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Keywords:

  • immunosuppression;
  • infectious risks;
  • monoclonal antibodies;
  • outcome;
  • viruses

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. HBV
  5. HCV
  6. Herpesvirus Infections
  7. Conclusions
  8. Transparency Declaration
  9. References

Clin Microbiol Infect 2011; 17: 1769–1775

Abstract

In recent years, immunomodulatory agents, such as monoclonal antibodies (mAbs), have been effectively utilized in the management of several malignancies, in transplant rejection, in autoimmune and inflammatory diseases, and in a range of further indications. However, the administration of mAbs is associated with an increased risk of infections, in particular of viral infections, that is not fully appreciated. The influence of mAbs on viral infections is likely to be relevant, impacting on the incidence, severity and timing of infections. Some of these viral infections may result in treatment delays and may be coupled with increased morbidity and mortality. Although all viral infections presumably play an important role in patients undergoing mAb treatment, and may affect outcome, some are more common than others, e.g. hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus, varicella-zoster virus and Epstein–Barr virus infections. This review focuses on the viral infections of primary clinical relevance, such as HBV, HCV, and herpesvirus infections, that may occur in patients undergoing immunomodulatory treatment.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. HBV
  5. HCV
  6. Herpesvirus Infections
  7. Conclusions
  8. Transparency Declaration
  9. References

The number of monoclonal antibodies (mAbs) and other biological therapies targeted at components of the immune system continues to expand. Data obtained from both clinical studies and post-marketing surveillance have shown that these agents may enhance susceptibility to infections. Increased rates of bacterial and mycobacterial infections have been observed among patients receiving mAbs and other biological therapies, and attention has recently been given to the risks of opportunistic infections, including Pneumocystis jirovecii infection and invasive mycoses [1,2]. However, the relationship between mAb treatment and the risk of viral infection is less well appreciated.

Some viruses are capable of establishing chronic infections (e.g. hepatitis B virus (HBV) and hepatitis C virus (HCV)) and exist in a latent form with the potential to reactivate following alterations of the host immune status (e.g. members of the human herpesvirus (HHV) family), whereas some of them are associated with an increased risk of malignancy (e.g. Epstein–Barr virus (EBV) and HHV-8)). Such infections may have implications for the screening and surveillance of patients prior to, during and after mAb treatment.

Patients who receive immunomodulating biological therapies are usually at a higher risk of developing infections, given their underlying disease, and the prior and concurrent treatment with other immunosuppressive agents. Therefore, one of the major problems in determining a causal relationship between biological therapy and infection is the fact that the underlying disease process itself, along with other immunosuppressive therapy administered previously or concurrently, can cause a state of immunosuppression. This is the case for patients with cancer, autoimmune diseases, and inflammatory conditions. In addition, in the event of rare infections, a strong association is difficult to prove, because of the small number of events observed. Even in randomized placebo-controlled trials and in large open-label studies, it is difficult to attribute the increased risk of infection to the mAbs alone, because of the large number of confounders observed [3,4].

In this article, we review the literature regarding the association between viral infection (e.g. HBV, HBC and herpesvirus infections) and mAb therapies, and discuss strategies for the screening, detection, prevention and treatment of these viral infections.

HBV

  1. Top of page
  2. Abstract
  3. Introduction
  4. HBV
  5. HCV
  6. Herpesvirus Infections
  7. Conclusions
  8. Transparency Declaration
  9. References

Reactivation of HBV infection is a well-described complication in the setting of cancer chemotherapy and in stem cell or organ transplantation, occurring in up to 50% of patients who do not receive anti-HBV drugs [5,6]. Mortality from liver failure after reactivation of HBV in patients receiving chemotherapy is reported in 4–60% of cases [7]. The risk of HBV reactivation is greater in patients with a high level of HBV replication at baseline, in patients with lymphoma, and in patients receiving chemotherapy regimens including corticosteroids or rituximab-based therapy [7]. Also, tumour necrosis factor (TNF)-α inhibitors, such as infliximab, etanercept, and adalimumab, may cause reactivation of HBV, even though the overall frequency of reactivation of HBV seems to be lower than with cancer chemotherapy.

HBV reactivation is usually subclinical, but can result in severe disease, including acute liver failure and death [5–8]. Recommendations have therefore been published [5,9,10] calling for universal screening for HBV infection with hepatitis B surface antigen (HBsAg) for all patients undergoing immunosuppressive treatment or chemotherapy. The American Society for the Study of Liver Disease and the European Association for the Study of the Liver recommend anti-HBV prophylaxis with nucleoside/nucleotide analogues for all patients with positive HBsAg receiving immunosuppression or chemotherapy, because this strategy drastically reduces HBV reactivation, hepatitis, and death [5,9]. Lamivudine has proven efficacy and safety in preventing HBV reactivation following chemotherapy for both haematological and solid malignancies [11]. A major concern with its prolonged use is the possibility of viral breakthrough following the emergence of resistance mutations (up to 24% at 1 year and 60% at 3 years) in the YMDD region of HBV DNA polymerase. Prophylaxis should begin 1 week prior to chemotherapy and should be maintained for at least 6–12 months after the end of immunosuppression, as HBV reactivation may occur after chemotherapy is discontinued [5,9,10]; lamivudine (100 mg orally once daily) should be administered to patients with low or undetectable HBV DNA levels at baseline, who will receive treatment for <1 year, whereas in patients with high HBV DNA levels (>2000 IU/mL) at baseline, who will receive anti-HBV prophylaxis for more than 1 year, new, more potent, drugs with less risk of resistance, such as tenofovir (300 mg orally once daily) and entecavir (for nucleoside-naïve patients, 0.5 mg daily orally, and for lamivudine-refractory/resistant patients, 1 mg daily orally), should be used [5,9]. With regard to patients with serological markers of a past HBV infection (HBsAg-negative and anti-hepatitis B core (HBcAb)-positive) undergoing immunosuppression or chemotherapy, the strategy is less clear. HBV reactivation for patients with resolved infection frequency is lower for HBsAg-positive patients, but for haematological patients receiving prolonged and intensive immunosuppression the risk is high and associated with a high mortality rate [12]. The American Society for the Study of Liver Disease [5] guidelines suggest quantification of HBV DNA in the serum, and, if it is undetectable, frequent follow-up by means of transaminase and HBV DNA testing. Currently, the Italian Society for the Study of Liver Disease advises anti-HBV prophylaxis for HBsAg-negative/anti-HBcAb-positive patients at risk of reactivation who have undetectable or low levels (100 copies/mL) of HBV DNA [10].

In patients with haematological and solid malignancies who develop HBV reactivation and have not received prophylactic anti-HBV drugs, chemotherapy must be suspended and hepatotoxic drugs discontinued. Prompt administration of anti-HBV therapy is vital. Lamivudine is effective for the treatment of patients with HBV reactivation after chemotherapy; however, the mortality rate of patients with HBV reactivation, once it has developed, remains high [13]. A better outcome might be obtained if lamivudine or other more effective anti-HBV drugs (tenofovir and entecavir) can be promptly started at the time of the initial rise in HBV DNA, before the viral load is too high [5].

To date, five TNF-α inhibitors have been approved by the Food and Drug Administration in the USA: infliximab, etanercept, adalimumab, certolizumab, and golimumab. Several of these agents are also approved for the treatment of ankylosing spondylitis, as well as of non-rheumatological diseases such as Crohn’s disease and psoriasis.

It is currently unknown whether HBV reactivation is a class effect or attributable to a particular TNF-α inhibitor. TNF-α is critically involved in the control of HBV replication and in stimulating anti-HBV T-cell responses [14], and the levels of TNF-α are elevated in patients with chronic HBV infection [15].

The use of anti-TNF-α drugs and HBV infection has been described in at least 30 patients (reviewed in [16]), and a variety of outcomes, ranging from asymptomatic to fatal hepatitis, have been reported. The majority of patients treated with anti-TNF-α drugs who did not receive concomitant anti-HBV therapy showed increased viral loads and serum transaminases (alanine transaminase (ALT)), and many of them developed hepatic dysfunction. The duration of anti-TNF-α therapy prior to HBV reactivation was variable, from a single dose to many months of maintenance treatment. The majority of cases of HBV reactivation have been associated with the more potent infliximab or adalimumab rather than with etanercept [16]. Prophylaxis prevents HBV reactivation in HBsAg-positive patients receiving infliximab [16]. There are insufficient data for routine prophylaxis with the use of etanercept and adalimumab to be advised, but, until such data become available, it seems prudent to administer prophylaxis.

Rituximab is a mAb that targets the CD20 antigen on the surface of normal and malignant B-lymphocytes; CD20 is present in up to 95% of B-cell non-Hodgkin lymphomas (NHLs). Rituximab is effective in a variety of haematological malignancies, both as a single agent and in combination with chemotherapy. Rituximab is widely approved for the treatment of B-cell NHL, as well as rheumatoid arthritis (RA) refractory to TNF-α inhibitors. The off-label uses of rituximab include treatment of autoimmune disorders, e.g. systemic lupus erythematosus, idiopathic thrombocytopenia purpura, and cryoglobulinaemia [16], and also solid organ transplantation [17,18]. The administration of rituximab results in a depletion of normal B-cells that may last for several months following treatment; the levels of B-cells may return to normal by 12 months after the end of treatment. A possible relationship between rituximab and HBV may be explained by the depletion of B-cells, which are crucial for both T-cell-mediated and antibody-mediated immunity.

HBV reactivation has been consistently associated with rituximab treatment in post-marketing reports, and has ranged from 25% to 39% of the reported cases, resulting in a high mortality rate of 52%, owing to hepatic failure [19–21]. If HBV reactivation occurs, rituximab and any concomitant chemotherapy should be discontinued; this results in anticancer treatment delays and in an inferior overall outcome. The addition of rituximab to cyclophosphamide, doxorubicine, vincristine and prednisone (CHOP) chemotherapy may increase the risk of HBV reactivation, but the precise magnitude of the increase is not known [20].

HBV reactivation has been increasingly reported in patients with resolved infection [20]. In a recent study of HBsAg-negative/anti-HBcAb-positive patients with NHL treated with rituximab–CHOP, 25% developed HBV reactivation [21].

HCV

  1. Top of page
  2. Abstract
  3. Introduction
  4. HBV
  5. HCV
  6. Herpesvirus Infections
  7. Conclusions
  8. Transparency Declaration
  9. References

Levels of TNF-α appear to be elevated in HCV-positive patients, and may be correlated with ALT levels, but the role of TNF-α in the progression of hepatitis remains unclear [22]. It is known that persistence and high levels of TNF-α, even when HCV RNA becomes undetectable during treatment, is associated with HCV relapse. TNF-α has been implicated in refractoriness to interferon therapy in patients with HCV. The mechanism by which TNF-α induces refractoriness to interferon in these patients remains unknown. Data relating to the use of anti-TNF-α in the setting of HCV infections are limited, but treatment with infliximab and etanercept appears to be relatively safe in HCV-positive patients, even if the durations of treatment and follow-up are relatively short (3–9 months) [22,23]. Anti-TNF-α therapy appears to be safe, and it should be used with caution in patients with chronic HCV infection. Patients should be followed closely while they are receiving anti-TNF-α therapy, with regular monitoring of ALT and of the HCV load.

The relationship between rituximab and HCV reactivation has been explored in several reports. A recent multicentre, retrospective Japanese study has demonstrated both the benefits and the risks of adding rituximab to CHOP chemotherapy in patients with diffuse large B-cell lymphoma and HCV infection [24]. HCV infection did not influence long-term progression-free survival, but the incidence of severe hepatic toxicity and the increase in HCV viral load in HCV-positive patients were significantly higher in HCV-negative patients. Other studies showed a lack of correlation between levels of HCV RNA and the extent of liver damage, and the variability in HCV RNA levels over time prevents firm conclusions being drawn regarding the association of rituximab with HCV infection and liver damage in patients with lymphoma [25,26]. Rituximab is being increasingly used for the treatment of HCV-related cryoglobulinaemic vasculitis, and the data from short-term studies show a clinical response, without relevant liver toxicity, even though, in some individuals, a small increase in HCV RNA levels was observed during treatment with rituximab [23]. Careful monitoring of hepatic function and HCV RNA in patients who are HCV-positive and receiving rituximab is recommended.

Herpesvirus Infections

  1. Top of page
  2. Abstract
  3. Introduction
  4. HBV
  5. HCV
  6. Herpesvirus Infections
  7. Conclusions
  8. Transparency Declaration
  9. References

Herpesvirus are common in the majority of populations, with serological evidence of past exposure to herpes simplex virus (HSV)-1, cytomegalovirus (CMV), EBV and varicella-zoster virus (VZV) being found in 80–90% of the adult population. Reactivation of herpesvirus infection is an important problem in transplant patients and in human immunodeficiency virus-positive patients, leading to recommendations regarding the prevention and management of this complication [27,28]. TNF-α is critically involved in the regulation of herpesvirus replication and dissemination, and experience with anti-TNF-α agents has shown herpesvirus reactivation to be relatively frequent in a number of cases, resulting in serious adverse events [16].

HSV

Reactivation of HSV has not been clearly associated with anti-TNF-α therapy. Occasional cases of HSV reactivation, including cases of HSV oesophagitis, three cases of HSV encephalitis, and one case of disseminated infection, in patients treated with infliximab or adalimumab have been reported (reviewed in [16,29]).

VZV

VZV reactivation is well documented in patients receiving anti-TNF-α therapy, and appears to be associated, in particular, with mAbs such as infliximab and adalimumab [16,30]. Analysis of a large series of patients with RA treated with anti-TNF-α therapy has shown an incidence of 11/1000 patient-years of herpes zoster (HZ) with adalimumab and infliximab, 8.9/1000 patient-years with etanercept, and 5.6/1000 patient-years with conventional disease-modifying anti-rheumatic therapy [30]. It is relevant to note that 18% of cases were multidermatomal, 13% of cases required hospitalization, and 5% of these patients developed recurrences, suggesting that HZ occurring in the setting of anti-TNF-α therapy may be severe [30]. In patients developing HZ, anti-TNF-α therapy should be interrupted, but can be safely restarted when vesicles have resolved and anti-VZV therapy with acyclovir or valaciclovir has been administered. Severe, atypical primary varicella has been reported in patients receiving anti-TNF-α therapy [16]. Attention should be given to the serological VZV status of patients before the start of immunosuppressive therapy. Vaccination is available, but a live vaccine is contraindicated in patients receiving immunosuppressive therapy or anti-TNF-α drugs.

CMV

CMV active infection is still a frequent cause of morbidity and mortality in immunocompromised patients and, in particular, in those undergoing solid organ and haematopoietic stem cell transplantation (HSCT). The impact of CMV infection and disease is less clearly defined for patients with haematological malignancies who receive conventional chemotherapy and/or mAbs, and for those patients receiving mAbs and immunomodulating agents for other diseases [16,19,20,31,32]. CMV disease manifestations include pneumonia, enteritis, encephalitis, retinitis, hepatitis, and marrow suppression.

TNF-α is involved in controlling CMV replication in vitro, but the role of anti-TNF-α therapy in these cases remains speculative, because the majority of patients receive multiple concomitant immunosuppressive drugs. Prospective studies in Crohn’s disease and RA have shown no evidence of significant CMV reactivation, as measured by pp65 antigenaemia or CMV PCR [16,33]. Similarly, infliximab treatment does not appear to affect colonic tissue viral load [33], even though several cases of CMV disease complicating TNF-α therapy, including pneumonia, have been reported [34]. Allogeneic haematopoietic stem cell transplant recipients with severe steroid refractory acute graft-versus-host disease (GVHD) are at high risk of CMV reactivation. A rate of CMV reactivation of 67% has been reported in these patients [35], most likely because of the heavy concomitant immune depression; the addition of anti-TNF-α therapy further increases the risk of CMV infection.

Alemtuzumab, a humanized anti-CD52 mAb, binds to the cell membranes of virtually all normal blood lymphocytes, as well as to most malignant B-cells and T-cells, causing profound and prolonged lymphopenia [36,37]. CD4 and CD8 T-lymphocyte counts reach their nadir c. 4 weeks after alemtuzumab administration, and lymphopenia may persist for over 1 year [36,37]. Alemtuzumab is indicated for the treatment of chronic lymphocytic leukaemia, and has been shown to be active in relapsed/refractory disease and in previously untreated patients [36]. Furthermore, alemtuzumab has shown efficacy in preventing GVHD in patients undergoing allogeneic HSCT [36].

An increased incidence of CMV infection (as defined by positive pp65 antigenaemia and/or plasma PCR for CMV DNA) associated with the use of alemtuzumab has been documented in 15–66% of patients with lymphoproliferative diseases examined [36–38]. A particularly high incidence of CMV infection (50–85%) has been observed in patients receiving alemtuzumab for T-cell depletion after non-myeloablative allogeneic HSCT [39,40]. The incidence of symptomatic CMV infection was as high as 18% [37–39], and sporadic cases of CMV disease have been reported [37,38]. The majority of CMV infections occurred within the first 3 months of alemtuzumab therapy, when the CD4 and CD8 cell counts were profoundly reduced [37–41]. Several recommendations [37,41,42] have been made: (i) weekly monitoring of CMV by pp65 antigenaemia and/or by PCR during alemtuzumab therapy; (ii) therapy with ganciclovir or valganciclovir for symptomatic patients with positive pp65 antigenaemia and/or CMV DNA; the approach to the asymptomatic patient with a rising CMV viral load is less clear, but, until definitive data become available, it seems prudent to administer pre-emptive therapy; the appropriate duration of antiviral therapy is unknown, but anti-CMV treatment should be given for 14–21 days until CMV viral load negativity; (iii) in cases of symptomatic infection with increasing CMV viral load, alemtuzumab therapy should be stopped and restarted following successful anti-CMV therapy and sustained negative CMV test results; and (iv) anti-CMV prophylaxis with antiviral drugs, including valganciclovir, high doses of acyclovir, and valacyclovir [43], should be given during alemtuzumab therapy and for at least 2 months after the end of treatment.

The use of rituximab as single agent does not appear to increase the incidence of CMV infection, whereas an increased rate of CMV reactivation has been reported after its use in combination with cytotoxic drugs [19,31]; in the setting of autologous HSCT, the risk of developing CMV infection has been reported to be significantly higher in rituximab-treated patients than in non-rituximab-treated patients [44].

EBV

Given the potency of alemtuzumab in depleting lymphocytes, there is an obvious concern about the development of a post-transplantation lymphoproliferative disease (PTLD) secondary to infection with EBV. In patients undergoing allogeneic HSCT, risk factors include the mismatch between the donor and the recipient, depletion of T-cells from the graft (use of alemtuzumab or anti-thymocyte globulin), and the severity and duration of the immunosuppression used to prevent GVHD [45]. In recipients of solid organ transplants, the risk factors for developing a PTLD include the degree of immunosuppression and the development of primary infection after transplantation [45]. Of 547 solid organ transplant recipients treated with alemtuzumab without antiviral prophylaxis, 56 (10%) developed 62 opportunistic infections, including three (5%) EBV infections with PTLD [46]. The association between T-cell depletion and a possible risk of PTLD supports the monitoring of EBV-seronegative recipients of organs from seropositive donors by quantitative molecular tests monthly for at least 1 year after induction therapy. For patients with detectable EBV DNA, the level of immunosuppression should be decreased and the frequency of monitoring of EBV DNA should be increased [47]. More than 50% of cases of PTLD respond to rituximab therapy, but this treatment may fail because of downregulation of the CD20 antigen on malignant B-cells or because of the absence of efficient antibody-mediated cellular toxicity effectors. The pre-emptive use of rituximab and adoptive immunotherapy with donor-collected EBV-cytotoxic T-cells has been shown to reduce the mortality of PTLD (reviewed in [48]). Data on the efficacy of infusion of donor lymphocytes are promising, with an overall survival rate of 41% (reviewed in [48,49]).

In patients receiving anti-TNF-α therapy, sporadic cases of EBV-related lymphoproliferative disease have been observed; cessation of therapy resulted in a regression of the lymphoma [50]; however, recent studies have highlighted a lack of a convincing association [51].

HHV-8

HHV-8 infection associated with Kaposi’s sarcoma has been observed in two renal transplant recipients receiving rituximab [52]; in contrast, rituximab has been successfully used as therapy for HHV-8 infection in a renal transplant recipient with severe HHV-8 primary infection [53]. Finally, in a prospective study, no HHV-8 reactivation was documented in 60 patients receiving infliximab for active Crohn’s disease [54]. The consequences of mAb therapies in these settings are still unclear.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. HBV
  5. HCV
  6. Herpesvirus Infections
  7. Conclusions
  8. Transparency Declaration
  9. References

Patients receiving the currently available mAbs are at high risk for the reactivation of latent viral infections and for the development of exogenous viral infections. Patients receiving biological agents should therefore be closely monitored before the start of therapy, and should receive prophylactic or pre-emptive therapy for the viral infections if monitoring is positive. Physicians dealing with patients receiving mAbs or immunomodulating therapies should pro-actively consider that viral infections may present with atypical signs and symptoms.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. HBV
  5. HCV
  6. Herpesvirus Infections
  7. Conclusions
  8. Transparency Declaration
  9. References