hepatitis B exacerbation during the chemotherapy, HBeAg seroconversion occurred in 3 patientsHui et al40Hui C.K. Cheung W.W. Au W.Y. et al.Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy.Gut. 2005; 54: 1597-1603Crossref PubMed Scopus (135) Google Scholar200546 lamivudine46 HBsAg+, 11 HBeAg+, 35 HBeAb+, 16 HBV, DNA ≥104 copies/mL33 NHL, 2 HL, 8 AML, 3 MMSteroids, anthracycline, and vinca alkaloid–containing regimens1 week before chemotherapyContinued 3.0–3.4 months after completion of chemotherapy100 mg/dayHBV reactivation in 23.9% of patientsNHL, non-Hodgkin's lymphoma; HL, Hodgkin's lymphoma; AML, acute myeloblastic leukemia; ALL, acute lymphoblastic lymphoma; CLL, chronic lymphoblastic leukemia; MM, multiple myeloma; CEOP, cyclophosphamide, epirubicin, vincristine, prednisolone; ABVD, adriamycin, bleomycin, vinblastin, decarbazine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; COPP, cyclophosphamide, vincristine, procarbazine, prednisolone; BACOP, bleomycin, doxorubicin, cyclophosphamide, vincristine, prednisone; ACVB, doxorubicin, cyclophosphamide, vindesine, bleomycin; m-BACOD, methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone; MACOP-B, methotrexate, doxorubicin, cyclophosphamide, prednisone, bleomycin; PACEBOM, prednisone, doxorubicin, cyclophosphamide, etoposide, bleomycin, vincristine, methotrexate; IDA+ARA-C, idarubicin, cytosine arabinoside; 2-CdA, 2-chlorodeoxyadenosine, cladribine; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; FEM, epirubicine, mytomycin-C, fluorouracil; FP, 5-fluorouracil, cysplatin. Open table in a new tab NHL, non-Hodgkin's lymphoma; HL, Hodgkin's lymphoma; AML, acute myeloblastic leukemia; ALL, acute lymphoblastic lymphoma; CLL, chronic lymphoblastic leukemia; MM, multiple myeloma; CEOP, cyclophosphamide, epirubicin, vincristine, prednisolone; ABVD, adriamycin, bleomycin, vinblastin, decarbazine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; COPP, cyclophosphamide, vincristine, procarbazine, prednisolone; BACOP, bleomycin, doxorubicin, cyclophosphamide, vincristine, prednisone; ACVB, doxorubicin, cyclophosphamide, vindesine, bleomycin; m-BACOD, methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone; MACOP-B, methotrexate, doxorubicin, cyclophosphamide, prednisone, bleomycin; PACEBOM, prednisone, doxorubicin, cyclophosphamide, etoposide, bleomycin, vincristine, methotrexate; IDA+ARA-C, idarubicin, cytosine arabinoside; 2-CdA, 2-chlorodeoxyadenosine, cladribine; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; FEM, epirubicine, mytomycin-C, fluorouracil; FP, 5-fluorouracil, cysplatin. Idilman et al34Idilman R. Arat M. Soydan E. et al.Lamivudine prophylaxis for prevention of chemotherapy-induced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies.J Viral Hepat. 2004; 11: 141-147Crossref PubMed Scopus (89) Google Scholar conducted a cohort study consisting of 18 inactive chronic HBV carriers. Eight patients were started on a daily dose of 100 mg prophylactic lamivudine on the same day as chemotherapy and continued for a year after the discontinuation of chemotherapy. No HBV reactivation was observed in patients who received prophylactic lamivudine in contrast to 50% HBV reactivation in patients who did not receive prophylactic lamivudine therapy. Despite these encouraging results, the optimal time to start and discontinue lamivudine prophylaxis in patients undergoing chemotherapy remains to be determined. One of the major concerns with early initiation and long-term lamivudine therapy exceeding 6 months' duration is the emergence of lamivudine-resistant mutant strains (YMDD mutation), which may occur in up to 32% of patients at 1 year.31Lau 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: 1742-1749Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar, 38Yeo W. Chan P.K.S. 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: 927-934Crossref PubMed Scopus (225) Google Scholar, 39Li Y.H. He Y.F. Jiang W.Q. et al.Lamivudine prophylaxis reduces the incidence and severity of hepatitis in hepatitis B virus carriers who receive chemotherapy for lymphoma.Cancer. 2006; 106: 1320-1325Crossref PubMed Scopus (99) Google Scholar However, YMDD mutation has been described in a relatively low percentage (1.6%) of patients receiving lamivudine prophylaxis during cytotoxic chemotherapy.40Hui C.K. Cheung W.W. Au W.Y. et al.Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy.Gut. 2005; 54: 1597-1603Crossref PubMed Scopus (135) Google Scholar The use of lamivudine also may be associated with acute flares of HBV on discontinuation of therapy. A flare of hepatitis after lamivudine withdrawal was reported in as many as 20% of patients.41Mancuso A. Luigi P. Lamivudine for chemotherapy-induced reactivation of HBV: prophylaxis or treatment?.Am J Gastroenterol. 2002; 97: 1268-1269Crossref PubMed Google Scholar In a prospective study of 4 HBsAg-positive lymphoma patients who received prophylactic lamivudine therapy until 4 weeks after the discontinuation of chemotherapy, HBV flare occurred 5 and 7 months after the discontinuation of lamivudine.42Dai M.S. Chao T.Y. Kao W.Y. Delayed hepatitis B reactivation after cessation of preemptive lamivudine in lymphoma patients treated with rituximab plus CHOP.Ann Hematol. 2004; 83: 769-774Crossref PubMed Scopus (122) Google Scholar In another recent study, 46 HBsAg-positive patients were treated with pre-emptive lamivudine throughout the chemotherapy, starting 1 week before the initiation of chemotherapy and ending 3 to 3.4 months after its completion.40Hui C.K. Cheung W.W. Au W.Y. et al.Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy.Gut. 2005; 54: 1597-1603Crossref PubMed Scopus (135) Google Scholar The total duration of lamivudine treatment ranged from 6.2 to 31.5 months. Despite these extended periods of treatment, HBV reactivation occurred after the withdrawal of lamivudine in 11 of 46 patients (23.9%), leading to liver failure in 3 patients. The reactivation rate after lamivudine withdrawal was significantly higher in patients with high prechemotherapy HBV DNA levels (≥104 copies/mL) compared with those who had low prechemotherapy HBV DNA levels (<104 copies/mL) (50% vs 10%). HBV reactivation was more frequent in HBeAg-positive patients compared to HBeAg-negative patients (45.5% vs 17.1%). These observations suggest that patients with higher HBV DNA levels (≥104 copies/mL) or positive HBeAg before chemotherapy may require a longer duration of pre-emptive lamivudine treatment after the completion of chemotherapy.40Hui C.K. Cheung W.W. Au W.Y. et al.Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy.Gut. 2005; 54: 1597-1603Crossref PubMed Scopus (135) Google Scholar However, there is no evidence to support the use of specific preventive treatments in different HBV populations. Interferon has not been shown to be effective in the prevention of chemotherapy-induced HBV reactivation because of its delayed effect.18Perrillo R.P. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.Gastroenterology. 2001; 120: 1009-1022Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar However, despite its disadvantages, successful treatment with alfa interferon in combination with lamivudine was reported in a lamivudine-resistant HBV carrier who had HBV reactivation 1 month after the completion of chemotherapy.43Ohmoto K. Tsuduki M. Yamamoto S. Combined lamivudine and interferon-α therapy for chemotherapy-induced reactivation of hepatitis B virus.Am J Gastroenterol. 2003; 98: 1215-1216PubMed Google Scholar Adefovir dipivoxil, an adenosine analogue, has been used as pre-emptive therapy in combination with lamivudine in patients who had developed YMDD mutation during lamivudine monotherapy40Hui C.K. Cheung W.W. Au W.Y. et al.Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy.Gut. 2005; 54: 1597-1603Crossref PubMed Scopus (135) Google Scholar and to prevent emergence of YMDD mutation.44Enomoto M. Nishiguchi S. Seki S. et al.Adefovir dipivoxil to prevent exacerbation of lamivudine-resistant hepatitis B infection during chemotherapy for non-Hodgkin's lymphoma.Am J Gastroenterol. 2004; 99: 1619Crossref PubMed Scopus (13) Google Scholar Adefovir dipivoxil may be considered in lamivudine-resistant patients and as a first agent in the prophylaxis of HBV recurrence.40Hui C.K. Cheung W.W. Au W.Y. et al.Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy.Gut. 2005; 54: 1597-1603Crossref PubMed Scopus (135) Google Scholar, 44Enomoto M. Nishiguchi S. Seki S. et al.Adefovir dipivoxil to prevent exacerbation of lamivudine-resistant hepatitis B infection during chemotherapy for non-Hodgkin's lymphoma.Am J Gastroenterol. 2004; 99: 1619Crossref PubMed Scopus (13) Google Scholar Although no data exist regarding entecavir, a nucleoside analogue recently approved by the Food and Drug Administration, it may prove to be effective for primary prophylaxis and in lamivudine- and adefovir-resistant cases. Every patient undergoing cytotoxic chemotherapy should be checked for HBsAg and total HBcAb before the initiation of treatment. HBeAg, anti-HBe, and serum HBV DNA levels should be tested in all HBsAg-positive patients. HBV DNA should be tested by HBV PCR assay with a detection limit of 102 copies/mL or less and should be monitored throughout the immunosuppressive therapy. Although there still are controversies regarding the timing for initiation and discontinuation of prophylactic antiviral treatment because of the limited number of large controlled studies, prophylactic therapy is highly recommended in HBsAg-positive patients to avoid reactivation. Although the prevalence and natural history of reactivation are different in the different groups of HBV patients, there are insufficient data to support particular regimens in different groups. Most of the studies addressing preventive therapy deal with mixed populations and do not address specific patient groups. We recommend initiating prophylactic therapy at least 1 week before the initiation of chemotherapy and discontinuing the treatment at least 6 months after the resolution of the immunocompromised state. The anti-HBV treatment can be discontinued only if there is no biochemical or serologic evidence (disappearance of HBeAg, appearance of HBeAb, and a decrease in HBV DNA levels by PCR to <104 copies/mL) to suggest HBV reactivation (increase in HBV DNA level or reappearance of HBeAg as discussed before). Antiviral treatment may be deferred in HBsAg-negative HBcAb-positive patients until HBV DNA becomes detectable during or after chemotherapy. Serum transaminase levels should be monitored throughout the immunosuppressive treatment and every 6 months after the discontinuation. Although there is no clear evidence in the literature to support a specific interval, we recommend checking hepatic biochemical tests at least once a month during cytotoxic chemotherapy in HBV patients. HBV serology and HBV DNA should be checked at least once every 2 months during treatment. Patients who have active liver disease owing to hepatitis B should be treated indefinitely or until seroconversion occurs (disappearance of HBeAg, appearance of anti-HBe, and a decrease in HBV DNA level by PCR to <104 copies/mL). The antiviral agent used most extensively as prophylactic therapy in clinical studies is lamivudine 100–150 mg daily. Although there are limited data on other antiviral medications, adefovir or entecavir may be considered as alternative treatments in lamivudine-resistant patients or as first-line drugs in primary prophylaxis of HBV reactivation.
Referência(s)