Minimizing infection risk with biologic therapy
The development of biologics has revolutionized the treatment of many neoplastic and inflammatory conditions over the past 30 years, leading to enormous growth in the sector; seven of the top ten best-selling medicines globally now are biologics . Although more selective in their targets and actions compared with standard immunosuppressive agents, many biologic agents can still lead to sufficient immunosuppression to allow standard and opportunistic infections a greater chance to cause disease in the host.
The decision to commence treatment with any immunosuppressive agent is the main opportunity for prescribers and patients to have a discussion around the potential benefits and risks of therapy. Assessment of the risks for future infections and how these may be avoided can be obtained through a careful history of previous vaccinations and potential future exposures, with consideration given to screening for latent tuberculosis infection (LTBI) and serologic tests for immunity to measles, mumps, and rubella (MMR), varicella and viral hepatitis.
Most biologic agents are sufficiently immunosuppressant that live vaccines should be avoided. Table 1 lists some commonly used live vaccines; a full list is available online . Therefore, prior to instigating therapy a unique opportunity exists to vaccinate against MMR and varicella if the patient is non-immune, and up until very recently this has been the only time to consider zoster vaccination to reduce the risk for future episodes of herpes zoster (shingles). We would recommend waiting at least 1 month after cessation of immune suppression before considering live vaccinations, and at least 6 months after stopping rituximab . In addition, immunosuppressive agents should not be started or recommenced until at least 4 weeks after live vaccines have been given.
While vaccination is safe, the response to inactive/recombinant vaccines may be blunted in those on biologic agents. There are various data on this effect, and other non-biologic agents such as methotrexate may have a greater effect on vaccine efficacy . Nonetheless, the ‘pre-biologic’ time is an opportunity to maximize the potential immune response to vaccines against pneumococcus, Neisseria meningitidis and hepatitis B virus. Even though the immune response may be lessened after commencing biologic therapy, the ongoing increased risk for infection means it is essential that prescribers counsel and advocate non-live vaccines for patients on an ongoing basis, particularly those for influenza virus and pneumococcus.
|Live attenuated||Inactivated/ recombinant/ subunit|
Pneumococcal (conjugate or polysaccharide
Table 1. Summary of commonly used vaccines. Information from . BCG, Bacillus Calmette-Guérin; DTaP, Diphtheria, tetanus, pertussis; Hib, Haemophilus influenzae b; HPV, Human papilloma virus; MMR, Measles, mumps, rubella
A major increase in the risk for tuberculosis (TB) reactivation was one of the first side effects recognized with biologic therapies . As approximately one third of the world’s population is infected with latent TB it is inherent on providers to screen for LTBI prior to instigating treatment, particularly with agents that modulate the tumor necrosis factor (TNF)-alpha pathway. Tuberculin skin testing (TST) or interferon gamma release assays (IGRAs) are both acceptable mechanisms for screening for LTBI. TST has the advantage of being cheaper and easier to administer, while IGRAs are more standardized, require only a single blood draw, and may be more specific, especially in the setting of previous BCG vaccination. However, there are concerns about false negatives with both tests, and a significant proportion of individuals test positive to one test yet not to another.Therefore, many have argued that in patients with a history of significant TB exposure, or those with immunosuppression at the time of screening, both a TST and IGRA should be performed .
If LTBI is confirmed, active TB should be ruled out and LTBI treatment commenced as soon as possible so as not to delay biologic therapy. While the standard LTBI treatment regimen is 9 months of isoniazid (with pyridoxine), there are other shorter regimens available such as rifampicin monotherapy, or isoniazid with rifampicin or rifapentine. Although these regimens are shorter, they have a higher risk of adverse reactions and drug–drug interactions, and have not been studied as extensively in these populations. It is safe to start biologic therapy after completing a month of LTBI treatment , although most would feel it is safe to proceed as soon as the patient is established on LTBI therapy .
Chronic hepatitis B virus (HBV) infection is common globally, especially in some areas of sub-Saharan Africa and southeast Asia. Patients may have asymptomatic untreated (often inactive) HBV. In addition there is an even larger group of patients with previous HBV infection. As HBV is a DNA virus which remains in hepatocytes even after clearance, there is a risk of reactivation with immunosuppression. We would recommend screening for HBV with hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) in all patients prior to starting biologics, in particular rituximab or TNF-alpha inhibitors . For those with untreated hepatitis B virus infection (HBsAg positive) we would start treatment with entecavir or tenofovir to prevent viral escape with immunosuppression. Lamivudine should be avoided due to the risk of resistance . For those with previously cleared hepatitis B virus infection (HBsAg negative but anti-HBc positive), close regular monitoring of liver function should be undertaken. While there are reports of high rates of HBV reactivation in anti-HBc positive individuals with rituximab, these have often been in conjunction with other systemic immunosuppression such as cytotoxic chemotherapy .
Reactivation of varicella zoster virus as shingles is common even without immunosuppression. There is debate as to whether biologic agents significantly increase the risk for shingles, particularly when compared with other immunosuppressive agents commonly used to treat these conditions . Up until recently, the live attenuated zoster vaccine was the only available vaccine to prevent shingles, and vaccination shortly before institution of biologic agents has been shown to be safe and effective in generating an immune response . The recent availability of a highly effective zoster subunit vaccine  may change this – however, while this is not a live vaccine its safety and efficacy in those receiving biologic agents has yet to be determined.
There have been case reports of other significant infections in those on biologics. Listeria infection, Pneumocystis jirovecii pneumonia (PCP), Legionella and histoplasmosis (among others) have all been reported to be either more common or more severe in those receiving biologic agents, with most cases reported in those receiving additional immunosuppressant agents such as high-dose glucocorticoids or methotrexate . There may be a role for consideration of trimethoprim–sulfamethoxazole (TMP/SMX) prophylaxis for patients with prolonged combination immunosuppression to prevent PCP and other bacterial infections. Patients should be counselled on risk of food-borne illnesses such as Listeria and advised on safe food preparation.
Individuals receiving biologic therapies should be advised on travel risks. The Centers for Disease Control and Prevention (CDC) maintains an excellent online database of destinations with specific risks and recommendations for each area . It is recommended that patients avoid mosquito bites with long clothing, nets, and the use of DEET and other insect repellants, as well as taking malaria prophylaxis where required. Patients should be given advice on prevention of food- and water-borne infections. Many countries require proof of yellow fever vaccination to enter . Immunosuppression (including most biologics) is a contraindication to the live yellow fever virus vaccine. Patients can stop biologic and other immunosuppressive agents (as outlined in the Vaccines section above) prior to yellow fever vaccination or can obtain a medical waiver if necessary. Those travelling with a waiver and without yellow fever vaccination need to exercise particular care to avoid mosquito bites.
Ongoing health care
As the risk for infection persists while on biologics it is important at each follow-up visit that risk is reassessed and that patients are counseled on how to prevent infections. Advice on hand hygiene, food safety, annual influenza vaccination, pneumococcal vaccination every 5 years, and tetanus boosters every 10 years, are recommended.
While biologic therapy does increase the risk for infection, careful screening and counseling, treatment of LTBI, the judicious use of vaccination, and ongoing risk-assessment during follow-up should reduce the potential for these patients to develop significant illness as an adverse effect of their treatment.
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