HBV Reactivation: Basics of New Warnings From Hepatologists

February 9, 2015

FDA boxed warnings about hepatitis B virus (HBV) reactivation risk relate only to ofatumumab and rituximab. Eminent hepatologists say everyone destined for immunosuppression should be tested for HBV first.

Di Bisceglie AM, Lok AS, Martin P, et al. Recent FDA Warnings on Hepatitis B Reactivation with Immune-Suppressing and Anti-Cancer Drugs: Just the tip of the iceberg? Hepatology. 2015;61:703–711 doi:10.1002/hep.27609.

Because of fatal hepatitis B reactivation in patients taking the anti-CD20 drugs [[{"type":"media","view_mode":"media_crop","fid":"31878","attributes":{"alt":"hepatitis B","class":"media-image media-image-right","id":"media_crop_1279487317159","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3361","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"width: 116px; height: 141px; float: right; margin: 3px;","title":" ","typeof":"foaf:Image"}}]]ofatumumab (Arzerra) and rituximab (Rituxan), the US Food and Drug Administration (FDA) has required a boxed warning to screen all patients for hepatitis B viral (HBV) infection before starting treatment with these agents. The authors of this article, hepatologists from six major US medical centers, say the same warning applies to other immunosuppressive drugs.

This article giving their expert advice is consistent with recommendations of the American Association for the Study of Liver Disease. The authors say that the reactivation risk is also found with corticosteroids and tumor necrosis factor-α inhibitors such as etanercept and especially infliximab. The risk is lower with methotrexate and azathioprine.

The FDA recommends testing for:

•   hepatitis B surface antigen (HBsAg) and
•   antibody to hepatitis B core antigen (anti-HBc).

If results are positive:

•   consult with hepatitis experts and
•   give prophylaxis.

If HBV is reactivated during treatment, stop immunosuppressive drugsimmediately. The mortality rate for HBV reactivation is up to 25%.

Both FDA and the review article recommend testing all patients needing immunosuppressive treatment, not just high-risk groups. Silent (asymptomatic) reactivation is common.

Basics about the tests:

•  HBV is diagnosed by the presence of HBsAg, and usually HBV DNA.
•  Reactivation usually occurs in patients who have HBV infection with HBsAg in the serum.
•  HBV DNApersistswithin hepatocytes in chronic HBV infection, even in those with undetectable levels of serum HBV DNA.
•  Anti-HBcpersists after clearance of HBV, and is a marker for current and previous infection. Patients with anti-HBc should be monitored for reactivation.
•  Anti-HBsAg
, in contrast, is a marker for immunity to HBV, either from previous infection or successful vaccination.
•  Anti-HBcwithout HBsAg or anti-HBs indicates resolved HBV infection. But patients with anti-HBc alone still have the potential for reactivation, and the authors recommend prophylaxis for them too, at least for anti-CD20 drugs.

The diagnostic challenge is that HBV reactivation is not just a serological or biochemical event, but is also associated with clinical signs of acute viral hepatitis and jaundice.

•   Silent HBV reactivation with increased HBV DNA but not aminotransferase is most common.
•   Mild reactivation is a rise in aminotransferase without jaundice or symptoms.•   Moderate reactivation is jaundice or symptoms of liver injury.
•   Severe reactivation is features of liver failure, and may be fatal.

You can readily prevent reactivation by initiating prophylactic antiviral therapy with antiviral agents before starting the immunosuppressive regimen, the authors say. Lamivudine is potent, safe, well-tolerated, and inexpensive, although viral resistance is common. Tenofovir and entecavir have a lower risk of resistance.