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Keywords:

  • chemotherapy;
  • hepatitis B virus;
  • hepatitis C virus;
  • immunosuppressive;
  • occult infection;
  • reactivation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pathophysiology of Reactivation of HBV and HCV Infection
  5. Clinical Evidence and Management of HCV Reactivation
  6. References

Reactivation of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection following anticancer chemotherapy and immunosuppressive therapy is a well-known complication. HBV reactivation has been reported to be associated with anti-CD20 monoclonal antibody rituximab-containing chemotherapy and tumor necrosis factor-α inhibitor-containing immunosuppressive therapy in HBV resolved patients (hepatitis B surface antigen negative and antibodies against hepatitis B core antigen positive and/or antibodies against surface antigen positive). On the other hand, HCV reactivation has been reported to be associated with liver damage or hepatic dysfunction, but fulminant hepatitis due to HCV reactivation is a rare complication. In this review, we describe the pathophysiology of the reactivation of HBV and HCV infection, as well as the clinical evidence and management of HCV reactivation.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pathophysiology of Reactivation of HBV and HCV Infection
  5. Clinical Evidence and Management of HCV Reactivation
  6. References

REACTIVATION OF HEPATITIS B virus (HBV) or hepatitis C virus (HCV) infection following anticancer chemotherapy and immunosuppressive therapy is a well-known complication. In particular, HBV reactivation is a potentially fatal complication that needs to be followed up carefully. Most HBV reactivation occurs in hepatitis B surface antigen (HBsAg) positive patients prior to treatment; however, HBV reactivation has been observed increasingly in HBV resolved patients without HBsAg, but with antibodies against hepatitis B core antigen (anti-HBc) and/or HBsAg (anti-HBs). Moreover, HBV reactivation has been reported to be associated with anti-CD20 monoclonal antibody rituximab-containing chemotherapy and tumor necrosis factor (TNF)-α inhibitor-containing immunosuppressive therapy in patients with prior resolved HBV infection. On the other hand, HCV reactivation has been reported to be associated with liver damage or hepatic dysfunction, but fulminant hepatitis due to HCV reactivation is a rare complication.

Hematopoietic stem cell transplantation (HSCT) is often the chosen treatment for hematological malignancies and it has been suggested that the incidence and clinical characteristics of reactivation of HBV or HCV infection may depend on immune reconstitution, which may be associated with graft-versus-host disease (GVHD) and the combined immunosuppressant, especially in the allogeneic HSCT setting.

As several review papers about HBV reactivation had been already reported, we described here the pathophysiology of the reactivation of HBV and HCV infection, as well as the clinical evidence and management of HCV reactivation.

Pathophysiology of Reactivation of HBV and HCV Infection

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pathophysiology of Reactivation of HBV and HCV Infection
  5. Clinical Evidence and Management of HCV Reactivation
  6. References

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
 HBVHCV
  1. DC, dendritic cells; HBV, hepatitis B virus; HCV, hepatitis C virus; IFN, interferon; NK, natural killer; NKT, natural killer T cells.

Innate immunity  
HepatocytesStealth responseType I and/or III IFN production
Main componentsNK and NKT cellsDC
Critical cytokinesIFN-γ, TNF-αType I and/or III IFN
Adaptive immunity  
ComponentsT cells and B cellsT 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.[1] Most occult HBV infection individuals are infected with replicable viruses, whose replication and gene expression are strongly inhibited by the host immune system.[2] 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.[3]

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.[12] 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

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.[13] 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,[14] 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.[25] 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,[26] 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.[5] 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]

Clinical Evidence and Management of HCV Reactivation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pathophysiology of Reactivation of HBV and HCV Infection
  5. Clinical Evidence and Management of HCV Reactivation
  6. References

Diagnosis for HCV reactivation

CHRONICALLY INFECTED PATIENTS have stable HCV RNA levels that may vary by approximately 0.5 log10 IU/mL;[35] therefore, an increase of the HCV viral load of more than 1 log l0 IU/mL may be a sign of HCV reactivation. It was also reported that HCV reactivation showed an at least threefold increase in serum ALT in a patient in whom the tumor had not infiltrated the liver, who had not received hepatotoxic drugs and who had had no recent blood transfusions or other systemic infections besides HCV.[6, 24] Changes in liver enzyme levels can be accompanied by the reappearance of HCV RNA or a sudden increase in the serum HCV RNA level.[6]

HCV reactivation after specific treatments

Patients with HCV infection who undergo HSCT or systematic chemotherapy including corticosteroids can experience severe hepatic dysfunction and fulminant hepatic failure (summarized in Table 2).

Table 2. Hepatic toxicity by HCV reactivation in HCV infected patients with hematological malignancies
AuthorYearDiseaseTreatmentNo. of cases with hepatic toxicityDeath from liver toxicity
  1. AA, aplastic anemia; ABVD, doxorubicin hydrochloride (adriamycin), bleomycin, vinblastine and dacarbazine; Allo-HSCT, allogeneic hematopoietic stem cell transplantation; AML, acute myeloid leukemia; auto-HSCT, autologous hematopoietic stem cell transplantation; CHOP, cyclophosphamide, vincristine and prednisolone; DLBCL, diffuse large B-cell lymphoma; MALT, extranodal-marginal zone lymphoma of the mucosa-associated lymphoid tissue; NHL, non-Hodgkin's lymphoma; R-chemo, rituximab plus steroids combined chemotherapy; R-CHOP, rituximab, cyclophosphamide, vincristine and prednisolone; R-CNOP, rituximab, cyclophosphamide, mitoxantrone, vincristine and prednisolone.

Kanamori et al.1992AMLAllo-HSCT2 patients2
Maruta et al.1994AML, AAAllo-HSCT9 patients2
Nakamura et al.1996Hematological malignanciesVarious regimens11 patients5
Vento et al.1996B-cell NHL and HLABVD or CHOP- like regimen2 patients1
Luppi et al.1998B-cell NHLVarious regimens20/35 patients2
Zuckerman et al.1998Hematological malignanciesVarious regimens18/33 patients (55%)0
Kawatani et al.2001Hematological malignanciesVarious regimens4/22 patients1
Hamaguchi et al.2002Hematological malignanciesAllo-HSCT40/589
Locasciulli et al.2003Hematological and solid malignanciesAllo-HSCT (21)/auto-HSCT (36)

21

6

2

1

Takai et al.2005Hematological malignanciesVarious regimens4/37 patients0
Aksoy et al.2006DLBCLRituximab0/1 patients0
Besson et al.2006DLBCLVarious regimens15/23 patients3
Visco et al.2006DLBCLCHOP-like, rituximab (35)5/132 patients1
Ennishi et al.2008DLBCL, MALT NHLR-CHOP-like1/5 patients0
Hsieh et al.2008DLBCLR-CNOP1/1 patients0
Ennishi et al.2010DLBCLR-chemo36/131 patients6
Arcaini et al.2010NHLR-chemo (28)24/160 patients3

Corticosteroids have traditionally been associated with cases of HCV reactivation.[27, 36] HCV reactivation has been associated with several immunosuppressive and chemotherapeutic agents, including rituximab, alemtuzumab, bleomycin, busulfan, cisplatin, cyclophosphamide, cyclosporin, cytarabine, dacarbazine, doxorubicin, etoposide, gemcitabine, methotrexate, vinblastine and vincristine;[27, 37-44] however, many patients with HCV reactivation during treatment with one of these drugs were simultaneously treated with corticosteroids.[38, 41, 42, 44, 45] In a study by Zuckerman et al.,[46] 18 of 33 (54%) patients had mild to moderate increases of ALT, which occurred 2–3 weeks after the withdrawal of chemotherapy. HCV positive patients did not demonstrate a higher incidence of severe hepatic dysfunction during chemotherapy for malignancies than HCV negative patients; however, liver test abnormalities during therapy are very common and are seen in 54% HCV positive patients and in 36% HCV negative patients.

Whether corticosteroid therapy alone or in combination with other agents leads to reactivation of HCV infection and acute exacerbation of chronic HCV infection remains to be determined. A possible relationship between rituximab and HCV reactivation in patients with cancer has been reported.[41, 44, 45] Only the administration of rituximab-containing chemotherapy was associated with both acute exacerbation and reactivation of chronic HCV infection.[24]

Ennishi et al. also showed that the incidence of severe hepatic toxicity in HCV positive patients was significantly higher than in HCV negative patients, and HCV infection was determined to be a strong risk factor for this adverse effect in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era.[44] These hepatic toxicities led to modification and discontinuation of immunochemotherapy, resulting in lymphoma progression. The study described that careful monitoring of hepatic function should be recommended for HCV positive patients, particularly those with high levels of pretreatment transaminase. More importantly, monitoring of HCV viral load demonstrated a marked enhancement of HCV replication, and it is suggested that increased HCV results in severe hepatic toxicity. Thus, HCV viral load should be carefully monitored in HCV positive patients who receive immunochemotherapy.

Severity of HCV reactivation versus HBV reactivation

The health consensus regarding HCV reactivation seems to be less severe than that of HBV reactivation (summarized in Table 3). Previous reports described that the incidence of post-chemotherapy liver injury in HBV carriers was significantly higher than that in HCV carriers,[5, 31, 32] namely, the incidence of post-chemotherapy liver injury in 25 HBV carriers (36%) was significantly higher than that in 37 HCV carriers (10.8%, P = 0.026),[31] and 44 (51.8%) of the 85 patients reported to have severe hepatitis along with hematological malignancies were HBV carriers, while only 11 (12.9%) were HCV carriers;[32] however, the mortality rates did not differ between HBV and HCV carriers (40.9% vs 45.5%) once severe hepatitis developed.

Table 3. Clinical state by HCV reactivation versus HBV reactivation
Severity or prognosisYearSurvey periodNo. of patientsCountry% of HBV% of HCVPCommentsReference
  1. HBV, hepatitis B virus; HCV, hepatitis C virus; HSCT, hematopoietic stem cell transplant; ND, not done.

  2. a

    Fifty-seven were anti-HCV positive; of these, 38 were also tested for HCV RNA.

Liver injury20051996–2002601Japan36% (9/25)10.8% (4/37)0.026Patients with hematological malignancies31
Severe hepatitis19961987–1991Surveillance in 250 hospitalsJapan51.8% (44/85)12.9% (11/85)NDIn 85 patients having severe hepatitis along with hematological malignancies32
Death from liver failure20031996–200090Italy3% (1/33)8% (3/38a)0.6Patients with HBV or HCV receiving HSCT (during 24 months)33
Hepatic failure20021986–1998135Japan10% (8/77)12% (7/58)NDPatients with HBV or HCV receiving HSCT34

In a large Italian study of 57 HCV infected patients who underwent HSCT, patients undergoing autologous HSCT had a significantly lower risk of reactivation post-transplant than the allogeneic group (16% vs 100%, P = 0.004). In the allogeneic HSCT group, HCV reactivation occurred mainly within 6 months after HSCT, whereas in the autologous group, reactivation occurred within the first 3 months post-transplant. In this cohort, one HBsAg positive and three anti-HCV positive patients before HSCT died of liver failure. The risk of death from liver failure was not significantly different between HBsAg and anti-HCV positive patients, being 3% and 8% at 24 months, respectively (P = 0.6), or between recipients of autologous (5%) and allogeneic HSCT (7%) (P = 0.34).[33]

In a Japanese multicenter study of 135 patients with HBV or HCV infection who received allogeneic transplants, transient hepatitis was more common in HBV infected patients than in HCV infected patients, but the rates of fulminant hepatitis and death due to hepatic failure were similar in both groups.[34]

Outcome of HCV infected hematological patients

As previously highlighted, there is no significant short-term impact of HCV on the outcome after HSCT. Nevertheless, the long-term impact of chronic HCV infection can be deleterious in the liver, causing significant fibrosis progression, liver failure and increased risk of hepatocellular carcinoma (HCC). One study reported the rapid progression of hepatitis C in patients with humoral immunodeficiency disorders.[47] Another group has recently reported a more rapid rate of fibrosis progression after HSCT, with median time to cirrhosis of 18 years, as compared to 40 years seen in the control group. HCV disease progression ranked third, behind infections and GVHD, as a cause of late death after HSCT.[48] Long-term survivors after HSCT thus appear to be at higher risk for HCV-related complications and treatment of HCV becomes critical. A possible explanation for the genesis of cirrhosis could be an immune imbalance or impaired regulation of B and T cells.[47, 48]

In various regimens for hematological malignancies, Ennishi et al. reported that hepatic disease progressed in four patients, and HCC was found to increase the risk of death from hepatic failure significantly in lymphoma patients receiving conventional chemotherapy, even during short-term observation.[44] Cox multivariate analysis showed that older age and advanced stage had significant adverse effects on overall survival (OS); however, HCV infection was not associated with poor progression-free survival (PFS) or OS. Besson et al. described that the overall proportion of subjects undergoing hepatic toxicity was 65% (15/23 patients). Outcome of HCV positive patients was poorer for OS (P = 0.02), but not for event-free survival (P = 0.13).[49] Visco et al. also described that only five of 132 patients (4%) had to discontinue chemotherapy due to severe liver function impairment.[50] Although previous papers mentioned that rituximab induced HCV reactivation after spontaneous remission in DLBCL,[45, 51] the addition of rituximab did not seem to affect patients' tolerance to treatment. Five-year overall survival of the entire cohort was 72%, while 5-year PFS of the 132 patients treated with intent to cure was 51%. The prognosis of HCV infected patients with DLBCL is still controversial.

Recently, Arcaini et al.[43] studied 160 HCV positive patients with NHL (59 indolent NHL, 101 aggressive). Among 28 patients treated with rituximab-containing chemotherapy, five (18%) developed liver toxicity, and among 132 independent patients who received chemotherapy, only nine (7%) had hepatotoxicity, suggesting that rituximab was related to a slightly higher occurrence of toxicity. Median PFS for patients who experienced liver toxicity was significantly shorter than median PFS of patients without toxicity (2 and 3.7 years, respectively, P = 0.03). HCV infected patients with NHL developed liver toxicity significantly, often leading to interruption of treatment.

Based on these findings, the impact of HCV infection on the outcome after HSCT or rituximab-containing chemotherapy seems to be deleterious for OS but not for event-free survival. Further studies are required in prospective multicenter cohorts.

Treatment of HCV infected patients with hematological malignancies

The long-term impact of chronic HCV infection can be deleterious to the liver, causing significant fibrosis progression, liver failure and increased risk of HCC. Interestingly, a more rapid rate of fibrosis progression was reported after HSCT.[48] Therapy for HCV infection in patients with hematological malignancy can be considered once a patient's immunity and bone marrow have recovered, immunosuppressive drugs have been stopped, and there is no evidence of GVHD, because the hematological adverse effects of anti-HCV drugs can exacerbate the toxicity of chemotherapy, which can involve complications such as severe cytopenias and potentially life-threatening infections.[52] Overall, antiviral therapy for HCV in patients (e.g. HIV, transplant) is often associated with poor response rates, even though patients with chronic HCV infection were treated with the combination of pegylated interferon-α and ribavirin.[53-55] The use of direct-acting antiviral drugs (such as recently approved inhibitors of nonstructural protein 3/4A [NS3/4A] protease [boceprevir or telaprevir], or NS5B polymerase inhibitors) has not been evaluated in patients with cancer. Boceprevir and telaprevir can inhibit hepatic drug-metabolizing enzymes such as cytochrome P450 (CYP)2C, CYP3A4 or CYP1A;[56] therefore, these agents potentially interact with various drugs that are co-administrated in patients with cancer. These new antiviral drugs should be used with caution in patients with cancer.

Large-scale studies are needed to better define which patients with cancer are most likely to benefit from simultaneous antiviral therapy and cytotoxic chemotherapy. Notably, antiviral treatment with pegylated interferon-α and ribavirin should not be used early in the post-transplant period (<2 years after transplantation) in patients who have undergone allogeneic HSCT as interferon-α therapy may precipitate or induce the development of GVDH.[57]

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pathophysiology of Reactivation of HBV and HCV Infection
  5. Clinical Evidence and Management of HCV Reactivation
  6. References