1. Top of page
  2. Summary
  3. Introduction
  4. Consideration one – Chronic viral infections
  5. Consideration two – latent herpes virus infections
  6. Consideration three – viruses associated with malignancy
  7. Other viruses
  8. Screening and vaccination
  9. Conclusions
  10. Acknowledgements
  11. References

Background  Anti-Tumour necrosis factor (TNF) therapy is now well established in the treatment of inflammatory bowel disease and the risk of opportunistic infection is recognized. However, specific considerations regarding screening, detection, prevention and treatment of chronic viral infections in the context of anti-TNF therapy in inflammatory bowel disease are not widely adopted in practice.

Aim  To provide a detailed and comprehensive review of the relevance of chronic viral infections in the context of anti-TNF therapy in inflammatory bowel disease.

Methods  Literature search was conducted using Medline, Pubmed and Embase using the terms viral infection, hepatitis, herpes, CMV, EBV, HPV, anti-TNF, infliximab, adalimumab, certolizumab pegol and etanercept. Hepatitis B and C and HIV had the largest literature associated and these have been summarized in Tables.

Results  Particular risks are associated with the use of anti-TNF drugs in patients with hepatitis B infection, in whom reactivation is common unless anti-viral prophylaxis is used. Reactivation of herpes zoster is the most common viral problem associated with anti-TNF treatment, and may be particularly severe. Primary varicella infection may present with atypical features in patients on anti-TNF.

Conclusion  Appreciation of risks of chronic viral disease associated with anti-TNF therapy may permit early recognition, prophylaxis and treatment.


  1. Top of page
  2. Summary
  3. Introduction
  4. Consideration one – Chronic viral infections
  5. Consideration two – latent herpes virus infections
  6. Consideration three – viruses associated with malignancy
  7. Other viruses
  8. Screening and vaccination
  9. Conclusions
  10. Acknowledgements
  11. References

Biological therapies targeting tumour necrosis factor (TNF)-α have become increasingly important agents in the management of inflammatory conditions, including the inflammatory bowel diseases (IBD) Crohn’s disease and ulcerative colitis. Drugs targeting TNF, including infliximab, adalimumab and certolizumab pegol have proven highly effective in otherwise medically refractory disease and are of particular benefit in the management of complex and fistulizing disease.1, 2 However, it has become clear from both clinical studies and post-marketing surveillance that these agents may increase susceptibility to infection. Increased rates of bacterial and mycobacterial disease are well documented, and attention has recently been drawn to the risks of opportunistic infections including Pneumocystis jirovecii, invasive mycoses and listeriosis.3–5 In contrast, the relationship between anti-TNF therapy and the risk of viral infection is less well appreciated. Although a majority of human viral infections are self-limiting, a number of viruses are capable of causing chronic infection [e.g. human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV)], some exist in latent form with the potential to reactivate following alterations in host immune status (e.g. members of the human herpes virus family) and some are associated with an increased risk of malignancy [e.g. Epstein-Barr virus (EBV), human papilloma virus (HPV), human herpes virus (HHV)-8]. Such infections may have implications for the screening and surveillance of patients prior to anti-TNF therapy.

In this article, we review the literature regarding chronic viral infection and anti-TNF therapy of relevance to patients with IBD. Safety aspects related to all three widely available drugs acting on TNF signalling [the monoclonal antibodies infliximab (human-murine chimeric IgG1), adalimumab (fully human IgG1), and the soluble TNF receptor fusion protein etanercept] are included. Although etanercept is ineffective in the treatment of IBD, reports describing its effects on viral infection are included to illustrate possible generic effects of TNF inhibition.

Consideration one – Chronic viral infections

  1. Top of page
  2. Summary
  3. Introduction
  4. Consideration one – Chronic viral infections
  5. Consideration two – latent herpes virus infections
  6. Consideration three – viruses associated with malignancy
  7. Other viruses
  8. Screening and vaccination
  9. Conclusions
  10. Acknowledgements
  11. References

Three chronic viral infections are particularly relevant to the safe use of anti-TNF therapy; HBV, HCV and HIV. HBV alone is estimated to affect 370 million people worldwide, whereas HCV infects almost 200 million and HIV, up to 40 million.6, 7 Substantial geographical variation exists for all three infections; the prevalence of chronic HBV in North America and Western Europe is up to 1% and that of HCV up to 2%, with significantly higher rates in specific regions and ethnic groups. As the indications for anti-TNF agents evolve, consideration of the safety of their use in patients infected with one or more of these viruses is becoming increasingly relevant.

Hepatitis B virus

Reactivation of HBV infection is a well described complication of immunosuppression in the setting of organ transplantation or cancer chemotherapy, occurring in up to 50% of patients where concomitant anti-viral therapy is not used.8 Although reactivation most commonly presents when immune reconstitution occurs following cessation of immunosuppression,9 an accelerated course of HBV infection may occur with long-term iatrogenic immunosuppression or in those co-infected with HIV.10 TNF-α is critically involved in the control of HBV viral replication and in stimulating anti-HBV T-cell responses,11 leading to specific theoretical concerns regarding the safety of anti-TNF agents in patients with HBV infection.

The use of anti-TNF drugs has been reported in 28 HBV infected patients (Table 1),12–32 with a variety of outcomes ranging from apparent viral clearance to fatal hepatitis. The majority of patients treated with anti-TNF drugs who did not receive concomitant anti-viral therapy demonstrated increased viral loads and serum transaminases and many developed clinically apparent hepatic dysfunction. The duration of anti-TNF therapy prior to HBV reactivation is highly variable, from a single dose to many months of maintenance treatment. A majority of cases of HBV reactivation have been associated with the more potent monoclonal antibodies infliximab or adalimumab rather than etanercept. Prophylactic treatment with lamivudine appears effective in preventing reactivation or adverse clinical outcomes in patients receiving anti-TNF.30–32

Table 1.   Experience with anti-TNF therapy in patients with hepatitis B virus infection, with and without lamivudine prophylaxis
IndicationAge/ GenderHBsAg status* HBV DNA*Anti-TNF drugDuration of therapyHBV reactivation Outcome/CommentsRef
  1. * Pre-treatment results.

  2. CD, Crohn’s disease; RA, rheumatoid arthritis; AS, ankylosing spondylitis; SA, spondyloarthropathy; IFX, infliximab; ETA, etanercept; ADA, adalimumab.

No lamivudine prophylaxis
 CD40/M+3.9 × 105 c/mLIFX6 infusionsNoReceived lamivudine therapy. Alive12
 RA49/M+N/AIFX8 infusionsYesAcute hepatitis. Treated with lamivudine. Alive Acute hepatitis. Resolved without anti-viral therapy. Alive13
 CD34/MN/AN/AIFX4 infusionsYes(Retrospectively found to be HBsAg+ anti-HBc+ HBeAg+)14
 CD38/M+Not detectedIFX3 infusionsYesSub-acute liver failure. Died Sub-fulminant hepatitis. Treated with lamivudine. Alive14
 CD50/MN/A IFX3 infusionsYesRetrospective analysis showed HBsAg+, DNA 20 IU/mL15
 CD28/F+Not detectedIFX1 infusionsYesIncreased HBV DNA & hepatitis. Not treated with anti-viral therapy. Alive16
 SA35/F+Not detectedIFX3 infusionsYesIncreased HBV DNA & hepatitis. Treated with lamivudine and IFX successfully continued17
 RA36/F+2720 IU/mLIFX1 yearNoHBV DNA became undetectable, although LFT deteriorated18
 AS43/M+Not detectedIFX14 weeksYesHBV DNA became positive. Successfully treated with lamivudine19
 AS41/M+Not detectedIFX24 monthsNoNo anti-viral prophylaxis, no evidence of reactivation Initial 5 doses of IFX without problems. After further single infusion HBV DNA increase and hepatitis19
 CD41/FN/AIFX>1 yearYesBecame HBsAg+. Treated with lamivudine20
 CD54/M+N/AIFX2 yearsYesFatal hepatitis. Died despite lamivudine therapy21
 AS73/MN/AETA14 monthsYesInitially anti-HBs+. Became HBsAg+. Successfully treated with lamivudine, allowing restarting of therapy22
 CD43/F+Not detectedIFX4 infusionsYesIncreased HBV DNA. Treated with lamivudine without effect, therefore IFX stopped. Successfully restarted 6 months later on lamivudine prophylaxis23
 RA62/FN/AN/AETA2 yearsYesHepatitis. Later successfully restarted ETA with lamivudine prophylaxis24
 RA63/F+Not detectedADA/ETA26 monthsNoNo change in HBV DNA25
 Stills28/F+Not detectedIFX2 infusionsUncertainFulminant hepatitis requiring liver transplant. However, HBV DNA negative throughout26
 RA32/F+N/AADA24 monthsNoMild transient transaminase rise. No change in HBV DNA27
 RA64/F+N/AETA30 monthsNoNo change in HBV DNA or transaminases27
 RA63/M+N/AETA/ADA18 monthsNoNo change in transaminases. HBV DNA not measured27
 RA48/F+Not detectedETA13 monthsYesSlight increase in transaminases. HBV DNA became detectable28
 AS38/F+Not detectedETA12 monthsYesHBV DNA became detectable28
 RA28/F+N/AADA/ETA>2 yearsNoNo evidence of reactivation. Later commenced lamivudine therapy29
Lamivudine Prophylaxis
 RA58/F+Not detectedIFX/ETA15 monthsNoNo reactivation observed30
 CD26/M+PositiveIFX5 infusionsNoNo reactivation observed14
 AS32/M+103–104 IU/mLIFX9 infusionsNoAlive31
 RA54/M+38 IU/mLETA/ADA21 monthsNoNo change in HBV DNA32
 RA53/M+1673 IU/mLETA>2 yearsNoNo change in HBV DNA32
 SA49/M+<380 IU/mLIFX7 monthsNoNo change in HBV DNA20

In light of such observations, recommendations have been made for routine HBV screening prior to initiation of anti-TNF drugs.33–36 However, significant questions regarding optimal screening, monitoring and anti-viral therapy strategies remain to be addressed.

A majority of reported cases were known to be infected with HBV prior to initiation of anti-TNF and to be HBsAg positive; therefore, simple determination of HBsAg status may be an effective screening strategy in this situation. However, cases of reactivation in HBsAg negative patients have been recorded and screening should be tailored to the individual risk of HBV infection. This issue is of particular relevance in patients who may have occult HBV infection, defined by the presence of HBV-DNA in the liver (with or without detectable HBV-DNA in serum) of individuals testing HBsAg negative by currently available assays.37 Occult HBV infection is well recognized in those co-infected with HCV.38 Similarly, false negative HBsAg results may result from infection with viral strains carrying mutations in the S-gene (escape mutants) producing HBsAg not recognized by some commercially available assays, despite comparable levels of HBV-DNA to wild type infection. Therefore, additional tests of HBV status may be indicated (including anti-HBc and HBV-DNA by sensitive nucleic acid amplification based assays) in patients judged to be at particular risk of HBV infection because of their ethnic background or local incidence rates, current or previous high-risk lifestyle practices, those who report a history of jaundice or liver problems of uncertain aetiology and those with known HCV infection.

In patients found to be at risk of HBV reactivation, the appropriate management strategy remains uncertain. Simple monitoring of transaminase levels and HBV viral load has been advocated as a potential strategy in some patients, but the required frequency of monitoring and effectiveness of this strategy is unproven. Furthermore, anti-viral drugs may not be immediately effective in suppressing viral replication and preventing irreversible liver damage in such patients. Previous reports have described the successful use of lamivudine prophylaxis; however, viral resistance commonly develops with prolonged use, detected in up to 30% after 1 year and 70% by 5 years, and the emergence of resistance has been associated with reactivation in patients on long-term anti-TNF therapy.39 The potential long-term nature of anti-TNF therapy may make adefovir, tenofovir and entecavir more suitable drugs, although the potential nephrotoxicity associated with adefovir and tenofovir may limit their use in this situation. When used, anti-viral therapy should be commenced at least a few days prior to anti-TNF treatment and continued for up to 6 months beyond the cessation of the anti-TNF drug, as recommended by consensus groups for other immunosuppressive therapies.6, 40

On the basis of reported experience, HBV need not be an absolute contraindication to anti-TNF therapy. Careful consideration of the risks and benefits for the individual patient is needed, with detailed counselling regarding the issues of uncertainty highlighted above. With close laboratory monitoring and the use of prophylactic anti-viral drugs, anti-TNF therapy may be used with an acceptable safely profile in HBV infected patients.

Hepatitis C virus

In contrast to its role in HBV infection, TNF-α appears to be pathogenic in HCV infection, triggering hepatocyte apoptosis and perpetuating liver inflammation, and interferon therapy is less effective in patients with elevated serum TNF-α levels.41 Furthermore, HCV has rarely been associated with acute complications in patients treated with chemotherapy or conventional immunosuppressants.42 It might therefore be cautiously assumed that anti-TNF agents may be safer in patients infected with HCV than with HBV. This would appear to be supported by reports of the use of anti-TNF drugs in more than 110 HCV infected patients (summarized in Table 2).28, 31, 32, 43–60

Table 2.   Experience with anti-TNF therapy in patients with hepatitis C virus infection
IndicationNumber of subjectsHCV genotypeAnti-TNF drugTreatment durationChanges in HCV viral load (VL)TransaminasesConcomitant anti-viral therapyRef
  1. CD, Crohn’s disease; RA, rheumatoid arthritis; PsA, psoriatic arthritis; Ps, psoriasis; AS, ankylosing spondylitis; IFX, infliximab; ETA, etanercept; ADA, adalimumab.

CD1N/AIFX1 doseBecame negativeStableNo43
RA51, 3IFX/ETAmean 8/18 monthsNo significant changeStableNo44
CD21IFX1 doseNon-significant fallStableNo45
RA11INF-No significant changeStableNo31
PsA3N/AETA3–7 monthsFell in 2 patients, increased in 1. No significant changesStableIn 1 patient46
RA3N/AETA/ADA3–39 monthsNo significant changeStableNo32
AS21, 3IFX/ADA12–13 monthsNo change in 1 patient. In 1 VL became negativeStableNo47
Various91, 2ETA6 monthsNo significant change, no reactivation in patients with negative VL at startStableNo48
RA24N/AETA/IFXmean 9 months (1–34 months)No significant change. Variable VLs unrelated to anti-TNFStableNo49
RA1N/AETA>1 yearBecame negative with anti-viral therapyStableTreatment initiated after 3 m50
Ps/PsA1N/AETA12 monthsNo significant changeStableNo51
Ps/PsA21, 4ETA>1 yearNo significant changeStableNo52
Ps1N/AETA6 monthsNo significant changeStableNo53
Ps1N/AETA1 yearNo significant changeStableNo54
RA31N/AIFX/ADA/ETAmean 20 months (7–44 months)Increased >2log10 in 3 patients No change in othersIn 1 patient increased ALT, without HCV VL change. Unchanged in othersNo55
RA8N/AIFX/ADA/ETAUp to 16 monthsNo change in 7 patients, significant increase in 1 on IFXIncreased AST in patient with increased HCV VL. Stable in 7/8No27
PsA11ETA2 yearsNo significant changeStableNo56
Various6N/AETAmean 14 monthsNo significant changeStableNo57
CD11IFX1 yearBecame negativeStableYes58
RA22, 3ADA/ETA12–16 monthsNo significant changeStableNo59
Ps11ETA>6 monthsNo significant changeStableNo60
RA4N/AETA12–23 monthsBecame detectable in 2 patients with negative baseline HCV VL. In others no significant changeStableNo28

In untreated subjects, HCV viral loads exhibit marked variation. Similar variation is seen in longitudinal studies of the effects of anti-TNF drugs in such patients, although significant elevations in HCV viral load are rare.49 In a number of patients anti-TNF therapy has been associated with a fall in viral load, occasionally resulting in viral clearance. This finding is extended by the results of a trial using etanercept as adjuvant therapy alongside interferon/ribavirin for the treatment of HCV, which saw a doubling of the rate of viral clearance, without apparent adverse effects.61 The majority of experience in treating HCV positive patients with anti-TNF has involved etanercept; however, improvement in HCV viral loads has been similarly noted in patients treated with both infliximab and adalimumab.

Overall, experience to date suggests an acceptable short-term safety profile when anti-TNF agents are used in HCV infected patients. However, such reports largely infer safety from measurement of viral load and liver function parameters and it is important to consider that even in the presence of advanced hepatic fibrosis, transaminases may be normal.62 In addition, progression of HCV associated liver disease cannot be predicted from viral loads.63 Studies assessing the effects of anti-TNF therapy upon liver histology or non-invasive markers of fibrosis are lacking or inadequate to permit definitive conclusions. Similarly, where pre-treatment liver histology is reported, patients have almost exclusively had minimal degrees of liver damage, preventing assessment of the safety of anti-TNF drugs in those with more advanced liver disease. The potential long-term effect of anti-TNF therapy on the risk of progression to advanced stages of fibrosis or cirrhosis, or indeed the development of hepatocellular carcinoma associated with HCV (or HBV) awaits definition. Finally, it is of note that anti-TNF therapy has been reported to promote the development of mixed cryoglobulinaemia in HCV infected patients.64

Despite these caveats, anti-TNF therapy in patients with HCV infection appears to present fewer challenges than in HBV infection. On the basis of current evidence, the use of anti-viral drugs in such patients is only indicated when conventional indications are fulfilled, where treatment of HCV would be undertaken regardless of anti-TNF treatment. In the context of using anti-TNF drugs for IBD, it is important to note that interferon therapy for HCV has been associated with exacerbation of intestinal inflammation.65

Human immunodeficiency virus

The role of TNF-α in HIV infection is unsettled; but, as in HCV infection, it is thought to contribute to disease pathogenesis, and may promote viral replication.66 Anti-TNF agents may therefore be expected to be used with relative safety in HIV positive patients. However, concerns exist regarding the safety of blocking an additional component of immunity in patients already at risk of opportunistic infection. An initial report of the use of etanercept in an HIV positive patient with psoriasis and a suppressed CD4 count (<200/mm3) appeared to validate this concern, with treatment stopped because of recurrent polymicrobial infection.67 However, in a further series of six patients with CD4 counts <200/mm3 treated with two doses of infliximab, no adverse events were noted.68 More recent studies have generally examined the use of anti-TNF drugs in patients with higher CD4 counts (with or without highly active anti-retroviral treatment (HAART)) and confirm the relative safety of adalimumab, infliximab or etanercept for treatment durations of up to 4 years (Table 3).56, 69–77 Anti-TNF therapy appears to have minimal impact upon HIV viral load or CD4 count.56, 67–77

Table 3.   Experience with anti-TNF therapy in patients with HIV infection
IndicationAnti-TNF drugDuration of therapyConcomitant HAARTInitial CD4 count (cells/mL)Change in CD4 count Initial HIV viral load (copies/mL)Effect on viral loadDisease responsecomplicationsReference
  1. HAART, highly active antiretroviral therapy; CD, Crohn’s disease; RA, rheumatoid arthritis; AS, ankylosing spondylitis; SA, spondyloarthropathy; IFX, infliximab; ETA, etanercept; ADA, adalimumab.

PsAETA>6 monthsYes<200Stable4200StableExcellentPolymicrobial infection66
CDIFX3 dosesYes505Stable<200StableExcellentNone70
PsAIFX15 infusions (2 years)Yes425Stable<50Increased to 2818 c/mL after dose 14ExcellentIncreased HIV VL, HAART changed71
PsAIFX25 infusions (4 years)Yes16Increased to 233300 000Decreased to 5900 c/mLExcellentNone71
CDIFX4 doses (4 months)No>1000Fell to 700 with IFX induction then recoveredN/ADecreasedExcellentHypersensitivity reaction to IFX72
Ps/PsAETA2 yearsYes380Stable (>450)<50StableExcellentNone56
RAETA4 yearsYes631Stable<50StableExcellentNone73
ASETA2.5 monthsYes634Stable256StableTransientNone73
SAETA/IFX/ADA4 yearsYes779Stable425StablePartialNone73
SAETA11 monthsNo733Stable<40StableExcellentNone73
PsAETA/ADA/IFX34 monthsNo750Stable22 148Transient increase to 438 503 c/mLExcellentInfusion reaction with IFX73
PAETA1 yearNo974Stable<400StableExcellentNone73
PsAETA/IFX55 monthsYes268Stable<50StableExcellentFacial Abscess73
PsAETA/a/IFX1 yearYes446Stable<400StableExcellentHypersensitivity reaction to ETA73
RAIFX, ETA>3 monthsYes236Stable<50StableExcellentHypersensitivity reaction to IFX74
ReitersIFX6 monthsYesN/AStable<400StableExcellentNone75
PsAINF3 dosesYes193StableUndetectableStable (undetectable)ExcellentNone76
PsETA20 weekYes435Increased to 633/mL<75StableExcellentNone77

It should be considered that the number of HIV-positive patients treated with anti-TNF agents remains small, limiting full assessment of their safety, particularly in patients with low CD4 counts or high viral loads. Notably, a number of conditions for which prophylaxis may be prescribed to HIV-positive patients (e.g. TB or Pneumocystis jerovecii) are themselves associated with anti-TNF therapy in otherwise immunocompetent individuals.3, 4 The role of prophylaxis in HIV patients without suppressed CD4 counts receiving anti-TNF treatment is undefined. Similarly, although the majority of reported patients received concomitant HAART, whether the use of anti-TNF treatment should influence the initiation of such therapy remains unknown.

In selected HIV-positive patients with adequate pre-treatment CD4 cell counts, anti-TNF drugs therefore appear to be a realistic therapeutic option if indicated by the underlying disease; however, close clinical and virological monitoring is needed. This should happen in consultation with experienced HIV physicians.

Consideration two – latent herpes virus infections

  1. Top of page
  2. Summary
  3. Introduction
  4. Consideration one – Chronic viral infections
  5. Consideration two – latent herpes virus infections
  6. Consideration three – viruses associated with malignancy
  7. Other viruses
  8. Screening and vaccination
  9. Conclusions
  10. Acknowledgements
  11. References

Members of the herpes virus family are ubiquitous in most populations, with serological evidence of exposure to HSV-1, CMV, EBV and VZV in >90% of the adult population. Following initial exposure, latent viral infection is established in neural (HSV and VZV) or haematopoietic cells (EBV and CMV). Reactivation of herpes virus infection is problematic in transplant recipients and patients with HIV, leading to recommendations regarding the prevention and management of this complication.78, 79 TNF-α is critically involved in regulation of herpes virus replication and dissemination80 and experience with anti-TNF agents has demonstrated herpes virus reactivation to be relatively common in a number of cases resulting in serious adverse events.

Herpes simplex virus

Although a number of cases of herpes simplex reactivation in patients treated with infliximab or adalimumab have been reported to the US Food and Drug Administration, including cases of HSV oesophagitis,81 only two detailed reports have been published.82, 83 In the first, a patient treated with methotrexate developed disseminated cutaneous HSV-2, TB and pulmonary aspergillosis following infliximab treament.82 The second concerned a case of disseminated HSV-1 infection in a child treated with 3 doses of infliximab for juvenile arthritis.83 Both patients recovered with anti-viral therapy.

Varicella zoster virus

Varicella zoster reactivation is well documented in patients receiving anti-TNF therapy and appears to be particularly associated with the monoclonal antibodies infliximab and adalimumab.84, 85 Retrospective single-institution series have suggested an incidence of symptomatic zoster reactivation in up to 3% of rheumatoid arthritis (RA) patients receiving anti-TNF therapy; however, a majority of patients were receiving concomitant corticosteroid therapy, a well documented risk for zoster.84 Analysis of a large German registry of patients with RA treated with anti-TNF therapy, which included adjustment for concomitant corticosteroid use, showed a doubling of risk associated with infliximab or adalimumab, to an incidence of 11/1000 per year.85 Notably, beyond this modestly increased incidence, 18% of cases were multidermatomal and 13% required hospitalization, supporting suggestions that zoster occurring in the setting of anti-TNF therapy may be more severe.86, 87 Up to 5% of patients may develop repeated recurrences.85 However, anti-TNF therapy can generally be safely restarted in the majority of patients after temporary cessation of anti-TNF therapy till vesicles have resolved, and conventional anti-viral therapy (acyclovir or valaciclovir).84

Of greater concern may be reports of severe primary varicella infection (including a fatality) in patients receiving anti-TNF therapy.88–92 A number of these patients had given a history of childhood varicella infection which was not corroborated by serological testing at the time of presentation. Furthermore, in some cases, the rash was atypical, highlighting the need for a high index of suspicion of primary varicella in patients becoming unwell whilst on anti-TNF treatment. Vaccination is available to prevent varicella, but is a live vaccine, contraindicated in patients receiving anti-TNF. Consideration should be given to serological assessment of varicella status prior to the need for anti-TNF treatment, to allow immunization, if indicated. Patients should be advised of the risk of acquiring primary varicella zoster if there is no prior history of infection or immunization and possibly receive prophylactic treatment in case of contact.


Cytomegalovirus infection and reactivation, a common clinical problem in a range of immunocompromised patients, have been reported to cause hepatitis, retinitis and disseminated infection including the haemophagocytic syndrome in a small number of subjects treated with infliximab.93–97 All patients were successfully treated with ganciclovir.

Whilst TNF is involved in controlling CMV replication in vitro, the role of anti-TNF therapy in these cases remains speculative, with the majority of patients receiving multiple concomitant immunosuppressant medications. Prospective studies in Crohn’s disease or RA patients have shown no evidence of significant CMV reactivation (measured by CMV-PCR) following infliximab infusion.98, 99 Similarly, infliximab treatment does not appear to affect colonic tissue CMV viral load.100

Consideration three – viruses associated with malignancy

  1. Top of page
  2. Summary
  3. Introduction
  4. Consideration one – Chronic viral infections
  5. Consideration two – latent herpes virus infections
  6. Consideration three – viruses associated with malignancy
  7. Other viruses
  8. Screening and vaccination
  9. Conclusions
  10. Acknowledgements
  11. References

The third consideration regarding the safety of anti-TNF therapy and viral infections is their effect upon viruses linked with malignancy. Whilst the risk of HBV, HCV and hepatocellular carcinoma has been discussed, other relevant viruses include EBV, associated with lymphoproliferative disease in the immunocompromised, and HPV, which underlies the majority of cases of cervical malignancy. A significantly increased risk of both conditions is seen with other forms of immunosuppression.101, 102

Epstein-Barr virus

Multiple studies have addressed the risk of lymphoma associated with anti-TNF treatment and estimates vary widely.103, 104 Cases of lymphoproliferative disease have been reported in patients treated with anti-TNF therapy, often after a relatively short interval from initial exposure, and although EBV status was only reported in a minority, their phenotype is typical of immunosuppression-associated disease.105, 106 Assessment of the direct role of anti-TNF agents in this situation is difficult as patients generally have previous or current exposure to other immunosuppressants, themselves linked to an increased risk of lymphoma. In some patients developing lymphoproliferative disease whilst treated with anti-TNF, cessation of therapy has resulted in regression of the lymphoma.105, 107, 108

In transplant patients, lymphoproliferative disease risk can be related to EBV viral load, with high loads conferring greater risk. In adults, infliximab causes transient elevations in EBV viral load in a minority of patients; however, levels do not reach those considered high risk for lymphoproliferative disease.98, 99, 109, 110 In a similar paediatric study, transient increases in EBV levels were seen in 28% of patients, although viral loads increased to a greater degree than in adults.111 Whilst inhibition of TNF signalling appears capable, to some extent, of interfering with control of chronic EBV infection, the long-term significance of transient reactivations in this setting remains to be determined.

Human papilloma virus

The incidence of HPV carriage and associated cervical and anogenital dysplasia and malignancy is increased in immunosuppressed post-transplant patients and those infected with HIV.102 IBD patients receiving immunomodulators including infliximab have been reported to have increased rates of pap smear abnormalities,112, 113 although this finding has not been universally confirmed.114 Specific effects of anti-TNF therapy on HPV-associated diseases remain unknown, with very few reported cases to suggest a significantly increased risk exists. Reports of florid cases of anogenital condylomata developing after treatment with etanercept or infliximab raise the possibility that such lesions may be more severe following anti-TNF treatment.115, 116

Other viruses

  1. Top of page
  2. Summary
  3. Introduction
  4. Consideration one – Chronic viral infections
  5. Consideration two – latent herpes virus infections
  6. Consideration three – viruses associated with malignancy
  7. Other viruses
  8. Screening and vaccination
  9. Conclusions
  10. Acknowledgements
  11. References

There is little information regarding the safety or otherwise of anti-TNF therapy with regard to other viruses linked to cancer risk in immunosuppressed individuals, such as HHV-8 and HTLV. A single case report records the development of Kaposi’s sarcoma, associated with HHV-8, in a patient with rheumatoid arthritis who had received nine infusions of infliximab in addition to methotrexate and leflunomide.117 However, in a prospective study of viral loads following infliximab infusion in sixty patients, no HHV-8 reactivation was detected at any point.98, 99

Screening and vaccination

  1. Top of page
  2. Summary
  3. Introduction
  4. Consideration one – Chronic viral infections
  5. Consideration two – latent herpes virus infections
  6. Consideration three – viruses associated with malignancy
  7. Other viruses
  8. Screening and vaccination
  9. Conclusions
  10. Acknowledgements
  11. References

Although a number of detailed guidelines regarding screening, vaccination, prophylaxis and treatment of viral infections in immunocompromised patients have been published, including patients with IBD, few specifically address biological therapy.33–36, 118, 119

The appropriate serological tests to assess viral status in patients commencing anti-TNF therapy are poorly defined. Although assessment of HBV status is widely supported, the most clinically relevant and cost effective approach remains unknown and probably varies according to both population rates and individual risk factors, as discussed above. Similarly, HCV or HIV testing may be justified in high-risk patients, but the benefits of pre-treatment testing in patients at low-to-average risk are unproven, particularly in view of the relative safety of anti-TNF therapy in this situation. The recent European Crohn’s and Colitis Organisation (ECCO) consensus statement advocates universal testing (HBsAg, anti-HBs and anti-HBc) and HBV vaccination as appropriate in all patients with IBD, but failed to achieve a consensus regarding the need for HCV testing.33 In contrast, a consensus statement regarding pre-anti-TNF testing in rheumatology patients recommends screening for HBV and HCV in all patients without defining the serological strategy.36 The appropriateness of testing for HIV in this situation is less certain, with the ECCO statement concluding that HIV testing should be considered in all patients with IBD (not just those contemplating anti-TNF therapy),33 whilst other consensus groups have failed to make any recommendations.35, 36 It is clearer that there is no role for determining or monitoring serological status with respect to common herpes viruses such as EBV, HSV or CMV, reflected in the ECCO consensus.

A specific difficulty relating to testing and vaccination in patients starting anti-TNF arises from the current pattern of use of these drugs, with patients often already on immunomodulators or corticosteroids. Live vaccination (e.g. varicella, herpes zoster, BCG) is relatively contraindicated in these patients, leading to suggestions that initial serological testing and vaccination should occur at the initial diagnosis of IBD.33, 34, 119 However, there is no evidence that vaccination reduces the rate or severity of infection in patients on conventional immunomodulator or biological therapy. Further studies are needed to determine the clinical efficacy and cost-effectiveness of this approach in patient groups with variable levels of risk.

Which vaccines if any beyond the usual childhood and adult schedules should be offered to patients receiving anti-TNF drugs is debated. ECCO guidelines advocate universal hepatitis B vaccination in IBD patients, although there is no strong evidence to support this strategy.33, 34, 119 Cross-sectional studies of vaccination in IBD have shown that many patients are unprotected against preventable viral diseases.120 When administered, vaccine responses may be reduced in patients treated with anti-TNF drugs, but are generally adequate.121

Although recommendations have been made for more frequent cervical screening in some high-risk groups, at present, there is insufficient evidence to support this requirement in patients receiving anti-TNF therapy. It is likely that immunization against HPV should be advocated, once this is more widely available.


  1. Top of page
  2. Summary
  3. Introduction
  4. Consideration one – Chronic viral infections
  5. Consideration two – latent herpes virus infections
  6. Consideration three – viruses associated with malignancy
  7. Other viruses
  8. Screening and vaccination
  9. Conclusions
  10. Acknowledgements
  11. References

In the assessment of safety of anti-TNF drugs, the risks of chronic viral infection have received limited attention, despite numerous reports of serious infectious complications with such pathogens. The uncontrolled nature of such reports mandates caution in ascribing risk directly to anti-TNF therapy, with the majority of patients receiving concomitant immunomodulators or corticosteroids, which may significantly increase the risk of opportunistic infection compared to anti-TNF monotherapy.122 However, a specific risk associated with the use of anti-TNF does appear to exist for patients with HBV infection, with reactivation common unless anti-viral prophylaxis is used. Similarly, reactivation of herpes zoster may be more common and severe in patients treated with anti-TNF therapy.

Although TNF undoubtedly plays a role in viral control, longitudinal studies of viral reactivation covering a large number of latent viruses are generally reassuring and anti-TNF drugs do not appear to impact negatively upon the short-term course of HCV or HIV infection in appropriately selected patients. Finally, viral infections including primary varicella infection may present with atypical features in patients on anti-TNF and physicians should actively consider a viral cause when such patients become unwell.


  1. Top of page
  2. Summary
  3. Introduction
  4. Consideration one – Chronic viral infections
  5. Consideration two – latent herpes virus infections
  6. Consideration three – viruses associated with malignancy
  7. Other viruses
  8. Screening and vaccination
  9. Conclusions
  10. Acknowledgements
  11. References

Declaration of personal interests: Dr Panaccione has served as a speaker for AstraZeneca, Abbott, Byk Solvay, Axcan, Jansen, Schering-Plough, Novartis, Centocor, Elan Pharmaceuticals and Prometheus. He has served as a consultant and an advisory board member for AstraZeneca, Ferring, Jansen, Schering-Plough and Novartis. He has received educational support from Axcan and research funding from Centocor, Millenium Pharmaceuticals and Elan Pharmaceuticals. Dr Ghosh has received research support from Centocor. He has served as a speaker at educational conferences for Abbott, Centocor, Procter and Gamble, Schering-Plough, UCB and Pfizer. He has served as an advisory board member for Shire, Abbott, Centocor, Schering-Plough, and Procter and Gamble. All other authors: None. Declaration of funding interests: None.


  1. Top of page
  2. Summary
  3. Introduction
  4. Consideration one – Chronic viral infections
  5. Consideration two – latent herpes virus infections
  6. Consideration three – viruses associated with malignancy
  7. Other viruses
  8. Screening and vaccination
  9. Conclusions
  10. Acknowledgements
  11. References
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