Review ArticleProphylaxis and treatment of hepatitis B in immunocompromised patients
Introduction
Immunosuppression due to the underlying disease or to drugs used in autoimmune diseases, anticancer therapy and in organ transplants can influence the hepatitis B virus (HBV), both in terms of reactivation and in terms of the acceleration of a pre-existing chronic hepatitis.
In this situation, the possibility of HBV relapse has been known for years, with clinical manifestations ranging from self-limiting anicteric to fulminant forms or to chronic hepatitis with an accelerated clinical course towards liver decompensation. In most cases, hepatitis B develops at the time of immune reconstitution as a consequence of the antiviral immune response and less frequently at the time of the enhanced replication during massive immunosuppression. Moreover hepatitis reactivation may influence the continuation of the specific treatments and the survival of immunosuppressed or transplanted patients [1].
The risk of clinical events is mainly observed in overt carriers of HBV, but can also develop in the “occult” condition of infection which has been widely described in the literature of the last decade [2].
Progress in the diagnostic procedures of the various virological conditions associated with HBV and in particular the recent availability of effective antiviral treatments has brought this problem to the fore although it is still debated.
This encouraged the Italian Association for the Study of the Liver (AISF) to organize a Consensus conference according to the Italian Institute of Health guidelines (www.pnlg.it) (Table 1), which was held in Turin on May 13th and 14th, 2005. The indications reported below are the conclusions which emerged during and after the meeting, from the systematic review of the literature and from the multi-disciplinary debate.
Section snippets
Virological characteristics
Persistant HBV infection is defined as overt when the hepatitis B surface antigen (HBsAg) is present in amounts well-detectable by sensitive immune assays and occult in HBsAg negative subjects with evidence of intrahepatic and/or serum HBV DNA [2]. In occult carriers, HBsAg can be completely absent or undetectable for very low amounts or polymorphisms.
Treatment strategies
The term prophylaxis was used to mean treatment with antiviral drugs of an inactive or occult infection, with the aim of preventing hepatitis reactivation. Prophylaxis was defined as: (1) universal prophylaxis (UP), if it is carried out on the entire population potentially at risk (inactive carriers and/or anti-core) or targeted prophylaxis (TP), if it is subordinate to the appearance of infection markers (HBV DNA and/or HBsAg) in the absence of hepatitis reactivation (Table 4).
Therapy (T) was
Treatment options
In Italy, the following drugs are available at present: interferons, either standard or pegylated (both little tolerated in the condition of immunosuppression, especially in transplant patients for the potential risk of rejection) and the nucleos(t)ides analogues (NAs), which include lamivudine and adefovir-dipivoxil for those with HBV monoinfection, with the addition of tenofovir and emtricitabine for patients with HBV–human immunodeficiency virus (HIV) coinfection. Entecavir will be
Monitoring
Once NAs therapy or prophylaxis has been started, monitoring will essentially be through testing serum HBV DNA and ALT levels every 3 months, to assess: (1) response to treatment (i.e. reduction of HBV DNA, preferably below the limit of sensitivity of the amplified techniques and ALT normalization) (BV) and (2) drug-resistance, which should be suspected in the case of virologic breakthrough while on-treatment, in order to activate an early rescue therapy (AIII) [11]. Resistance can be defined
Impact on different specialist fields
Data regarding hepatitis B in immunocompromised patients are very heterogeneous, so the statements reported here below required an extensive review of the literature and the inclusion of expert opinions where information was lacking. As a result there was a strong indication to promote studies aimed at defining the natural history of hepatitis B in these patients, to assess – also prospectively – different treatment protocols, to promote close cooperation among different specialists and,
Background
During chemotherapy hepatitis B can make its appearance in two different phases: (1) during the treatment, in relation to the intense bone marrow suppression, which is associated with a strong viral replication and, sometimes, with the emergence of a fulminant hepatitis in the form of fibrosing cholestasis, (2) after the end of therapy, as during the immuno-reconstitution phase the immune response can bring on a reactivation of hepatitis whose clinical course may be more or less severe
Dialysis
The incidence of overt carriers of HBsAg among dialysed patients is 0–7% in developed countries and 10–20% in developing ones. In these subjects, the frequent normality of the transaminase makes clinical judgment difficult, confirming the fundamental role of the virological markers (quantitative HBV DNA) and of the liver biopsy to distinguish between active and inactive carriers (baseline). In this setting, data about the condition of occult carrier among anti-core patients are scarce and
Background
The risk of post-transplantation hepatitis B is strictly influenced from both recipient and donor virological characteristics:
- (a)
HBsAg positive recipients: in the absence of pre- and post-operative prophylaxis the risk of post-transplantation hepatitis B is over 80%. In this condition, the use of antivirals before transplant (one single antiviral in the case of wild type virus, combined with a second one that is active on the mutants, in the condition of drug resistance with active replication),
Background
Reports regarding the reactivation of HBV in the rheumatology setting are episodic, during the course of hydroxychloroquine, azathioprine, methotrexate and tumour necrosis factor (TNF) inhibitors. The few data available all refer to active and inactive HBsAg- carriers. Instead reports on anti-CD20 derive from haematological experience, and like in haematology the risk of HBV reactivation in the rheumatology setting would appear to be linked both to the phase of immuno-suppression and to that of
Background
The indications in this setting, refer to the recently published European Association for the Study of the Liver (EASL) guidelines. Cirrhosis and liver cancer are the second cause of death worldwide in HIV carriers (3–4 million), 9% of whom have HBV infection. Coinfection with HIV increases the rate of chronic HBV infection, reduces the annual rate of seroconversion to anti-HBe and to anti-HBs and it may be linked to the reactivation of the occult infection in HBsAg negative subjects in the
Conclusions
The literature on hepatitis B in immunosuppressed patients is heterogeneous. It refers mainly to the pre-analogue nucleos(t)ides era and the period prior to the introduction of the modern techniques of determination and quantification of the viremia, which raises many doubts and difficulties about the interpretation of the studies and leaves several aspects still a matter of debate. This encourages the proposal of a network of communication between different specialists involved, in order to
Conflict of interest statement
None declared.
Acknowledgements
To Mrs. Susan Phillips for the language revision and to Mrs. Monica Moretti, Mrs. Clara Grossi and Silvia Carenzi, MD, for their precious assistance in the preparation of the first AISF Single Topic conference and of the manuscript. We want to thank all the scientific associations who endorsed the meeting and the participants in the different groups of discussion and in the plenary session.
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