From OncoLog, February 2013, Vol. 58,
Chronic Viral Hepatitis in Cancer Patients Requires Personalized Management
By Bryan Tutt
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.
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
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
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
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
|“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.
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
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.”
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
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.
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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