Preventing Hepatitis B Virus Reactivation During Immunochemotherapy for Lymphoma

Administering prophylactic antiviral treatment is effective in preventing hepatitis B virus (HBV) reactivation in patients with B-cell non-Hodgkin lymphoma (NHL) being treated with an anti-CD20 monoclonal antibody. However, overexposure to antiviral medication can lead to adverse events and drug resistance. In a study published in Blood, researchers evaluated an alternative approach to treating these patients with antiviral medications: using monthly DNA monitoring to determine which patients with resolved HBV infection are at the highest risk of developing HBV-related hepatitis while receiving obinutuzumab or rituximab.

Shigeru Kusumoto, MD, PhD, from the Nagoya City University Graduate School of Medical Sciences in Japan, and authors found that detectable HBV DNA at baseline was strongly associated with later HBV reactivation, according to their analysis of patients receiving obinutuzumab- or rituximab-containing immunochemotherapy enrolled in the phase III GOYA and GALLIUM trials. Administering pre-emptive nucleoside analog treatment (NAT) based on HBV-positive DNA results prevented most, but not all, patients from developing HBV-related hepatitis.

HBV assessments were performed at baseline and then monthly thereafter, until at least one year after the last dose of the study drug was administered. HBV DNA was measured in serum using a quantitative, real-time polymerase chain reaction (PCR) assay.

When patients were determined to have a virus reactivation (defined as HBV DNA ≥29 IU/mL), immunochemotherapy was held and NAT (including entecavir, lamivudine, adefovir, and tenofovir) was started. If HBV DNA became undetectable or if reactivation was not confirmed, immunochemotherapy was restarted; if HBV DNA exceeded 100 IU/mL while a patient was on NAT, immunochemotherapy was discontinued.

Prophylactic NAT was allowed by investigator discretion.

Among the 326 patients with resolved HBV infection, 27 patients (8.2%) had HBV reactivation, including 21 (6.4%) with HBV DNA ≥100 IU/mL. Reactivation occurred a median of 125 days (range = 85-331) after the first dose of either obinutuzumab or rituximab. For the 16 participants who experienced an HBV reactivation during immunochemotherapy, 12 withheld study treatment but no patients discontinued immunochemotherapy due to HBV reactivation, the authors reported.

Of the 27 patients with HBV reactivation, 25 were in the group of patients who did not receive prophylactic NAT (n=25/232; 10.8%). In this group, HBV DNA levels reached a median peak of 342 IU/mL (range = 101-1,230 IU/mL). The researchers added that “HBV-related hepatitis was not observed among these 25 patients, although relatively high-peak HBV DNA levels … were seen in three patients.”

However, nine patients of the 25 patients had late HBV reactivation, occurring a median of 196 days (range = 153-310) after completion of immunochemotherapy. “The observation of [delayed] HBV reactivation … suggests that HBV DNA monitoring is necessary for at least one year after completion of lymphoma treatment,” the authors wrote.

Among the 94 patients who received prophylactic NAT, two (2.1%) had HBV reactivation: One at 18 months after stopping NAT and one while on NAT.

Estimated HBV reactivation rates were lower among those who received prophylactic NAT, compared with those who did not:

  • 1 year: 1.5% vs. 10.6%
  • 2 years: 1.5% vs. 11.9%

This translated to a reduced risk of HBV reactivation in patients who received prophylactic NAT (hazard ratio [HR] = 0.09; 95% CI 0.02-0.41; p=0.002).

In multivariate analyses (accounting for baseline age and sex), the following factors were associated with a higher risk for HBV reactivation:

  • older age (by decade; HR=1.63; 95% CI 1.00-2.37; p=0.035)
  • seronegative for hepatitis B surface antibodies (anti-HBs) at baseline (HR=4.00; 95% CI 1.71-9.37; p=001)
  • a diagnosis of diffuse large B-cell lymphoma (DLBCL)
  • detectable baseline HBV DNA levels (HR=18.22; 95% CI 6.04-54.93; p<0.001)

Based on these results, the authors concluded that, “pre-emptive NAT avoids unnecessary antiviral treatment thereby reducing drug costs.” However, for patients with clearly defined risk factors for HBV reactivation (i.e., anti-HBs seronegativity or detectable HBV DNA at baseline), prophylactic NAT may be appropriate. Also, “as prophylactic NAT cannot be continued indefinitely in patients with resolved HBV infection, HBV DNA monitoring is necessary after stopping prophylactic NAT to diagnose delayed HBV reactivation.”

When the researchers looked across each trial’s drug regimen, they did not observe any significant difference in the risk of HBV reactivation between obinutuzumab- and rituximab-based immunochemotherapy. However, this analysis was limited by the imbalance of baseline risk factors between the two groups of trial participants, “which was unsurprising given that HBV reactivation was not a major endpoint in either trial.” They added that each trial also used slightly different approaches to managing HBV reactivation and in defining the criteria for initiating pre-emptive NAT, which may have confounded results.

“Considering all these points, pre-emptive NAT guided by HBV DNA monitoring appears to be a reasonable strategy for most patients with resolved HBV infection,” they concluded. “Further basic research and clinical trials are now warranted to improve our understanding of the pathogenesis of HBV reactivation in [patients with DLBCL] who receive anti-CD20 antibodies with chemotherapy and to determine whether DLBCL truly increases the risk of reactivation compared with other lymphoma types,” the researchers noted.

Authors report financial relationships with Chugai Pharmaceutical Co. and Roche.


Kusumoto S, Arcaini L, Hong X, et al. Risk of HBV reactivation in patients with B-cell lymphomas receiving obinutuzumab or rituximab immunochemotherapy. Blood. 2018 October 19. [Epub ahead of print]