Entecavir May Prevent HBV Reactivation in Lymphoma Patients

Laurie Barclay, MD

June 24, 2013

Antiviral prophylaxis with entecavir might help prevent rituximab-associated hepatitis B virus (HBV) reactivation in patients with lymphoma and resolved hepatitis B, according to a randomized controlled trial.

Yi-Hsiang Huang, MD, PhD, from Taipei Veterans General Hospital in Taiwan, and colleagues investigated the impact of antiviral prophylaxis on the prevention of HBV reactivation. The results were published online June 17 in the Journal of Clinical Oncology.

"HBV reactivation is becoming an increasingly concerning issue with more widespread use of immunosuppressive agents," said Jordan J. Feld, a hepatologist at the Toronto Western Hospital Liver Centre and assistant professor of medicine at the University of Toronto, who was approached by Medscape Medical News for comment.

"Reactivation occurs because of loss of immune control of viral replication, which can lead to various clinical scenarios, ranging from asymptomatic rises in HBV DNA levels to severe, life-threatening, and even fatal fulminant hepatitis," Dr. Feld said. "Most of the literature on HBV reactivation has evaluated patients who are hepatitis B surface antigen (HBsAg) positive at baseline, in whom the risk of reactivation with standard lymphoma chemotherapy may be over 50%."

Study Details

The study involved 80 patients with lymphoma and resolved hepatitis B who were going to be treated with rituximab plus chemotherapy. They were randomly allocated to receive entecavir, either prophylactically or in the event of HBV reactivation (control group). In the prophylactic group, entecavir was started before chemotherapy and ended 3 months after the completion of chemotherapy; in the control group, therapeutic entecavir was started at the time of HBV reactivation and HBsAg reverse seroconversion.

In 58 patients (72.5%), hepatitis B surface antibody was present, and in 50 patients (62.5%), HBV DNA was undetectable. There was more HBV reactivation during follow-up (mean duration, 18 months) in the prophylactic group than in the control group (2.4% vs 17.9%; P = .027).

Table. Cumulative HBV Reactivation Rates After Chemotherapy

Time After Chemotherapy Prophylactic Group, % Control Group, %
6 months 0.0 8.0
12 months 0.0 11.2
18 months 4.3 25.9


In the control group, HBsAg reverse seroconversion after HBV reactivation occurred in 4 patients (50%), and cumulative HBsAg reverse seroconversion at 6 months was 0%, at 12 months was 6.4%, and at 18 months was 16.3%. These rates were significantly higher than those in the prophylactic group (P = .032). Patients could develop HBV reactivation and HBsAg reverse seroconversion whether viral load was detectable or undetectable.

"As noted previously, the risk of reactivation extended beyond the period of chemotherapy," Dr. Feld said. Although more patients in the control group experienced HBV reactivation, only 1 patient had significant associated hepatitis, with a peak alanine transaminase of 117 U/L but no evidence of hepatic decompensation, he reported. "In the other patients, HBV DNA was rapidly suppressed after the introduction of entecavir with no clinical sequelae."

Study Strengths and Limitations

"This study clearly shows that antiviral prophylaxis lowers the risk of HBV reactivation in patients who are anti-HBs positive and receiving rituximab-based chemotherapy," said Dr. Feld. "Notably, although the risk of reverse seroconversion was lower in patients who had antibodies to the HBV core protein (anti-HBc positive) at baseline, the presence or absence of HBV DNA was not predictive of reactivation or reverse seroconversion."

Limitations of this study include the small sample size and the lack of an active comparator for prophylaxis, according to Andrew M. Evens, DO, MSc, associate professor of medicine and deputy director for clinical and translational research at UMass Memorial Cancer Center, and director of the lymphoma program at the University of Massachusetts Medical School in Worcester.

"The main strength of this study is that it is one of the few prospective clinical studies to examine HBV reactivation in lymphoma in the postrituximab era," Dr. Evens told Medscape Medical News in an email. Another strength is that entecavir is a more potent anti-HBV agent than older agents such as lamivudine, he explained.

However, Dr. Feld wondered whether a cheaper agent such as lamivudine would have been sufficient prophylaxis for patients with low or undetectable HBV DNA at baseline.

Clinical Implications

Dr. Evens noted that patients with "resolved" HBV infection, defined as the absence of HBsAg and the presence of HBV core antibody (HBcAb), historically have a very low (<1% to 2%) incidence of HBV reactivation, HBsAg reverse seroconversion, and other liver-associated morbidity and mortality with standard cytotoxic chemotherapy.

"Resolved HBV is somewhat of a misnomer, because these patients still harbor replication-competent HBV DNA in their hepatocytes," Dr. Feld noted. "The loss of HBsAg indicates potent immune control but not true resolution of infection. Hence, with potent immune suppression, HBV reactivation can still occur in this setting."

The management of patients with resolved HBV (anti-HBc positivity) is an important issue because it affects up to 2 billion people worldwide.

Several recent case series, a meta-analysis (Ann Oncol. 2011;22:1170-1180), and a prospective clinical trial (J Clin Oncol. 2009;27:605-611) have shown that rituximab is associated with an increased risk for HBV reactivation in lymphoma patients with resolved HBV infection. Dr. Feld suggested that this adverse effect of rituximab is due to its potent long-term effects on B-cell depletion.

"HBV reactivation and other severe liver-related toxicity, including liver failure and death, have been documented with single-agent rituximab," Dr. Evens noted. "Furthermore, the risk of HBV reactivation in lymphoma patients treated with rituximab/CHOP therapy is approximately 20% to 25%, compared with 0% in patients treated with CHOP alone. The optimal strategy to prevent HBV reactivation in such patient populations is not known."

Future Directions

Dr. Evens recommended that cost-effectiveness analyses and studies of patients with active or a history of HBV infection be conducted. Over the past decade, these areas have been excluded from most clinical studies with antibody or related novel targeted therapeutics.

"It is not known if immediate (pretreatment) antiviral prophylaxis, as done in the current study, is the best approach, compared with a deferred pre-emptive strategy to initiate antiviral therapy with rising HBV DNA titers," Dr. Evens said. "Moreover, with deferred pre-emptive treatment, the most appropriate HBV DNA level to initiate antiviral therapy warrants investigation," he added.

Other unanswered questions noted by Drs. Evens and Feld include the ideal duration of anti-HBV therapy after the completion of rituximab therapy. There is a documented risk or "delayed" HBV reactivation in patients treated with rituximab-based therapy 9 to 12 months after the last rituximab dose, which is presumably related to the relatively long half-life of this antibody.

"Despite receiving entecavir only after reactivation, patients in the control arm had no apparent clinical consequences of reactivation," Dr. Feld reported. "Therefore, one could argue that the strategy of close monitoring with intervention at HBV reactivation or reverse seroconversion would be an effective approach. However, serial HBV DNA testing is expensive and compliance may be insufficient in a real-world setting, so it would be useful to know if serial HBsAg testing would be adequate."

"HBV reactivation occurs frequently in patients who are anti-HBc positive and receiving rituximab-based chemotherapy, and antiviral prophylaxis and close monitoring with the introduction of therapy at reactivation both seem to be safe and effective," Dr. Feld concluded. "If HBsAg monitoring is adequate, this may be a preferable and likely more cost-effective strategy. If compliance with follow-up and monitoring is a concern, this study clearly shows that antiviral prophylaxis is a safe and effective approach."

The National Science Council and the Taipei Veterans General Hospitals University System of Taiwan supported this study. The study authors, Dr. Feld, and Dr. Evens have disclosed no relevant financial relationships.

J Clin Oncol. Published online June 17, 2013. Abstract


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