Immunity to HBV and HCV
BECAUSE HBV AND HCV are not cytopathogenic, it is widely accepted that both viral control and liver pathology are mediated by the host immune system (Table 1). Many studies of host genetics and immunology demonstrate an important role for T lymphocytes in protective immunity against HBV and HCV.
Table 1. Putative host immune system of HBV and HCV infection
|Innate immunity|| || |
|Hepatocytes||Stealth response||Type I and/or III IFN production|
|Main components||NK and NKT cells||DC|
|Critical cytokines||IFN-γ, TNF-α||Type I and/or III IFN|
|Adaptive immunity|| || |
|Components||T cells and B cells||T cell and B cells|
The occurrence of HBV reactivation in patients with signs of resolved infection, particularly anti-HBc positive patients, relies on the existence of occult HBV infection. Patients with occult HBV infection are supposed to harbor HBV covalently closed circular DNA in the nuclei of their hepatocytes after the resolution of acute infection. Most occult HBV infection individuals are infected with replicable viruses, whose replication and gene expression are strongly inhibited by the host immune system. The exact mechanisms of inhibition have not yet been determined, but long-lasting specific host T-cell immune surveillance against HBV epitopes and epigenetic factors are presumably the major causes of long-term viral suppression.
In contrast, although HCV reactivation following immunosuppressive therapy is rare,[4-8] fibrosing cholestatic hepatitis C (FCH) occurs in HCV positive liver transplant recipients with immunosuppressive therapy.[9-11] Whether immunosuppressive therapy leads to HCV reactivation in patients with cancer in whom the infection has cleared either spontaneously or secondary to therapy is uncertain. When HCV RNA clearance is achieved either spontaneously or in response to antiviral therapy in recipients of solid organ transplants, no relapse is observed in plasma, liver or peripheral blood mononuclear cells during chronic immunosuppressive treatment with agents such as calcineurin inhibitors, corticosteroids, antimetabolites, anti-thymocyte globulins, or anti-interleukin-2-receptor blockers. This finding suggests the complete and permanent cure of HCV infection resulting from the elimination of HCV before transplantation.
Immunosuppression and viral replication in HBV reactivation
In general, there are three periods of HBV reactivation in patients with signs of resolved infection (Fig. 1).
Figure 1. Pathophysiology of the reactivation of HBV and HCV infection. Reactivation of HBV or HCV as a result of chemotherapy can generally be divided into three stages. The first stage is characterized by enhanced viral replication, the second stage is the functional restoration of the immune system, and 3rd stage is the recovery stage. ALT, alanine aminotransferase; CTL, cytotoxic T lymphocyte; HBV, hepatitis B virus; HCV, hepatitis C virus; cccDNA, covalently closed circular DNA; MHC, major histocompatibility complex.
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The initial stage of HBV reactivation caused by chemotherapy-induced immune suppression is characterized by enhanced viral replication, as reflected by increases in the serum levels of HBV DNA, hepatitis B e-antigen (HBeAg) and HBsAg, indicating that suppression of a normal immunological response to HBV leads to enhanced viral replication and widespread infection of hepatocytes. In particular, in cases of positive anti-HBs antibody, reactivation of HBV typically starts with a decrease of anti-HBs antibody titers. This may be related to the use of biologic therapy, such as anti-CD20 monoclonal antibody rituximab and anti-CD52 antibody alemtuzumab, which cause profound and long-lasting immunosuppression; however, a decrease of anti-HBs antibody titers is seen in all cases, including those on biologic drug-free chemotherapy, namely, tumor necrosis factor-α inhibitors.
There are at least two mechanisms by which immunosuppressive agents may increase HBV replication and expression. As the host immune response to the virus plays a crucial role in controlling HBV infection, suppression of such immune responses should increase viral replication. Meanwhile, immunosuppressive agents may have a more direct stimulatory effect on viral replication. In fact, corticosteroid increases HBV DNA and RNA production in vitro by stimulating HBV transcription, by binding to the glucocorticoid responsive element and augmenting the HBV enhancer I;[15, 16] however, it is controversial whether corticosteroid increases the secretion of HBsAg and HBeAg.[15-17] Although combinations of immunosuppressive agents may cause an increase in levels of intracellular HBV DNA, lower concentrations of prednisolone were presumably unable to stimulate HBV replication, so the doses of these compounds should be kept as low as practically possible when used clinically.
In the second stage of reactivation, functionality of the immune system is restored after chemotherapy is discontinued. Infected hepatocytes with recognizable viral antigens on their surface may then be exposed and would be cleared by T lymphocytes, leading to hepatic injury and necrosis. Clinically, this can lead to hepatitis with an increase in alanine aminotransferase (ALT) levels, hepatic failure and even death. Concurrently, HBV DNA levels may decrease by improved cytopathic and non-cytopathic immune mechanisms.[18, 19]
The third stage of reactivation is the recovery phase, during which clinical hepatitis resolves and HBV markers return to baseline levels.[20, 21]
The retrospective and prospective studies of HBV reactivation in HBsAg negative patients with hematological malignancies were summarized in previous reviews.[22-24] As for the reason for considerable variation (1.0–23.3%) in the incidence of HBV reactivation in lymphoma patients with HBV resolved infection following rituximab-containing chemotherapy, there may be differences among institutions both in the study subjects (HBV serological status including baseline anti-HBs titer, steroid-containing chemotherapy, and salvage therapy including transplantation) and the assays used for HBV-related markers (cut-off values, sensitivity). Several guidelines for the management of HBV reactivation have been published by Asian, American and European societies (American Association for the Study of Liver Diseases, Asian Pacific Association for the Study of the Liver, and European Association for the Study of the Liver). In January 2009, the Japanese guideline was announced for HBV reactivation following immunosuppressive therapy and systemic chemotherapy. Although the details of this guideline have been omitted from this review, in principle, antiviral prophylaxis is recommended for HBsAg positive patients before treatment. For HBV resolved patients, monthly monitoring of HBV DNA levels is recommended during and for at least 1 year after the end of immunosuppressive therapy or chemotherapy. Preemptive antiviral therapy should be started as soon as possible if HBV DNA is detected during this monitoring; however, there is little evidence of HBV DNA monitoring to prevent hepatitis due to HBV reactivation in HBV resolved patients.
Reactivation of HCV infection
Although HCV reactivation is rare, hepatic toxicity related to chemotherapy is higher among patients with chronic HCV infection than in HCV uninfected patients, suggesting that HCV reactivation occurred and can cause clinically relevant complications.
Hepatitis C virus-related liver dysfunction generally occurs 2–4 weeks after the cessation of chemotherapy.[27-30] A widely accepted hypothesis considering the pathogenesis indicates enhanced viral replication with a consequent increase in the number of infected hepatocytes following immunosuppressive treatment (Fig. 1). Withdrawal of immunosuppressive therapy leads to restoration of the host immune function, resulting in the rapid destruction of infected cells and hepatic injury.[27, 31] Severe liver dysfunction was found to occur at a lower incidence in HCV positive patients than HBV positive patients. The reason for this phenomenon is unknown; however, if severe hepatitis secondary to viral reactivation develops, mortality rates of HBV infected and HCV infected patients seem to be similar.[32-34]