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Boxed warning draws attention to HBV reactivation
The FDA recently revised the prescribing information of ofatumumab and rituximab, adding a boxed warning and recommendations to reduce the risk for hepatitis B virus reactivation.
The risk for hepatitis B virus (HBV) reactivation was previously described in the warnings and precautions section of the prescribing information of both drugs. The labeling change was the result of an FDA review of HBV reactivation cases that continue to be reported in patients treated with these agents.
Prevention of HBV reactivation in patients who receive chemotherapy is clinically important for two key reasons. First, HBV reactivation can lead to significant morbidity and mortality. Second, HBV reactivation can cause delays in, or prevent delivery of, anticancer therapy.
Debbie Blamble
HBV reactivation has been reported in many cancer populations, but it most commonly occurs in patients with hematologic malignancies. This article will review the new FDA recommendations for rituximab (Rituxan; Genentech, Biogen Idec) and ofatumumab (Arzerra, GlaxoSmithKline), as well as highlight data related to these recommendations.
HBV screening
The prescribing information for rituximab and ofatumumab recommends health care professionals screen all patients for HBV infection before treatment initiation.
Screening should be done by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb or anti-HBc). Cases of reactivation have been reported in patients who have been HBsAg-positive, as well as those who were HBsAg-negative but HBcAb-positive.
Several groups have made recommendations about HBV screening of cancer patients who undergo chemotherapy.
Since 2008, the CDC has recommended HBV screening for patients who receive cytotoxic or immunosuppressive therapy.
The European Association for the Study of the Liver (EASL) published an updated clinical practice guideline on the management of chronic HBV infection in 2012. The EASL recommends screening all patients about to receive chemotherapy and immunosuppressive therapy for chronic HBV infection using HBsAg and HBcAb.
The Institute of Medicine and the American Association for the Study of Liver Diseases only recommend screening patients with risk factors for HBV infection, such as those born in areas with high HBV infection prevalence, as well as those with household or sexual contact with someone who has HBV infection, a history of injectable drug abuse, multiple sexual contacts or a history of sexually transmitted diseases.
In 2010, ASCO published a provisional clinical opinion on HBV infection screening in cancer patients who receive chemotherapy. The opinion at that time was that the evidence was insufficient to recommend routine screening for prior HBV infection of all cancer patients.
However, physicians may consider screening patient populations at high risk of chronic HBV infection or those patients who receive highly immunosuppressive therapy. Patient populations considered at high risk for chronic HBV infection include those born in countries with HBsAg prevalence of at least 2% (such as the Asia-Pacific region), those with a history of injectable drug abuse, and those infected with HIV.
Highly immunosuppressive therapy would include hematopoietic stem cell transplantation, as well as anti-CD20 monoclonal therapy such as rituximab.
Guidelines from the National Comprehensive Cancer Network are similar to the opinion from ASCO.
Analyses have demonstrated that routine screening of all solid tumor patients about to undergo chemotherapy is not cost-effective. Screening all patients with lymphoma who receive rituximab-based therapy would be cost-effective, even in patient populations in which the prevalence of chronic HBV infection is low. However, surveys and retrospective data show that not all providers routinely screen all patients who receive chemotherapy for HBV, including those considered to be high risk. Additional studies are needed to help providers determine who to screen outside of high-risk patient populations.
Monitoring and prophylactic antiviral therapy
If patients have evidence of prior HBV infection, the prescribing information for rituximab and ofatumumab recommends providers consult physicians with expertise in HBV management with regard to monitoring and consideration of HBV antiviral therapy.
HBsAg-positive or HBcAb-positive patients should be tested at baseline for HBV viral load using HBV DNA levels. At this point, patients with active HBV disease should be treated accordingly. HBV DNA should be monitored monthly while on immunosuppressive therapy, and then every 3 months after completion of therapy for at least 6 to 12 months. Some recommend continued monitoring for 6 to 12 months after completion of antiviral therapy to look for withdrawal HBV reactivation.
Additionally, HBsAg-positive or HBcAb-positive patients should receive prophylactic antiviral therapy. Alternatively, HBsAg-negative but HBcAb-positive patients with undetectable HBV DNA levels could be monitored using HBV DNA and alanine aminotransferase with pre-emptive antiviral therapy at the time of detectable HBV DNA levels.
Several nucleoside and nucleotide analogues are available for HBV infection management. The optimal agent is unknown. Lamivudine — a nucleoside analogue dosed at 100 mg orally daily that is generally well tolerated — is the one most studied for the prevention of HBV reactivation in this setting. Meta-analyses have demonstrated that lamivudine significantly decreases the risk for HBV reactivation, as well as associated morbidity and mortality.
Unfortunately, lamivudine is associated with a high rate of acquired resistance with time (24% at 1 year and 49% at 3 years in non-oncology populations).
In patients who may need extended duration of antiviral therapy (longer than 12 months) or those who have high levels of HBV DNA detected (>2,000 IU/mL), more potent antivirals should be considered, such as entecavir (Baraclude, Bristol-Myers Squibb) or tenofovir (Viread, Gilead).
Data with the use of other antivirals for this indication is limited. These agents also tend to be more expensive than lamivudine. However, early reports seem to demonstrate the superiority of entecavir over lamivudine for the prevention of HBV reactivation in patients with lymphoma receiving chemotherapy.
Ideally, prophylactic antivirals should be started at the same time or just before initiating cancer chemotherapy (ie, 1 week before). The length of antiviral therapy is a subject of debate, but it generally is recommended to extend for at least 6 to 12 months after completion of chemotherapy, depending on the guideline.
Cases of HBV reactivation have been reported as long as 12 months (for ofatumumab) to 24 months (for rituximab) after completion of therapy. So, prolonged prophylaxis and monitoring should be considered in high-risk patients (ie, high HBV DNA levels). Finally, it is recommended that chemotherapy be discontinued immediately in patients who develop HBV reactivation.
Summary
The FDA has recommended that all patients about to receive rituximab or ofatumumab be screened for HBV infection. To comply with the FDA recommendation, providers will need to incorporate decision support tools into their ordering processes to help identify patients about to receive rituximab or ofatumumab for screening.
In the United States, rates of routine HBV screening of patients with cancer about to receive chemotherapy have been low to date due to lack of data and consensus on which populations will benefit most from screening. At a minimum, patients with risk factors for HBV infection or those about to undergo immunosuppressive therapy — such as stem cell transplantation or anti-CD20 monoclonal antibodies — should be screened for HBV infection.
Although prophylactic antiviral therapy can reduce HBV reactivation, the best antiviral therapy — including duration of therapy — is currently unknown and should be the focus of future clinical trials.
References:
Artz AS. J Clin Oncol. 2010;28:3199-3202.
FDA Drug Safety Communication: Boxed Warning and new recommendations to decrease risk of hepatitis B reactivation with the immune-suppressing and anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab). Available at: www.fda.gov/Drugs/DrugSafety/ucm366406.htm. Accessed on Jan. 29, 2014.
Hwang JP. Support Care Cancer. 2012;20:2999-3008.
For more information:
Debbie Blamble, PharmD, BCOP, is an oncology clinical pharmacy specialist at The University of Texas MD Anderson Cancer Center. She can be reached at The University of Texas MD Anderson Cancer Center, Division of Pharmacy, 1515 Holcombe Blvd., Houston, TX 77030; email: dblamble@mdanderson.org.
Disclosure: Blamble reports no relevant financial disclosures.