Biologic Psoriasis Therapies Pose Limited Risk for Hepatitis B Reactivation

A recent systematic review of the literature has confirmed that biologic therapies can reactivate hepatitis B virus (HBV) in patients with plaque psoriasis.¹ Although the study found that any prior HBV exposure was associated with the risk for viral reactivation, patients with chronic HBV were far more likely to experience reactivation than those with evidence of HBV exposure but without hepatitis. Antiviral prophylaxis greatly reduced the risk for viral reactivation in the chronic HBV cohort.¹ The study’s findings underscore the importance of screening all patients with psoriasis for HBV infection before prescribing a biologic drug or other immunosuppressive therapy.^1,2

Screening for Hepatitis B Virus Exposure

Worldwide, around 2 billion people have been exposed to HBV, and more than 350 million are living with chronic HBV.^2,3 In the United States, an estimated 21,000 cases of HBV are diagnosed each year and between 850,000 and 2.2 million people have chronic HBV.⁴ Thus, most dermatologists will encounter patients with psoriasis who have been or will be exposed to HBV. All immunosuppressive agents (biologic and nonbiologic) are associated with an increased risk for hepatitis reactivation, and many agents used to treat psoriasis have immunomodulatory effects.² In addition, some treatments for psoriasis are potentially hepatotoxic.^1-3 Therefore, experts recommend screening all patients with psoriasis for HBV infection before starting immunosuppressive therapy.^1-3 Patient reports of hepatitis exposure are unreliable because many people clear the virus without ever realizing they were infected.

At a minimum, patients should be screened for the following serologic markers: hepatitis B surface antigen (HBsAG), hepatitis B surface antibody (anti-HBs or HBsAb), and total hepatitis B core antibody (anti-HBc or HBcAb).² Serological results are combined to identify different phases of HBV infection (see table).⁵ Patients with no evidence of HBV exposure are considered “susceptible” and should be inoculated against HBV before starting immunosuppressive therapy.² A booster vaccination should be considered for patients who were vaccinated but have an HBsAb titer <10 mIU/mL, indicating nonresponse to vaccination.² Patients found to have acute or chronic HBV infection should be referred to a hepatologist for evaluation and additional testing before starting immunosuppressive therapy.²

Biologic Therapy and Hepatitis B Reactivation

Clinicians typically favor newer biologic agents for managing patients with psoriasis with liver dysfunction because they are less hepatotoxic than older immunosuppressive agents such as methotrexate and cyclosporine.^1-3 Classes of biologic agents used to treat psoriasis include tumor necrosis factor (TNF)-α inhibitors and monoclonal antibodies that block various interleukins (ILs).¹

Studies in patients with chronic HBV and rheumatoid arthritis or Crohn disease have linked TNF-α inhibitors to a high risk for HBV reactivation.^6,7 The mechanism behind HBV reactivation is unclear, although evidence from vitro and in vivo studies suggests blocking TNF-α compromises the immune system’s ability to clear the virus.⁶ Inhibition of TNF-α may also enhance HBV replication.

Although no universal definition of HBV reactivation exists, it is commonly defined as “an increase in HBV replication of at least 1 log 10 copies/mL or conversion of serum HBV DNA results from negative to positive.”¹ Soon after HBV reaction, patients who screened positive for HBsAG will exhibit an increase in serum HBV-DNA levels, whereas patients who initially screened negative for HBsAg or had an undetectable serum level of HBV-DNA will screen positive for HBsAG or serum HBV-DNA.⁶

The consequences of HBV reactivation are potentially severe. Although some patients may experience nothing more than an asymptomatic increase in serum liver enzymes, others may develop severe hepatitis or suffer potentially fatal liver failure.⁸ Mitigating hepatic injury depends on early detection and appropriate management, which may include immunosuppressive therapy and starting antiviral therapy.⁶

Quantifying Hepatitis B Reactivation Risk in Patients With Psoriasis Using Biologic Therapy

The most comprehensive examination of hepatitis reactivation risk in patients with psoriasis treated with biologic therapy was a systematic analysis that comprised 49 studies (3 hepatitis C virus [HCV], 46 HBV): 1 prospective, 15 retrospective, and 33 case series or reports.¹ Biologic therapies used in the studies included the TNF-α inhibitors etanercept (53%), adalimumab (22%), infliximab (8%), and golimumab (0.3%); the IL-12/23 blocker ustekinumab (13%); the IL-17 blocker secukinumab (0.9%); and 2 biologics that are no longer marketed (alefacept and efalizumab).¹

Cumulatively, the studies included 215 patients with moderate to severe psoriasis broadly classified as having chronic HBV (n = 40) or as being seropositive for HBV but without active hepatitis (n = 175).¹ The latter group consisted mainly of patients with resolved past HBV infection but may have included some who had occult HBV infection or a false-positive anti-HBc result.¹

In the chronic HBV cohort, 20% of patients (8/40) experienced HBV reactivation, which translated to an annual reactivation rate of 14%.¹ Stratifying patients with chronic HBV according to use of antiviral prophylaxis yielded a much lower reactivation rate for patients who received prophylaxis (3/26) than for those who did not (5/14; 12% vs 36%, respectively); the annual reactivation rates were 7.7% vs 26%, respectively.¹ The reactivation rate for patients who were positive for anti-HBc but who did not have hepatitis was 1% (2/175), and the annual reactivation rate was a negligible 0.32%.¹

The review has several imitations, including the authors’ decision not to stratify results by biologic used, the lack of randomized controlled trials, and the inconsistent quality of the incorporated studies.¹ The findings support the safety of biologic therapies for patients with prior HBV exposure who do not have chronic HBV, however, and suggest these patients may not require prophylaxis.

It is possible the risk for viral reactivation differs between TNF-α inhibitors, and more potent inhibitors may carry more risk.^9,10 For example, reported HBV reactivation rates in HBsAg-positive patients treated with more potent TNF-α inhibitors infliximab, adalimumab, or certolizumab range from 12% to 39% compared with 1% to 5% with etanercept.¹⁰ However, these ranges combine rates observed in patients treated for different conditions and cannot be reliably extrapolated to patients with psoriasis. Also compromising the reliability of risk assessments between TNF-α inhibitors is the fact that most of the incidence rates come from case reports or retrospective studies, and not well-conducted trials.⁹

The IL blockers are newer agents used to treat psoriasis, and less is known about how they affect the risk for HBV reactivation with prolonged use in patients with psoriasis. In a small trial of ustekinumab in patients with concomitant psoriasis and HBV exposure, 2 of 7 patients with chronic HBV who did not receive antiviral prophylaxis experienced HBV reactivation (29%) compared with no patients who had occult HBV or who received antiviral prophylaxis.¹¹ The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group conducted reviews of infectious disease rates associated with various interleukins, immunoglobulins, and complement factors that included several IL blockers approved for plaque psoriasis in the United States or the European Union.¹² The group concluded that ustekinumab was associated with a low risk for HBV reactivation, but that the IL-17 blockers secukinumab, ixekizumab, or brodalumab did not increase the risk for HBV reactivation.¹² One caveat is that some trials of IL-17 blockers, including the phase 3 studies for ixekizumab in patients with psoriasis, excluded people with chronic HBV, whom data show have a higher risk for viral reactivation with immunosuppressant use.¹³

Conclusion

In patients with psoriasis who were previously exposed to HBV or who have chronic HBV, immunosuppressive therapies can cause viral reactivation, although the risk is minimal for patients with resolved or occult infection. Studies have associated both nonbiologic and biologic therapies with a risk for reactivation. Therefore, screening is advised for all patients with psoriasis contemplating treatment with an immunosuppressive agent and monitoring of HBV viral load in patients who are anti-HBC-positive but HBsAG-negative. Although biologic agents are safe to use in patients with psoriasis with chronic HBV, treatment should be undertaken in consultation with a hepatologist, and these patients should be monitored for signs of viral reactivation. Large-scale prospective studies are needed to better understand the risk for HBV reactivation in patients with psoriasis undergoing treatment with biologic therapies, and to compare the risk for reactivation between different biologic therapies.

References

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12. Winthrop KL, Mariette X, Silva JT, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors) [published online February 2, 2018]. Clin Microbiol Infect. doi: 10.1016/j.cmi.2018.02.002.
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