Prevention Strategies to Minimize the Infection Risk Associated with Biologic and Targeted Immunomodulators
Received 1 October 2019
Accepted for publication 29 January 2020
Published 18 February 2020 Volume 2020:13 Pages 513—532
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Eric Nulens
Elaheh Kordzadeh-Kermani,1 Hossein Khalili,1 Iman Karimzadeh,2 Mohammadreza Salehi3
1Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; 3Department of Infectious Diseases, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Correspondence: Hossein Khalili
Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, P.o. Box 14155/6451, Tehran, Iran
Tel/Fax +98 216 695 4709
Email [email protected]
Abstract: The introduction of biologic and targeted immunomodulators is a significant breakthrough in the therapeutic area of various fields of medicine. The occurrence of serious infections, a complication of secondary immunosuppression associated with these agents, leads to increased morbidity and mortality. Implementing preventive strategies could minimize infection-related complications and improve therapeutic outcomes. The purpose of this review is to focus on current evident approaches regarding screening, monitoring, preventing (immunization and chemoprophylaxis), and management of infections in patients who are candidates for about 70 biologic and targeted immunomodulators. Recommendations are based on relevant guidelines, especially the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document series published in 2018.
Keywords: biologic immunomodulators, targeted immunomodulators, immunization, chemoprophylaxis
Biologic immunomodulators are biosimilar medications synthesized by living organisms structurally related to antibodies, interleukins, and receptors that specifically target oncogenic cells or immune system pathways.1 Targeted immunomodulators such as BCR-ABL tyrosine kinase inhibitors, phosphatidylinositol-3-kinase inhibitor, bruton tyrosine kinase inhibitors, and mammalian target of rapamycin (mTOR) inhibitors are small molecules which affect intracellular signaling cascades that eventually modulate protein expression.2
The availability of biologic and targeted immunomodulators has revolutionized pharmacotherapy of diseases in diverse aspects of medicine, including onco-hematology, rheumatology, nephrology, transplantation, neurology, pulmonology, and dermatology. Despite their therapeutic benefit, concerns regarding the potential risk of infections have been a challenge for using these agents in clinical practice.3 Severe infection is a significant cause of morbidity and mortality in patients treated with immunosuppressants. Most patients on immunomodulator drugs require long term therapies; however, a significant number of these patients do not receive appropriate preventive care regarding infections.4
Biologic and targeted immunomodulators are categorized into several pharmacologic classes. Unlike traditional immunosuppressants, immune suppression associated with these agents is specific to certain signals in the immune system, occasionally causing profound immune suppression mimicking primary immunodeficiency disorders.5–7 Depending on their mechanism of action and impact on the immune system, the infection risk associated with these therapies varies among pharmacologic classes; some affect intracellular signaling pathways, some bind to receptors of cellular immunity while some others inhibit the actions of cytokines (Table 1).
Table 1 Biologic and Targeted Immunomodulators Classification and Their Impacts on the Immune System
The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts Consensus have reviewed articles and made recommendations to instruct clinicians on the strategies to prevent and manage infections associated with biologic and targeted immunomodulators.8–13 In this review, we aim to focus on evidence-based strategies according to the latest guidelines to provide practitioners guidance regarding screening, chemoprophylaxis, vaccination, and management of infections in patients on biologic and targeted immunomodulators.
We conducted a literature search in databases including Scopus, Medline, Embase, Cochrane Database Systematic Reviews and Google Scholar from January 2007 to August 2019 using the search terms related to each of the agents along with “infection”, “vaccination”, “screening”, “prophylaxis”, “monitoring”, “immunization”, “immune response”, “treatment”, and “management”. Polyclonal antibodies (e.g., anti-thymocyte globulin, rozrolimupab), and monoclonal antibodies that lack prominent immunosuppressive effects (e.g., trastuzumab) were beyond the scope of our review and are not considered here. We included articles and guidelines from the latest updates of ESCMID, The Infectious Diseases Society of America (IDSA), The European League Against Rheumatism (EULAR), National Comprehensive Cancer Network (NCCN), American College of Rheumatology (ACR), American College of Gastroenterology (ACG), The American Association for the Study of Liver Diseases (AASLD), The Canadian Dermatology Association (CDA), European Conference on Infections in Leukaemia (ECIL), The Advisory Committee on Immunization Practices (ACIP), The American Society of Transplantation (AST), European Conference on Infections in Leukaemia (ECIL), The German Society of Hematology and Medical Oncology and the International Consensus Guidelines on the Management of Cytomegalovirus.8–29 We also included recommendations from Uptodate online, the relevant review articles, expert opinions, and European Medicines Agency (EMA) drug labels, especially on subjects that the guidelines do not offer an opinion. The recommendations regarding screening for infections, immunization, prevention, and monitoring of infections in patients candidates for biologic and targeted immunomodulators were finally categorized by the class of immunosuppressive agents.
Of the relevant articles we found, data were obtained from 31 guidelines as well as consensus recommendations and 17 review papers. Comprehensive recommendations were not found on subjects such as prophylactic measures for prevention of pneumocystis pneumonia in biologic therapy of rheumatologic diseases, screening of infections for patients undergoing basiliximab induction, preventive measures to prevent infections associated with abatacept, immunization in patients undergoing treatment with new generations of anti-CD20 monoclonal antibodies and late onset neutropenia associated with anti-CD20 monoclonal antibodies. Such data were obtained from expert opinions, review articles, the EMA drug labels and clinical trials. The recommendations regarding screening, prophylaxis, monitoring, and immunization of infections associated with biologic and targeted immunomodulators are summarized in Tables 2–5.
Table 2 Evidence and Recommendations on Screening of Infections in Patients Candidates for Biologic and Targeted Immunomodulatory Therapies
Table 3 Evidence and Recommendations on the Prevention and Management of Infections in Patients Candidates for Biologic and Targeted Immunomodulatory Therapies
Table 4 Evidence and Recommendations on Monitoring of Patients on Biologic and Targeted Immunomodulatory Therapies
Table 5 Evidence and Recommendations on Immunization of Patients on Biologic and Targeted Immunomodulatory Therapies
The growing number of approved biologic and targeted immunomodulators on the market and their various approved and off-label indications explain the necessity to guide health care professionals in the prevention and management of infections and define the relative risk of particular infections associated with these agents. This study reviewed and summarized prevention strategies, including screening, monitoring, immunization, prophylaxis, and management of infections associated with about 70 biologic and targeted therapies based on relevant guidelines, especially ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus document series published in 2018.8–13
The Risk of Hepatitis B Virus (HBV) Reactivation
Extensive studies have shown that the risk of HBV reactivation is highest with anti-CD20 targeted agents including rituximab, ofatumumab, obinutuzumab,27,30 and probably ocrelizumab.31 These agents are associated with a significant risk of HBV reactivation in both HBs Ag-positive and HBs Ag-negative/anti-HBc-positive patients. Studies have shown that tenofovir and entecavir are significantly more effective than lamivudine in preventing HBV reactivation in patients on anti-CD20 monoclonal antibodies.32,33 Therefore, ESCMID recommends either tenofovir or entecavir-based regimens for antiviral therapy in both active and occult hepatitis B patients who are candidates for anti-CD20 targeted agents.10
HBs Ag-positive patients are at high risk of HBV reactivation with alemtuzumab. Also, HBs Ag-negative/anti-HBc-positive patients are moderate to high risk for reactivation of hepatitis B; Therefore, ESCMID recommends that all patients with active hepatitis B should receive antiviral prophylaxis. Individuals with occult infection could either receive prophylaxis or be monitored for reactivation of HBV based on the indication of alemtuzumab and concomitant use of corticosteroids in certain clinical conditions (e.g., transplantation, multiple sclerosis)10,30
Anti-TNF monoclonal antibodies are considered as moderate to high risk for reactivation of hepatitis B in active infection and moderate risk for occult infection. The risk of HBV reactivation in HBsAg-positive patients is moderate with etanercept, and HBsAg-negative/anti-HBc-positive patients are probably at low risk for seroconversion with etanercept. Accordingly, ESCMID recommends antiviral prophylaxis with either tenofovir or entecavir only for HBsAg-positive patients under TNF inhibitors.13
Tocilizumab, abatacept, ustekinumab, mogamulizumab, and BCR-ABL tyrosine kinase inhibitors are associated with a moderate risk of HBV reactivation.30 Data on the risk of HBV reactivation with tofacitinib is limited; In a study, reactivation of hepatitis B occurred in 2 of 4 HBs Ag positive patients.34 Reactivation of HBV did not occur in any of the HBs Ag-negative/anti-HBc-positive patients. Few case reports have demonstrated fatal HBV reactivation in HBs Ag-positive patients receiving 5–10 mg/day everolimus for renal cell carcinoma and breast cancer.35,36 Therefore, ESCMID recommends antiviral prophylaxis only in HBs Ag-positive patients treated with mTOR inhibitors, janus kinase (JAK) inhibitors, BCR-ABL tyrosine kinase inhibitors, IL-6 targeted immunomodulators, ustekinumab, and mogamulizumab. Pre-emptive antiviral prophylaxis is reasonable in occult HBV infections during treatment with these agents.8–13
The Risk of Pneumocystis Carinii Pneumonia (PCP)
The greatest risk of PCP infection is attributed to alemtuzumab, and universal prophylaxis is required in solid organ transplant recipients and patients with hematologic diseases who have received this agent. Limited data suggest the risk of PCP with bortezomib in multiple myeloma patients treated with high dose corticosteroids; however, the overall risk is low.37,38 The incidence of PCP with TNF inhibitors, tocilizumab, and rituximab is also low; however, several studies have demonstrated that the risk of infection is increased in particular conditions including age >65 years, concurrent long-term corticosteroid use (e.g., ≥ 15 mg/day prednisolone for more than four weeks), and co-existence of either pulmonary diseases or underlying granulomatosis with polyangiitis.38,39 Comparative studies have shown a greater risk with TNF inhibitors, particularly infliximab than tocilizumab.40 Eighteen cases of ibrutinib associated PCP have been published; in most of them, the patients were neutropenic.41 Currently, trimethoprim/sulfamethoxazole is the drug of choice for the primary prophylaxis of PCP in different clinical conditions such as hematological malignancies and stem cell transplantation. Second-line choices for PCP prophylaxis in the case of trimethoprim/sulfamethoxazole intolerance include pentamidine inhalation, oral dapsone, and oral atovaquone.26 These recommendations regarding PCP prophylaxis can be extrapolated to the setting of biologic and targeted immunomodulators.
The Risk of Progressive Multifocal Leukoencephalopathy (PML)
The incidence of PML appears to be greatest with monoclonal antibodies targeting α4-integrin. PML associated with efalizumab and natalizumab has been reported 1 in 300 patients and 1 in 1000 patients, respectively.42,43 In contrast, to date, no case of PML has been reported with vedolizumab.44 Fifteen case reports of PML have been reported in patients treated with fingolimod. Treatment duration, age, and JC virus (JCV) antibody titer could be associated with the occurrence of fingolimod-induced PML.45,46 Cases of PML have been reported with anti-CD20 monoclonal antibodies (15 cases with rituximab and 5 cases with ocrelizumab); however, most of these cases could be attributed to previous natalizumab or fingolimod therapy. Therefore, it is reasonable to monitor MRI for signs and symptoms of PML (e.g., visual disturbance, progressive paresis, cognitive impairment) when switching from either natalizumab or fingolimod to anti-CD20 therapies.47 Currently, there is no standard and specific therapy for PML. The offending agent should be discontinued permanently. Plasma exchange (e.g., 3–5 exchanges over 5 to 8 days) has been used for the reversal of natalizumab-associated PML. However, this modality often leads to immune reconstitution inflammatory syndrome (IRIS) phenomenon, which is a neurological deterioration associated with brain swelling and risk of herniation.48
The Risk of Latent Tuberculosis
Rheumatoid arthritis itself is associated with increased risk of tuberculosis reactivation up to 3.17 times. In patients with rheumatoid arthritis treated with TNF inhibitors, the risk is increased up to 17 fold than the general population.49 When compared with etanercept, other anti-TNF monoclonal antibodies are associated with a statistically significant higher risk of tuberculosis reactivation. Ai et al. demonstrated that the risk of tuberculosis reactivation with adalimumab and infliximab is 3.88 and 2.78 times more than etanercept, respectively. The effect of anti-TNF monoclonal antibodies on inducing T-cell apoptosis, complement-dependent cytotoxicity, and pharmacokinetic properties could explain the higher potential of adalimumab and infliximab over etanercept in reactivating latent tuberculosis.19,50 Statistical difference between infliximab and adalimumab has not been found; however, the risk of latent tuberculosis reactivation with infliximab was 1.28 times more than adalimumab.49 Another meta-analysis showed that the incidence rate of tuberculosis was highest with infliximab and certolizumab, followed by adalimumab, golimumab, tofacitinib, tocilizumab, etanercept, abatacept, and rituximab (44/9277; 13/4396; 30/12757; 4/3209; 11/6507; 9/12905; 3/7164; 2/7743; and 2/11962, respectively).51 The incidence of tuberculosis reactivation was similar in adalimumab- and golimumab-treated patients.51 It is noteworthy that the results could be affected by several confounding factors such as including patients from tuberculosis endemic areas in most of the certolizumab trials. The incidence rate of tuberculosis was 5–10 times more than the general population in North America and Western Europe (an incidence rate of 5–20 times were reported for anti-TNF therapies in these areas). A cohort study demonstrated that the risk of tuberculosis is higher with infliximab- and anakinra-treated groups versus etanercept recipients (adjusted risk ratio: 1.6, 1.3, and 1.2, respectively).52 Results of clinical trials have reported 10 cases of tuberculosis in 2588 ruxolitinib-treated patients.53 Limited reports of tuberculosis following ustekinumab therapy exist; however, no case of latent tuberculosis reactivation has been reported with secukinumab so far.54
The incidence of tuberculosis in kidney transplant recipients and multiple sclerosis patients treated with alemtuzumab was found to be 0.67% and 0.3%, respectively;55 however, in a small study conducted in a high endemic area, the incidence of tuberculosis in patients with hematologic malignancies and autoimmune cytopenias was 31–45%.56 Few cases of tuberculosis reactivation have been reported in metastatic renal cell carcinoma patients receiving mTOR inhibitors,57,58 and in one case report in lung transplantation, reactivation of latent tuberculosis has been attributed to mTOR inhibitors.59
In summary, available data indicate that the risk of tuberculosis is greatest with monoclonal antibodies against TNF and alemtuzumab (because of insufficient data and diversities in sample size, we could not compare the risk) followed by JAK inhibitors and IL-1 targeted agents. Limited cases of reactivation of tuberculosis exist on mTOR inhibitors used in chemotherapy. The risk of tuberculosis reactivation with rituximab and tocilizumab was not more than the general population and appeared to be negligible.54 Accordingly, ESCMID recommends anti-TB prophylaxis in patients who are candidates to receive TNF inhibitors, alemtuzumab, JAK inhibitors, and mTOR inhibitors (used in chemotherapy regimens). Isoniazid for nine months, rifampin for four months, or the combination of isoniazid and rifampin for three months could be considered for the treatment of latent tuberculosis in the setting of biologic and targeted immunomodulators.
The Risk of Herpes Simplex Virus (HSV) and Varicella-Zoster Virus (VZV) Infections
Compared to the bortezomib-free regimens, the incidence of herpes zoster infection increased up to two-fold when bortezomib was added to the chemotherapeutic regimen of multiple myeloma patients (11% and 22.3%, respectively).60 Tofacitinib-treated patients experienced HSV infection with an incidence rate of 4.4 per 100 patient-years and up to 7.7 per 100 patient-years in the Asian population versus 1.5 per 100 patient-years in rheumatoid arthritis patients receiving placebo.42,61 The incidence rates of HSV infection in patients with rheumatoid arthritis receiving TNF inhibitors and rituximab were 1.6 (golimumab) to 2.4 (certolizumab) and 2.2 per 100 patient-years, respectively. Incidence rates and hazard ratios were not statistically significant among TNF inhibitors and rituximab; glucocorticoids were associated with increased risk of infection.62
The graph represented by Arvin et al. in 2015 demonstrates comparative incidence of VZV infections associated with disease-modifying therapy of multiple sclerosis; the incidence of VZV infection is greatest with alemtuzumab 12 mg/day (7–45 per 1000 patient-year) followed by fingolimod 0.5 mg/day (6–17.5 per 1000 patient-year), natalizumab (8–16 per 1000 patient-year), and rituximab (8–13 per 1000 patient-year).63
ESCMID recommends HSV/VZV prophylaxis for proteasome inhibitors- and alemtuzumab-treated patients (for all their indications) and also considers HSV prophylaxis in fingolimod-treated patients that concurrently receive corticosteroid pulse therapy. Acyclovir/Valacyclovir could be taken into account as prophylaxis of HSV/VZV in susceptible patients discussed above.11
The Risk of Cytomegalovirus (CMV) Infection
Alemtuzumab is associated with a remarkable risk of CMV infection, particularly in hematologic malignancies and solid organ transplant recipients, and CMV prophylaxis is recommended in these populations. However, the risk of CMV infection in patients with multiple sclerosis treated with alemtuzumab is less than 1 per 100 patient-years.10 Therefore, ESCMID does not recommend CMV prophylaxis for multiple sclerosis patients on alemtuzumab.10,64 Dasatinib has been associated with CMV reactivation, particularly in post-HSCT patients (adjusted hazard ratio, 7.65; 95% confidence interval, 1.84–31.7);9,65 and ESCMID recommends monitoring of CMV infection in these individuals. Besides dasatinib, regular monitoring of CMV PCR and signs as well as symptoms of CMV disease is also recommended for patients receiving mogamulizumab.12 Finally, the third international consensus on CMV in solid organ transplant weakly recommends CMV prophylaxis for donor/recipient seropositive patients who were candidates for either bortezomib or eculizumab therapy as treatment of solid organ transplant rejection or a part of desensitization protocol.15 Antiviral options for CMV prophylaxis include intravenous ganciclovir, oral valganciclovir, and high doses of oral valacyclovir.15
Immunization in Patients on Biologic and Targeted Immunomodulators
According to IDSA guidelines published in 2013, live vaccines, including measles, mumps, and rubella (MMR), live-attenuated influenza vaccine (LAIV), Bacillus Calmette–Guérin (BCG) vaccine, oral polio vaccine (OPV), live-attenuated HSV, and yellow fever should be avoided ≤ 2–4 weeks before initiation and during treatment with immunosuppressants.16 The international guidelines recommend inactivated influenza, pneumococcal, toxoid tetanus, hepatitis A vaccine, hepatitis B, and human papillomavirus vaccines in patients with autoimmune rheumatologic diseases including those under biologic and targeted immunomodulators.18,20,21
The live-attenuated HSV vaccine should be preferably administered ≥ 4 weeks prior to the initiation of immunosuppressive agents for high risk individuals including those older than 50 years. ACIP does not make any recommendations on the administration of recombinant Zoster vaccine (Shingrix®) in highly-immunocompromised patients due to lack of data on efficacy and safety in this population;24,25 however, recombinant zoster vaccine, has demonstrated greater efficacy than live-attenuated HSV vaccine (Zostavax®), decreases the risk of HZ in patients older than 70 years and also appears an interesting alternative to live-attenuated HSV vaccine in immunocompromised patients.
Humoral response to vaccine is generally not impaired in patients on TNF alpha inhibitors (except infliximab),66 anakinra,67 canakinumab,68 abatacept,69 belimumab,70 natalizumab,71 ustekinumab,72 IL-17-targeted agents,73 tocilizumab,74 probably proteasome inhibitors75 and alemtuzumab (in doses approved for multiple sclerosis).76 Meanwhile, immune response to vaccines is significantly decreased in patients receiving rituximab66 and alemtuzumab (used in hematologic malignancies).77 No data exist for immunization in patients under CD19 and CD22 targeted therapies; based on their impact on humoral immunity vaccine response is probably diminished during treatment with these agents. Immune response to vaccine may be attenuated in patients on efalizumab,78 BCR-ABL tyrosine kinase inhibitors,79 tofacitinib80 and ibrutinib.81 Patients treated with vedolizumab have shown reduced response to oral vaccines but not injectable ones.42 Interestingly, mTOR inhibitors have been shown to enhance immune response to certain vaccines.82
Biologic and targeted immunomodulators are associated with increased risk of particular bacterial, fungal, and viral infections based on their impact on the immune system. In order to minimize the potential infection risk, screening, immunization, monitoring, and prophylactic protocols should be implemented. Limited information exists on the risk of infections associated with the recently developed biologic agents including CD19, CD22; CD30; CD38; CD319; CD40; CCR4–targeted agents; second and third generation anti-CD20 monoclonal antibodies, second and third generations of BCR-ABL tyrosine kinase inhibitors; and their impact on patient response to immunization. Consequently, consensus guidelines do not make comprehensive recommendations regarding these agents. Further clinical research will guide us regarding the necessary safety measures to minimize the infection risk of these agents.
The authors report no conflicts of interest in this work.
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