Reactivation or flare of chronic hepatitis B: need for better definitions.
Michal R. Pijak, Slovak Medical Univesity, Bratislava, Slovakia,
21 March 2006
We read with a great interest the case report by Ratziu et al (1), which is a useful contribution to a better understanding of the mechanisms and management of hepatitis B virus (HBV) reactivation during antiviral therapy with nucleoside analogues. In this regard we would like to emphasize the need for standardized definition of terms used in association with an acute deterioration of chronic hepatitis B (CHB).
Ratziu et al rightly conclude that “Adefovir resistance resulted in viral breakthrough with hepatitis flare-up and liver decompensation”. However, 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”. Acute 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 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.
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.
Michal R. Pijak, MD
Igor Huzicka, MD
Frantisek Hrusovsky, MD
References
1. Ratziu V, Thibault V, Benhamou Y, Poynard T: Successful rescue therapy with tenofovir in a patient with hepatic decompensation and adefovir resistant HBV mutant.
Comp Hepatol 2006,5:1.
2. Lok AS, McMahon BJ: Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B.
Hepatology 2001,34:1225-1241.
3. Perrillo RP: Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.
Gastroenterology 2001,120:1009-1022. Review.
4. Flink HJ, Sprengers D, Hansen BE, van Zonneveld M, de Man RA, Schalm SW, Janssen HL; HBV 99-01 Study Group: Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon {alpha}-2b therapy.
Gut 2005,54:1604-1609.
5. Liaw YF, Pao CC, Chu CM, Sheen IS, Huang MJ: 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, Zondervan PE, Schalm SW: Acute exacerbation of chronic hepatitis B virus infection after withdrawal of lamivudine therapy.
Hepatology 2000, 32:635-639.
7. Perrillo RP, Schiff ER, Davis GL, Bodenheimer HC Jr, Lindsay K, Payne J, Dienstag JL, O'Brien C, Tamburro C, Jacobson IM, 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, Kao JH, Chang CF, Wu HL, Shau WY, Chen DS: 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, 86:230-235.
10. Di Marco V, Marzano A, Lampertico P, Andreone P, Santantonio T, Almasio PL, Rizzetto M, Craxi A, 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, 40:883-891.
11. Sheen IS, Liaw YF, Tai DI, Chu CM: Hepatic decompensation associated with hepatitis B e antigen clearance in chronic type B hepatitis.
Reactivation or flare of chronic hepatitis B: need for better definitions.
21 March 2006
We read with a great interest the case report by Ratziu et al (1), which is a useful contribution to a better understanding of the mechanisms and management of hepatitis B virus (HBV) reactivation during antiviral therapy with nucleoside analogues. In this regard we would like to emphasize the need for standardized definition of terms used in association with an acute deterioration of chronic hepatitis B (CHB).
Ratziu et al rightly conclude that “Adefovir resistance resulted in viral breakthrough with hepatitis flare-up and liver decompensation”. However, 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”. Acute 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 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.
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.
Michal R. Pijak, MD
Igor Huzicka, MD
Frantisek Hrusovsky, MD
References
1. Ratziu V, Thibault V, Benhamou Y, Poynard T: Successful rescue therapy with tenofovir in a patient with hepatic decompensation and adefovir resistant HBV mutant.
Comp Hepatol 2006,5:1.
2. Lok AS, McMahon BJ: Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B.
Hepatology 2001,34:1225-1241.
3. Perrillo RP: Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.
Gastroenterology 2001,120:1009-1022. Review.
4. Flink HJ, Sprengers D, Hansen BE, van Zonneveld M, de Man RA, Schalm SW, Janssen HL; HBV 99-01 Study Group: Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon {alpha}-2b therapy.
Gut 2005,54:1604-1609.
5. Liaw YF, Pao CC, Chu CM, Sheen IS, Huang MJ: 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, Zondervan PE, Schalm SW: Acute exacerbation of chronic hepatitis B virus infection after withdrawal of lamivudine therapy.
Hepatology 2000, 32:635-639.
7. Perrillo RP, Schiff ER, Davis GL, Bodenheimer HC Jr, Lindsay K, Payne J, Dienstag JL, O'Brien C, Tamburro C, Jacobson IM, 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, Kao JH, Chang CF, Wu HL, Shau WY, Chen DS: 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, 86:230-235.
10. Di Marco V, Marzano A, Lampertico P, Andreone P, Santantonio T, Almasio PL, Rizzetto M, Craxi A, 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, 40:883-891.
11. Sheen IS, Liaw YF, Tai DI, Chu CM: Hepatic decompensation associated with hepatitis B e antigen clearance in chronic type B hepatitis.
Gastroenterology 1985, 89:732–735
Competing interests
None declared