Neil Canavan

November 10, 2011

November 10, 2011 (San Francisco, California) — Two separate studies, performed at the University of Texas M.D. Anderson Cancer Center in Houston, demonstrate the potentially life-threatening impact of reactivation of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in patients undergoing immunosuppressive chemotherapy.

The data, presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting, suggest that greater surveillance for HBV and safer hematologic-sparing treatments for HCV are required.

In the first study, lead investigator Jessica P. Hwang, MD, MPH, and colleagues looked at HBV reactivation during cancer treatment using a retrospective dataset from her institution. "This is a topic that is gaining momentum in public health, oncology, as well as hepatology landscapes," she explained. However, because of the lack of large population-based studies, the current prevalence of HBV reactivation in patients undergoing cancer treatment is unclear. "Our goals were to determine the prevalence and predictors of HBV screening and reactivation in a comprehensive cancer center."

What is known is that HBV reactivation can occur at anytime during chemotherapy or after chemotherapy, during the recovery phase of the immune system's reconstitution. "This can lead to poor outcomes, hepatic flares, liver failure, and death," Dr. Hwang said. "It's important to identify these patients accurately so that effective oral antiviral therapy can be initiated."

The study by Dr. Hwang and colleagues explored 2 issues: the existence of inconsistent guidelines for screening cancer patients for HBV, and the lack of adherence to the guidelines that are in place.

The 3 entities that have addressed HBV and cancer are the Centers for Disease Control and Prevention (CDC), the AASLD, and the Association of Clinical Oncology (ASCO).

On screening and treatment, the CDC and AASLD recommendations are in agreement: All patients with cancer who are about to undergo immunosuppressive therapy should be tested for HBV and screened for hepatitis B surface antigen (HBsAg), hepatitis B core antigen (anti-HBc), and antibodies against HBsAg (anti-HBs). If there is a positive test result, HBV prophylaxis should be initiated.

Recommendations from ASCO are less comprehensive: Only those about to undergo "highly" immunosuppressive regimens (i.e., stem cell transplants or treatment with rituximab) and patients "at risk" for HBV should be tested, and screening should only be for HBsAg and anti-HBc (recommended treatment is the same).

"Although there is agreement on the importance of antiviral prophylaxis, ASCO does not advocate the use of all 3 screening tests," Dr. Hwang noted. Furthermore, the ASCO guidelines require that oncologists be aware of the risk factors for HBV infection, and that they take the time to actually perform HBV screening. The discrepancies in recommendations led Dr. Hwang's team to examine current practices at the M.D. Anderson Cancer Center.

The retrospective chart review gathered data on screening, positive tests, and HBV reactivation for all chemotherapy-naïve cancer patients seen at the M.D. Anderson over a 4-year period. Evidence of viral reactivation was defined as an alanine aminotransferase (ALT) level of at least 100 U/L plus total bilirubin of at least 2.5 mg/dL; detectable HBV levels when HBV was previously undetectable; or HBV DNA of at least 100,000 copies/mL.

The screening period was 2 months before the first or second round of chemotherapy. Both solid tumor and hematologic malignancies were considered. Risk factors for HBV prior to screening included International Classification of Diseases, Ninth Revision (ICD-9) codes for HCV, HIV, liver disease, and hepatitis.

Approximately 71,000 charts were reviewed. Of the 10,729 patients receiving potentially immunosuppressive chemotherapy, Dr. Hwang and colleagues found that only 1787 patients (17%) were screened for HBV. Tests used were HBsAg (1665 patients); HBsAg and anti-HBC (87 patients); and anti-HBc (35 patients). "If we just look at the patients with HBV risk factors, only 1 of 5 patients were screened," Dr. Hwang reported.

Of those screened, 34 patients were found to have HBV reactivation. Fourteen of the 34 were found to have chronic HBV infection, and anti-HBc was detected in 20 patients. Of the total reactivation cohort, 23 patients had hematologic cancers, 11 had solid tumors, and 10 had been treated with rituximab.

Predictors of those chosen for screening were being male, having HBV risk factors, having a hematologic malignancy, and the use of rituximab. Predictors of HBV reactivation were being male, being Asian or black, and having HBV risk factors. "Interestingly, Asian and black race did not predict screening, yet they were more often testing positive," said Dr. Hwang.

Most striking was the lack of use of HBV therapy after a positive test. Of the 34 patients, 9 received prophylaxis (2 later died), 11 received treatment after HBV reactivation (8 died), and 14 received no treatment (10 later died).

"It does not appear that we are following the CDC and AASLD recommendations," Dr. Hwang pointed out, adding that M.D. Anderson is not even adhering to ASCO recommendations.

"Preventable reactivation does occur, is occurring, and prophylaxis has been shown to dramatically reduce mortality in cancer patients with HBV," she explained.

HCV Reactivation

A study from the same institution looked at HCV reactivation in patients who had undergone treatment with rituximab and gemcitabine. In this retrospective chart review, investigators looked at the records of 308 HCV-infected patients treated at M.D. Anderson over a 1-year period. HCV exacerbation was defined as a greater than 3-fold increase in ALT in the absence of hepatotoxic drugs, systemic coinfection, recent blood transfusions, and tumor infiltration of the liver.

"We found that 11% of patients who received this chemotherapy developed reactivation of HCV," reported coinvestigator Harrys Torres, MD, assistant professor of infectious diseases at M.D. Anderson. "Interestingly, none of these patients died with liver failure, which is different than with HBV reactivation."

What concerns Dr. Torres is that HCV reactivation necessitates discontinuation of chemotherapy. "We have to stop chemo in 50% of cases," he said. "It seems that HCV reactivation does not compromise the patient from the biologic standpoint, but from the oncologic standpoint, with treatment interruptions," it does.

Treating HCV concurrently with the administration of chemotherapy is not an option. "Current HCV agents are associated with anemia and neutropenia, and these patients already have some sort of hematologic toxicity with the chemotherapy," Dr. Torres said. "In the near future, we're hoping to see new drugs that can be given orally once a day that would allow chemotherapy to continue."

Dr. Hwang reports receiving grant funding from Bristol-Myers Squibb. Dr. Torres reports consulting for Merck, Astellas, and Vertex.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting: Abstracts 172 and1732. Presented November 7, 2011.

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