Entecavir Lowers HBV Reactivation Risk Better Than Lamivudine

Veronica Hackethal, MD

December 26, 2014

Among HBV carriers receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for diffuse large B-cell lymphoma, entecavir (Baraclude, Bristol-Myers Squibb) is better than lamivudine (Epivir, GlaxoSmithKline) for preventing hepatitis B virus (HBV)-related hepatitis and reactivation, according to a randomized phase 3 trial conducted in China.

Results of the study showed a significantly lower incidence of HBV-related hepatitis with entecavir compared with lamivudine (0% vs 13.3%; difference, 13.3% [95% confidence interval, 4.7% - 21.9%]; P = .003).

The entecavir group also had significantly lower incidence of HBV reactivation compared with lamivudine (6.6% vs 30.0%; difference, 23.4% [95% confidence interval, 10.2% - 36.6%]; P = .001).

The study was published in the December 17 issue of JAMA.

Although prior research has suggested that entecavir prophylaxis lowers the risk for HBV reactivation in patients receiving chemotherapy, this is the first randomized trial comparing entecavir with lamivudine.

"Our data provide compelling evidence that entecavir reduces HBV reactivation and clinically meaningful end points such as hepatitis and chemotherapy treatment delay," lead author Tongyu Lin, MD, from the Department of Medical Oncology at the Sun Yat-sen University Cancer Center in Guangzhou, China, told Medscape Medical News. "Entecavir is recommended as prophylactic antiviral treatment in seropositive hepatitis B surface antigen cancer patients receiving rituximab-based chemotherapy for B-cell [non-Hodgkin lymphoma] and chronic lymphocytic leukemia.

"Entecavir is more expensive than lamivudine but appears cost-effective, at least among patients with active hepatitis B, due to decreased spending on subsequent hepatitis-related complications," Dr Lin added.

HBV infection is a worldwide problem, especially among those with B-cell non-Hodgkin lymphoma, whose rate of HBV infection is approximately 30%, Dr Lin explained. Patients who are positive for the HBV surface antigen and receiving chemotherapy for lymphoma have an HBV reactivation rate of up to 50%, he added.

Reactivation Risk

R-CHOP is the standard first-line therapy for diffuse large B-cell lymphoma. Past studies have suggested that rituximab, an anti-CD20 monoclonal antibody, increases the risk for HBV reactivation in patients previously positive for HBV. Reactivation of HBV in patients receiving chemotherapy can cause treatment disruption and potentially life-threatening complications such as fulminant hepatitis and liver failure.

In September 2013, the US Food and Drug Administration placed a boxed warning on the product labeling for rituximab (Rituxan, Roche) and ofatumumab (Arzerra, GlaxoSmithKline) about the risk for HBV reactivation in patients who had previously tested positive for the virus. The warning recommended that all patients receiving these medications be screened for HBV.

"This study defines entecavir as the standard of care for HBV prophylaxis in patients with positive surface antigen," Jeremy Abramson, MD, assistant professor in the Department of Medicine at Harvard Medical School in Boston, Massachusetts, and clinical director in the lymphoma program at Massachusetts General Hospital, also in Boston, told Medscape Medical News. Dr Abramson authored a linked editorial, along with Raymond Chung, MD, who is also from Harvard Medical School.

These results can be extrapolated to any HBV carrier with any B-cell leukemia or lymphoma receiving chemotherapy plus an anti-CD20 monoclonal antibody such as rituximab, ofatumumab, or obinutuzumab, according to Dr Abramson.

"The risk of HBV reactivation applies similarly to these populations. There are no serious risks commonly associated with entecavir, which is very well tolerated," Dr Abramson continued.

"HBV reactivation is potentially devastating, and is nearly always preventable [with screening]," he emphasized, "These studies are a reminder that physicians treating cancer patients must be mindful of checking patients at baseline for HBV surface antigen, surface antibody, and core antibody. Efforts should be redoubled to identify all such persons with chronic or cleared HBV infection."

Future research will need to look at HBV subtypes and mutations associated with lamivudine resistance to determine which patients might benefit most from entecavir. Research will also need to look at the optimal duration of antiviral prophylaxis, which has yet to be determined.

Study Details

Dr Lin and colleagues conducted a randomized, open-label phase 3 study from February 2008 through December 2012 at 10 medical centers in China. A total of 121 patients were randomly assigned to receive either entecavir (n = 61) or lamivudine (n = 60).

The trial was part of a larger study looking at 3 vs 2 weeks of standard R-CHOP for diffuse large B-cell lymphoma (rituximab [375 mg/m2 intravenously on day 1], cyclophosphamide [750 mg/m2 intravenously on day 2], doxorubicin [50 mg/m2 intravenously on day 2], vincristine [1.4 mg/m2, up to a maximal dose of 2 mg, intravenously on day 2], and prednisone [60 mg/m2 per day] for 5 days).

Participants seropositive for the hepatitis surface antigen and naive to antivirals were randomly assigned to receive 0.5 mg entecavir daily (n = 61) or 100 mg lamivudine daily (n= 60). They started antiviral prophylaxis 1 week before beginning R-CHOP and stopped antivirals 6 months after completing chemotherapy.

Participants self-paid for the treatment, with neither patients nor investigators blinded to treatment assignment. Data collection staff and the statistician, however, were blinded.

The participants were followed for a median of 40.7 months (range, 8.6 - 62.3 months) and received a median of 6 cycles of R-CHOP.

One patient (1.6%) in the entecavir group experienced treatment disruption compared with 11 (18.3%) in the lamivudine group (percentage difference, 16.7%; 95% confidence interval, 6.4% - 27.0%; P = .002).

No significant differences were found in adverse effects between entecavir vs lamivudine (24.6% vs 30.0%, respectively; difference, 5.4% [95% confidence interval, −10.5% to 21.3%]; P = .50). No grade 3 or 4 adverse events occurred.

This study was supported by a grant from the Foundation of 5010 Clinical Trials of Sun Yat-sen University. The authors have disclosed no relevant financial relationships. Dr Abramson reports receiving personal fees from scientific advisory board membership for Genentech. Dr Chung reports receiving grants from Gilead Sciences, Mass Biologics, Vertex, and Merck and personal fees from Abbvie, Enanta and Idenix.

JAMA. 2014;312:2505-2507, 2521-2530. Article abstract, Editorial extract

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