More than 2 billion people globally are affected by the Hepatitis B virus (HBV)—particularly those living in Southeast Asia, Africa, and South America, where HBV is considered endemic.1 Although widespread vaccination programs have reduced the overall rate of HBV, the number of carriers has continued to grow.

In patients with rheumatoid arthritis (RA), a “substantial” number have coexisting HBV infection, according to Der-Yuan Chen, MD, of the Division of Allergy, Immunology, and Rheumatology at the Taichung Veterans General Hospital in Taiwan, and colleagues. In a paper published in the Journal of Microbiology, Immunology, and Infection, Dr Chen and colleagues also noted that due to the use of immunosuppressive and biological agents, an RA diagnosis is a risk factor for HBV reactivation.1

The current slate of available biological and targeted RA therapies includes drugs such as tumor necrosis factor-a inhibitors (TNF-a), B-cell targeting antibodies, interleukin (IL)-6 receptor inhibitors, T-cell costimulatory molecule inhibitors, and Janus kinase (JAK) inhibitors. However, cytokines, B-cells, costimulatory molecules, and JAK all play a critical role in controlling HBV infection—making HBV reactivation a challenge for rheumatologists who treat RA.


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Adding to this challenge is the potentially fatal nature of HBV reactivation following biological or targeted therapies; risk status stratification, therefore, is crucial when initiating biological or targeted RA therapies.

RA and HBV Risk

By itself, HBV represents a public health problem of considerable importance.2 In the RA population, this problem becomes significant. Approximate HBV reactivation incidence is between 10% and 40% in the general population, and occurs in 3 phases: an increase in HBV replication, a liver disease activity period marked by elevated alanine aminotransferase (ALT) and jaundice, and a recovery period, where HBV-DNA and ALT decrease to baseline levels and Hepatitis B surface antigen (HBsAg) may be negative.

According to the current literature, physicians have observed HBV reactivation in patients with RA treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, high dose corticosteroids, and biological and targeted DMARDs.3-5 For those taking biological and targeted therapies—infliximab, etanercept, adalimumab, rituximab, tocilizumab, abatacept, and tofacitinib, among others—HBV reactivation risk varies based on both HBV infection status before initiation of RA therapy and the degree of medication-related immunosuppression.

Dr Chen and colleagues point out that there are 3 serological HBV markers—HBsAg, Hepatitis B core antibody-immunoglobulin G (HBcAb-IgG), and Hepatitis B surface antibody (HBsAb)—that can, in addition to HBV-DNA viral loads, be used to risk stratify patients by HBV infection status. Patients with HBsAg-positive and negative HBV, for example, have a “marked difference” in HBV reactivation risk status.

Patients with RA and chronic HBV or patients who are Hepatitis B e antigen (HBeAg)-positive have the highest risk for reactivated HBV, and the risk is generally higher in those with occult HBV infections.

Therapeutic Options

Of the available biological and targeted therapeutic agents for RA, rituximab is significantly associated with HBV reactivation. A 2011 study of patients with lymphoma undergoing rituximab-based chemotherapy showed an incidence of reactivated HBV of between 27% and 80%.6 More recently, researchers reported that premedication with corticosteroids followed by rituximab therapy can also increase the risk for reactivated HBV in the RA population.7 TNF-a inhibitors have also been associated with elevated reactivated HBV risks in those who are HbsAg-positive who are not provided with antiviral prophylaxis.4,5

In 2011, a group of Taiwanese researchers5 investigated the virological, serological, and biochemical evidence of HBV reactivation in a small cohort of 88 patients with RA undergoing TNF-a therapy. In a subgroup of 10 patients who were HBsAg-positive, no patients had a documented HBV reactivation; these 10 patients received prophylactic lamivudine and experienced “significantly decreased” viral loads at 12 months (153,860±80,120 IU/ml at baseline vs 313±235 IU/ml at 12 months). Comparatively, 5 patients from a group of 8 who did not receive antiviral prophylaxis experienced HBV reactivation with a significant increase in viral loads following TNF-a therapy initiation (9375±5924 IU/ml vs 49,710,000±40,535,000 IU/ml).5

HBsAg positivity or negativity is of importance when determining the risks for patients who are receiving biological or targeted therapies. According to Dr Chen’s team, HBsAg-positive patients have an “extremely high” HBV reactivation risk when no antiviral prophylaxis is administered—particularly in those taking rituximab where the risk is up to 50%.1 Safety data of abatacept, published in Arthritis Care and Research,8 also showed that patients who did not receive prophylactic antiviral medications experienced reactivated HBV.

Among patients who are HBsAg-negative, reactivated HBV risk is “low, but not zero,”1 with some studies reporting that HBsAb levels might decline and HBsAg seroreversion may occur after initiation of TNF-a or rituximab therapy.1

Benefits of Antiviral Prophylaxis

Antiviral prophylaxis has been well documented as a strategy to reduce reactivated HBV incidence, HBV hepatitis severity, and mortality1—but to provide the most protection, high-risk patients should be identified before the initiation of biological or targeted therapies.

“Risk assessment and management strategies for [reactivated] HBV in RA patients… have not been widely reported,” wrote Dr Chen and colleagues. Nor has the optimal duration of this prophylaxis: 2 studies in patients undergoing rituximab chemotherapy for hematological malignancies demonstrated that from  6 to 12 months of prophylaxis may be sufficient,6,9 but additional RA-specific data are needed to draw further conclusions. A study specific to RA found that 71% of patients with RA who received and discontinued antiviral prophylaxis developed reactivated HBV between 3 and 21 months after discontinuation,10 but this optimal duration, the researchers wrote, “may vary with different antiviral drugs and treatment used.”1

According to Dr Chen and colleagues, it is prudent for rheumatologists to screen all patients for HBV infection before the initiation of biological therapy. Two organizations—the European Association for the Study of the Liver and the American Association for the Study of Liver Disease—have both recommended HBsAg and HBcAb screening in patients who are at risk for HBV reactivation; these serological tests, as well as HBsAb, should be performed before therapy initiation. HBV-DNA viral loads should be examined in situations where evidence of HBV infection is present.

For patients who have no natural or vaccine-induced HBV immunity, rheumatologists should consider recommending the HBV vaccine,11 with early data indicating that “vaccines might be safer in the setting of immunosuppression than previously thought.”

For patients who are HBsAg-negative, management can be more difficult as management strategies for these patients have not yet been established.1 For patients with occult HBV, antiviral prophylaxis is recommended before initiating rituximab, TNF-a inhibitors, and a number of other biologics and targeted therapies.

“Considering the high cost of antiviral therapy and [the] relatively low risk of [reactivated] HBV, universal antiviral prophylaxis may be impractical in RA patients with resolved HBV infection,” Dr Chen and colleagues noted, adding that regular monitoring of ALT levels and HBV-DNA loads at 3-month intervals is the most “rational approach” for reactivated HBV-associated hepatitis prevention.1

“[Reactivated] HBV is a potentially fatal complication,” Dr Chen and colleagues noted. Engaging in risk-stratification practices can mitigate the potential for fatalities, with pretherapy screening the most effective tool currently available.

“Future prospective studies are needed to investigate the optimal frequency of serum HBV-DNA monitoring and the duration of antiviral prophylaxis in RA patients [both] during and after biological or targeted therapy,” they concluded.

References

  1. Chen Y-M, Yang S-S, Chen D-Y. Risk-stratified management strategies for HBV reactivation in RA patients receiving biological and targeted therapy: A narrative review. J Microbiol Immunol Infect. 2019;52(1):1-8. doi:10.1016/j.jmii.2017.10.002
  2. Guo L, Wang D, Ouyang X, et al. Recent advances in HBV reactivation research. Biomed Res Int. 2018:2931402. doi:10.1155/2018/2931402
  3. Calabrese LH, Zein NN, Vassilopoulous D. Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: Assessment and preventive strategies. Ann Rheum Dis. 2006;65(8):983-989. doi:10.1136/ard.2005.043257
  4. Zingarelli S, Frassi M, Bazzani C, Scarsi M, Puoti M, Airò P. Use of tumor necrosis factor-alpha-blocking agents in hepatitis B virus-positive patients: Reports of 3 cases and review of the literature. J Rheumatol. 2009;36(6):1188-1194. doi:10.3899/jrheum.081246
  5. Lan J-L, Chen Y-M, Hsieh T-Y, et al. Kinetics of viral loads and risk of hepatitis B virus reactivation in hepatitis B core antibody-positive rheumatoid arthritis patients undergoing anti-tumor necrosis factor alpha therapy. Ann Rheum Dis. 2011;70(10):1719-1725. doi:10.1136/ard.2010.148783
  6. Evens AM, Jovanovic BD, Su Y-C, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: Meta-analysis and examination of FDA safety reports. Ann Oncol. 2011;22(5):1170-1180.
  7. Pyrpasopoulou A, Douma S, Vassiliadis T, Chatzimichailidou, Triantafyllou A, Aslandis S. Reactivation of chronic hepatitis B virus infection following rituximab administration for rheumatoid arthritis. Rheumatol Int. 2011;31(3):403-404. doi:10.1007/s00296-009-1202-2
  8. Kim PS, Ho GY, Prete PE, Furst DE. Safety and efficacy of abatacept in eight rheumatoid arthritis patients with chronic hepatitis B. Arthritis Care Res. 2021;64(8):1265-1268. doi:10.1002/acr.21654
  9. Burton MJ, Winthrop KL, Baddley JW. Hepatitis reaction with rituximab sparks drug safety alert. The Rheumatologist. https://www.the-rheumatologist.org/article/hepatitis-reaction-with-rituximab-sparks-drug-safety-alert/. Published January 1, 2015. Accessed September 16, 2021.
  10. Mo Y-Q, Liang A-Q, Ma J-D, et al. Discontinuation of antiviral prophylaxis correlates with high prevalence of hepatitis B virus (HBV) reactivation in rheumatoid arthritis patients with HBV carrier state: a real-world clinical practice. BMC Musculoskeletal Disord. 2014;15:449. doi:10.1186/1471-2474-15-449
  11. Meroni PL, Zavaglia D, Girmenia C. Vaccinations in adults with rheumatoid arthritis in an era of new disease-modifying anti-rheumatic drugs. Clin Exp Rheumatol. 2018;36(2):317-328.