OncoLog

 

From OncoLog, February 2013, Vol. 58, No. 2

Chronic Viral Hepatitis in Cancer Patients Requires Personalized Management

By Bryan Tutt

Chronic viral hepatitis is life-threatening for many patients but curable or manageable for others. But in patients who have both viral hepatitis and cancer, cancer treatment may exacerbate the viral infection and lead to other complications, such as liver failure or even death.

Chronic infections with hepatitis B virus (HBV) or hepatitis C virus (HCV) are associated with the development of hepatocellular carcinoma (HBV or HCV infections account for 78% of cases worldwide). Other cancers are as common in patients with HBV or HCV as they are in the general population. And the prevalence of HCV and HBV make them an important public health concern.

According to the U.S. Centers for Disease Control and Prevention (CDC), between 800,000 and 1.4 million Americans are infected with HBV and 2.7–3.9 million with HCV. It is estimated that half of these people do not know they are infected because a person chronically infected with either virus can have a very low viral load, a normal serum alanine aminotransferase (ALT) level, and an absence of symptoms. The large population with undiagnosed HBV or HCV infection and the risks that cancer treatments pose for patients with the viruses make HBV and HCV important concerns in cancer care.

Treating HCV

The high rate of chronic HCV infection and its frequent concurrence with cancer led physicians at The University of Texas MD Anderson Cancer Center to establish an HCV clinic in 2009. This was the first clinic in the United States devoted specifically to managing HCV infection in cancer patients. About 300 patients are seen at the clinic each year; most have cancers that are unrelated to their chronic HCV infection.

Because cancer usually is the more immediate threat, its treatment typically takes precedence in patients who also have HCV. “HCV treatment lasts 6–12 months; most of our patients do not want to delay cancer treatment that long, or their cancer is one that needs to be treated immediately,” said Harrys A. Torres, M.D., director of the HCV clinic and an assistant professor in the Department of Infectious Diseases, Infection Control, and Employee Health.

Dr. Torres works with oncologists to determine the HCV-related risks that may arise from their patients’ cancer treatments. For example, immunosuppression following stem cell or bone marrow transplantation can cause reactivation of the virus (i.e., sharp increases in the serum ALT level and viral load), as can treatment with monoclonal antibodies such as rituximab. Of greater concern is the hepatotoxicity of some anticancer drug regimens. Most chemotherapy drugs are processed in the liver and pose dangers to patients with cirrhosis, but the risks related to some treatment regimens are not well known. Therefore, Dr. Torres said, “We are studying what can happen with HCV in cancer patients and which chemotherapy regimens can be safely used.”

“We avoid concomitant HCV therapy and chemotherapy because interferon and ribavirin are myelosuppressive and cause anemia, neutropenia, and thrombocytopenia.”

— Dr. Harrys Torres

Once the immediate threat of cancer has been addressed, Dr. Torres focuses on the chronic HCV infection. The standard treatment for patients with HCV genotype 1 comprises pegylated interferon alfa-2a or -2b, ribavirin, and telaprevir or boceprevir. The latter two drugs are not approved for use in patients with other HCV genotypes, who receive interferon and ribavirin only. Whether a patient receives HCV treatment—and the timing of such treatment—depends on many factors. “We avoid concomitant HCV therapy and chemotherapy because interferon and ribavirin are myelosuppressive and cause anemia, neutropenia, and thrombocytopenia,” Dr. Torres said. Instead, many patients begin HCV treatment after the completion of chemotherapy or stem cell transplantation.

However, HCV treatment is not always delayed. “If a patient with HCV and hepatocellular carcinoma is recommended for a liver transplant, we begin HCV treatment while the patient is on the transplant list to eradicate the virus before the donor organ becomes available, thus preventing the infection of the new liver,” Dr. Torres said, adding that a study in this patient population was recently approved. “This will be the first clinical trial of HCV treatment from our institution,” he said. In this study, liver cancer patients from the largest liver transplant centers in the Texas Medical Center (The Methodist Hospital and St. Luke’s Episcopal Hospital) will be referred to MD Anderson’s HCV clinic for antiviral treatment before transplantation.

Immediate HCV treatment might also be recommended for a patient who needs chemotherapy with hepatotoxic drugs that would cause liver failure unless the virus is first eradicated.

A patient’s life expectancy may affect his or her decision to undergo HCV treatment. “The reason for HCV treatment is usually to prevent problems 10–20 years down the road,” Dr. Torres said. “A patient with metastatic cancer and a life expectancy of 5 years would not typically be a candidate for HCV treatment because the discomfort, adverse events, and inconvenience caused by the treatment would likely outweigh its benefits.”

“Until we have further evidence, I can’t say for certain whether oncologists should screen all patients for HBV and HCV, but they should at minimum screen those with known risk factors.”

— Dr. Jessica Hwang

Quality of life issues also may affect patients’ decisions. “I talk to my patients and tell them what side effects to expect from HCV treatment,” Dr. Torres said. These include flu-like symptoms and depression. “Some patients who have been through both chemotherapy and HCV treatment have told me that the HCV treatment is worse.”

Dr. Torres said that about 27% of his patients receive HCV treatment, which is similar to the treatment rate among HCV patients without cancer nationwide. The HCV cure rate among cancer patients is 30%–40%, which is lower than that in the general HCV patient population but similar to that in other immunocompromised patients. Dr. Torres said this rate may improve given the approval of the targeted drugs telaprevir and boceprevir about a year ago; it remains to be seen whether the drugs will produce a higher rate of lasting response among immunocompromised HCV patients.

Treating HBV

As is the case with HCV, monoclonal antibodies and other cancer treatments can reactivate chronic HBV infection. In fact, viral reactivation during cancer treatment is more likely among HBV patients than among HCV patients. Diagnostic criteria for HBV reactivation vary, but the first sign is an increase in the patient’s baseline viral load. This is followed by an increase in serum ALT.

“The risk of HBV reactivation during cancer treatment ranges from 14%to 72%,” said Marta Davila, M.D., a professor in the Department of Gastroenterology, Hepatology, and Nutrition. “If the patient becomes immunosuppressed, HBV can become very active and can multiply rapidly in the liver. Once the immune system improves after chemotherapy is concluded, the immune system will attack the virus in the liver, and patients can get fulminant hepatitis.” Chemoembolization of liver tumors or radiation delivered directly to the liver also can cause HBV reactivation.

Unlike HCV treatment, however, HBV treatment usually can be given prior to and during the cancer treatment. The main goal of HBV treatment is sustained viral suppression, and Dr. Davila said that the oral antiviral medications approved for this purpose—lamivudine, adefovir, entecavir, tenofovir, and telbivudine—can be given without interfering with chemotherapy or stem cell transplantation. Of these drugs, lamivudine has undergone the most study and has proved to reduce the rates of HBV reactivation in patients undergoing chemotherapy or stem cell transplantation. Since long-term use of lamivudine can result in drug resistance, entecavir and/or tenofovir are currently the first-line drugs for HBV therapy.

Decisions regarding a patient’s need for antiviral therapy and the duration of such therapy depend largely on whether the HBV surface antigen (HBsAg) and antibody to the HBV core antigen (anti-HBc) are present; the patient’s viral load is also important. Patients who test positive for HBsAg are given antiviral therapy. For those with a high viral load (>105 copies/mL), the antiviral therapy will likely continue for years after their cancer treatment is finished.

Patients who test negative for HBsAg but positive for anti-HBc undergo additional testing for the antibody to HBsAg (anti-HBs). Those negative for anti-HBs likely have an occult HBV infection; therefore, they typically receive antiviral therapy as a prophylaxis against reactivation. These patients continue receiving antiviral therapy for up to 12 months after the completion of chemotherapy or stem cell transplantation. Patients who test positive for both anti-HBc and anti-HBs do not need prophylactic antiviral drugs but are monitored closely for reactivation during cancer treatment.

If indicated, antiviral therapy is begun at least a week before the initiation of chemotherapy or preparation for stem cell transplantation. Dr. Davila prefers to begin antiviral treatment several weeks before cancer treatment to reduce the patient’s viral load as much as possible; however, even if it is started after chemotherapy, the antiviral therapy may prevent HBV reactivation.

Dr. Davila monitors all her patients’ viral loads during cancer treatment. An increase in viral load may be a sign of HBV reactivation. Depending on the situation, Dr. Davila may add a second antiviral drug or monitor the patient more closely. “Antiviral drugs greatly reduce the risk of HBV reactivation, but it’s not a 100% guarantee,” she said.

“Antiviral drugs greatly reduce the risk of HBV reactivation.”

— Dr. Marta Davila

The chemotherapy regimen is sometimes altered in patients with cirrhosis to avoid the use of or reduce the doses of hepatotoxic drugs. “We try to identify patients with cirrhosis with imaging studies, usually computed tomography, and sometimes with a liver biopsy,” Dr. Davila said. She noted that although cirrhosis is not always detected by imaging, and biopsy is contraindicated in some patients, HBV patients with no signs of cirrhosis receive the same chemotherapy as cancer patients without the virus.

Refining screening guidelines

Which cancer patients should be screened for HBV and HCV has not been determined. Drs. Torres and Davila share the opinion that all cancer patients who may receive cytotoxic or immunosuppressive therapy should be screened for both viruses; however, they acknowledge that the benefits of such testing are not established.

The CDC guidelines for HCV screening in the general population were revised last year to include anyone born between 1945 and 1965 as well as people with risk factors for HCV infection. Dr. Torres said he believes that screening according to these guidelines would detect most, but not all, HCV infections in cancer patients.

The likelihood of HBV reactivation during cancer treatment has led some oncologists to advocate for more thorough and standardized HBV screening guidelines. The CDC in 2008 recommended that all patients receiving immunosuppressive therapy be screened for HBV. However, in 2010 the American Society of Clinical Oncology published a provisional clinical opinion stating that the evidence needed to determine the net benefits and harms of HBV screening was insufficient.

Determining which patients should be screened is the mission of Jessica Hwang, M.D., M.P.H., an associate professor in the Department of General Internal Medicine. In a retrospective study, Dr. Hwang and her colleagues found that certain groups of cancer patients, such as those with hematologic malignancies and those scheduled to receive rituximab, had a high rate of HBV screening but that cancer patients overall did not. “Our study showed that there were low rates of screening, even among patients at risk for HBV,” she said.

To determine which groups of cancer patients would benefit from screening, a prospective study is being planned that will screen all participants for HBV prior to cancer treatment and, once a large pool of data is available, apply models of different screening strategies. “We will enter several screening models to see whether screening according to certain risk factors or clinical predictors, like types of cancer or types of therapy, would have detected all the patients with HBV,” Dr. Hwang said. The study, which is funded by the National Cancer Institute, is planned to begin at MD Anderson, and Dr. Hwang hopes to expand the study to community oncology centers such as those in the Community Clinical Oncology Program. “We seek to find evidence that will provide cost-effective screening guidelines that can be incorporated into clinical practice,” she said.

“Until we have further evidence, I can’t say for certain whether oncologists should screen all patients for HBV and HCV,” Dr. Hwang said, “but they should at minimum screen those with known risk factors.” Dr. Davila agreed. She said, “If you think a patient has risk factors for viral hepatitis, please screen the patient.”

FURTHER READING

Hwang JP, Fisch MJ, Zhang H, et al. Low rates of hepatitis B virus screening at the onset of chemotherapy. J Oncol Pract. 2012;8:e32–e39.

Hwang JP, Vierling JM, Zelenetz AD, et al. Hepatitis B virus management to prevent reactivation after chemotherapy: a review. Support Care Cancer. 2012;20:2999–3008.

Mahale P, Kontoyiannis DP, Chemaly RF, et al. Acute exacerbation and viral reactivation of chronic hepatitis C infection in cancer patients. J Hepatol. 2012;57: 1177–1185.

Torres HA, Davila M. Reactivation of hepatitis B virus and hepatitis C virus in patients with cancer. Nat Rev Clin Oncol. 2012;9:156–166.

For more information, contact Dr. Marta Davila at 713-563-8906, Dr. Jessica Hwang at 713-745-4516, or Dr. Harrys Torres at 713-792-6503.

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