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• Reactivation or flare in chronic hepatitis B: need for better definitions
  Michal R. Pijak
  Published on: 18 April 2016
• Lamivudine in HBV carriers with malignancies
  Ramazan Idilman
  Published on: 18 April 2016

• Published on: 18 April 2016

  Reactivation or flare in chronic hepatitis B: need for better definitions

  • Michal R. Pijak, assistant professor of medicine
  • Other Contributors:
    • Igor Huzicka, Stefan Hrusovsky

  Dear Editor,

  We read with a great interest the article by Hui et al. (1), which is a useful contribution to a better understanding of the mechanisms of hepatitis B virus (HBV) reactivation after withdrawal of preemptive lamivudine in patients with haematological malignancy. We feel, however, that the authors did not provide an exact definition of the term reactivation which is crucial for appropriate...

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  Dear Editor,

  We read with a great interest the article by Hui et al. (1), which is a useful contribution to a better understanding of the mechanisms of hepatitis B virus (HBV) reactivation after withdrawal of preemptive lamivudine in patients with haematological malignancy. We feel, however, that the authors did not provide an exact definition of the term reactivation which is crucial for appropriate diagnosis and management of a patient with an acute deterioration of chronic hepatitis B (CHB).

  The definitions adopted by the National Institute of Health workshop on management of hepatitis B (2) define reactivation as „Reappearance of active necroinflammatory disease of the liver in a person known to have the inactive HBsAg carrier state or resolved hepatitis B“. A cute exacerbation or flare of hepatitis B is then defined as „Intermittent elevations of aminotransferase activity to more than 10 times the upper limit of normal and more than twice the baseline value.“ Unfortunately, no additional comment accompanies the two semantically related terms, hence it is not clear whether they can be used synonymously. Curiously, the European guidelines do not provide any definitions. Because of these deficiencies, we propose more specific definitions and diagnostic criteria for these terms.

  First of all, we suggest that the term reactivation should only be used in the context of viral reactivation, i.e. an abrupt increase or restoration of viral replication. The use of this term for designation of biochemical or histological deterioration should be abandoned, as it may be caused by and needs to be differentiated from other triggers, such as drug toxicity, alcohol abuse or superinfection with other hepatotropic viruses (3). On the other hand, viral reactivation can be either asymptomatic or associated with clinical exacerbation. Thus, the term flare should only be used when biochemical and/or histological criteria indicating sudden increase of necroinflammatory activity are fulfilled.  

  Flares due to viral reactivation should be further differentiated from host induced (immunological) flares (4). The latter may occur spontaneously during the natural course of the disease (5), in relation to therapy with immunostimulatory agents such as interferon (3,4) or after sudden withdrawal of immunosuppressive drugs, e.g. corticosteroids (3). As for the former, other identifiable causes of viral reactivation should be kept in mind besides immunosuppressive agents. These include development of resistance during therapy with nucleoside/nucleotide analogues (3,6) or, less likely, with interferon (3,7). Viral reactivation often follows stopping these treatments (3,6). Viral induced flares may also occur during the natural course of the disease (8,9). Importantly, both viral induced and host induced flares can occasionally be life threatening (10,11). Host induced flares, however, are associated with suppression of viral replication and may herald spontaneous (8,9) or treatment induced (3,4) sustained virological response. Important virological and biochemical markers that can be used to differentiate viral and host-induced flares in clinical practice are summarized in the table. Histological verification shall remain optional.  

  In conclusion, accurate definitions of reactivation and flare might prove useful both in the clinic in order to choose optimal therapeutic intervention as well as in research of virus-host interactions in CHB.

   

   

  Table. Diagnostic criteria for different types of flares of chronic hepatitis B

   

  Type of flare	Host induced	Virus induced (symptomatic viral reactivation )
  Pathogenetic mechanism	Suppression of persistently active viral replication: - Chronic hepatitis B	Acceleration of persistently active viral replication: - Chronic hepatitis B	Restoration of suppressed viral replication: - Inactive HBV infection - Resolved hepatitis B
  Causes	- Spontaneous - IFN treatment	- Spontaneous - Immunosuppression* - IFN/NA treatment§	- Spontaneous - Immunosuppression*
  Virological characteristics	Decrease in serum HBV-DNA by > 1 log within the following four months	Increase in serum HBV-DNA of > 1 log within the previous four months	Reappearance of serum HBsAg or HBeAg/ HBV-DNA, and/or decline/disappearance of anti-HBs
  Biochemical characteristics	Increase of ALT (? 5x ULN or ? 2x baseline value) preceding a decrease in serum HBV-DNA	Increase of ALT (? 5x ULN or ? 2x baseline value) following an increase in serum HBV-DNA	Recurrence of ALT activity
  Histological characteristics	Significant increase of necroinflammatory activity		Recurrence of necroinflammation

  * Due to treatment or disease (e.g. HIV)

  § Due to withdrawal or development of resistance

  ALT, alanine aminotransferase; ULN, upper limit of normal; HBV, hepatitis B virus; IFN, interferon; NA, nucleoside analogues.

   

   

  References

   

  1. Hui CK, Cheung WW, Au WY, et al. Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy. Gut 2005;54:1597-603.

  2. Lok AS, McMahon BJ. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B. Hepatology 2001;34:1225-41.

  3. Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 2001;120:1009-22.

  4. Flink HJ, Sprengers D, Hansen BE, et al. Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon {alpha}-2b therapy. Gut 2005;54:1604-9.

  5. Liaw YF, Pao CC, Chu CM, et al. Changes of serum hepatitis B virus DNA in two types of clinical events preceding spontaneous hepatitis B e antigen seroconversion in chronic type B hepatitis. Hepatology 1987;7:1-3.

  6. Honkoop P, de Man RA, Niesters HG, et al. Acute exacerbation of chronic hepatitis B virus infection after withdrawal of lamivudine therapy. Hepatology 2000;32:635-9.

  7. Perrillo RP, Schiff ER, Davis GL, et al. A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group. N Engl J Med 1990;323:295-301.

  8. Liu CJ, Chen PJ, Lai MY, et al. A prospective study characterizing full-length hepatitis B virus genomes during acute exacerbation. Gastroenterology 2003;124:80-90.

  9. Davis GL, Hoofnagle JH, Waggoner JG. Spontaneous reactivation of chronic hepatitis B virus infection. Gastroenterology 1984;86:230-5.

  10. Di Marco V, Marzano A, Lampertico P, et al. Italian Association for the Study of the Liver (AISF) Lamivudine Study Group, Italy. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology 2004;40:883-91.

  11. Sheen IS , Liaw YF, Tai DI, et al . Hepatic decompensation associated with hepatitis B e antigen clearance in chronic type B hepatitis. Gastroenterology 1985; 89 :732–5

   

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  Conflict of Interest:
  None declared.

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• Published on: 18 April 2016

  Lamivudine in HBV carriers with malignancies

  • Ramazan Idilman

  Dear Editor,

  I read with interest the article by Hui et al. reporting hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with hematological malignancy on completion of cytotoxic chemotherapy.[1] Reactivation of hepatitis B virus (HBV) infection is a well-recognized complication of chemo/immunosuppressive therapy in HBs-Ag positive inactive carriers.[2][3] It occurs in 14% to 50% of such in...

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  Dear Editor,

  I read with interest the article by Hui et al. reporting hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with hematological malignancy on completion of cytotoxic chemotherapy.[1] Reactivation of hepatitis B virus (HBV) infection is a well-recognized complication of chemo/immunosuppressive therapy in HBs-Ag positive inactive carriers.[2][3] It occurs in 14% to 50% of such individuals.[2][3]

  Several investigators have examined the efficacy and tolerability of lamivudine therapy as a prophylactic agent preventing HBV reactivation in inactive HBV carriers with hemato/oncological malignancies who receive chemotherapy.[4][5][6] The principal aims of these studies have been 1) to determine the effect of lamivudine prophylaxis on the rate of HBV reactivation in such individuals, and 2) to define the safety and duration of lamivudine prophylaxis in these cases. Based on the results of these studies, current investigators have drawn the following conclusions: First, lamivudine prophylaxis prevents hemotherapyinduced HBV reactivation in these cases. Second, lamivudine is safe and tolerable in such individuals.[4][5][6]

  There are no clear data in the literature to indicate how long prophylactic lamivudine therapy should be continued in HBV carriers with hemato/oncological malignancy who will receive chemotherapy. Lamivudine produces a rapid reduction in HBV replication within days to weeks of its initiation in immunocompetent individuals with chronic HBV infection.[7] In immunocompetents, long-term (> than 1 year) antiviral therapy is required to eradicate HBV infection because of the high rate of HBV replication (plasma half-life of HBV, 24 hours) and the relatively slow turnover rate of HBV-infected hepatocytes (half life, 10-100 days). In immunosuppressive subjects, several investigators have suggested that the duration of lamivudine treatment in cases with inactive HBV infection receiving hemo/immunosuppressive therapy should continue for at least six months following the last dose of therapy.[4][5][6][8]

  In our experience, because one HBV reactivation in the 3 lamivudine untreated group occurred 12 months after the individual’s chemotherapy had been discontinued, lamivudine prophylaxis was maintained for a full year following discontinuation of any chemotherapy.[6] Hui et al. reported a high rate of HBV reactivation (23.9%) after withdrawal of lamivudine in the lamivudine treatment group.[1] The investigators reported that several factors are responsible for this high recurrence rate, such as high HBV-DNA levels and e-antigen positivity prior to chemotherapy.[1] However, based on the results of previous studies, a short term (3 months) between the end of chemotherapy and lamivudine discontinuation may also affect HBV reactivation in such individuals. Thus, longterm lamivudine prophylaxis in individuals with hemato/oncological malignancy at risk for HBV reactivation seems to be reasonable.

  According to published data, the risk of developing lamivudine-resistant HBV increases with the duration of lamivudine treatment.[7] Resistance rates between 15% and 40% have been reported after two years of lamivudine treatment in immunocompetents with chronic HBV infection.[7] None of the individuals with hematological malignancy who received lamivudine in our experience developed a lamivudine-resistant virus after a mean of 14 months of continuous lamivudine therapy.[6] This result was comparable with that of Rossi et al. who reported no development of lamivudine resistance in HBV carriers with lymphoid malignancies treated with chemotherapy.[4]

  In conclusion, although the ideal protocol of lamivudine prophylaxis for the prevention of HBV reactivation in individuals receiving chemotherapy for hemato/oncological malignancies is not yet established, it would appear prudent to begin lamivudine at the time of the initiation of the chemotherapy and to continue it throughout the period of chemotherapy administration and for at least one but possibly two years following the discontinuation of the chemotherapy.

  Address for correspondence:
  Ramazan Idilman, M.D.,
  Associate Professor
  Ankara University School of Medicine,
  Department of Gastroenterology,
  Ibn-i Sina Hospital,
  Sihhiye, Ankara-Turkey
  06100
  e-mail: idilman@dialup.ankara.edu.tr
  Fax: +90 312 363 6213

  References

  1. Hui CK, Cheung WWW, Au WY, et al. Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with hematological malignancy on completion of cytotoxic chemotherapy. Gut 2005;54:1597- 603.

  2. Hoofnagle JH, Dusheiko GM, Schafer DF, et al. Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Intern Med 1982; 96:447-49.

  3. Yeo W, Chan PKS, Zhong S, et al. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy. J Med Virol 2000;62:299-307.

  4. Rossi G, Pelizzari A, Motta M, et al. Primary prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HBsAg carriers with lymphoid malignancies treated with chemotherapy. Br J Haematol 2001;115:58-62.

  5. 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;100:391-96.

  6. Idilman 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 Hepatitis 2004;11:141-47.

  7. Papatheodoridis GV, Dimou E, Papadimitropoulos V. Nucleoside analogues for chronic hepatitis B: Antiviral efficacy and viral resistance. Am J Gastroenterol 2002;97:1618-28.

  8. Idilman R. Lamivudine prophylaxis in HBV carriers with hematooncological malignancies who receive chemotherapy. J Antimicrob Chemother 2005;55:828-31.

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  Conflict of Interest:
  None declared.

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