Case Challenges

A 59-year-old man with hepatitis B reactivation 
during treatment for Hodgkin’s lymphoma

Tim McCarthy, MD 

Tim McCarthy

A 59-year-old man with a medical history significant for hypertension became symptomatic with subacute onset of lower extremity weakness and sharp pain.

He was seen in consultation by neurology, which performed several tests. A spinal MRI showed marked aortocaval adenopathy from L2-L4 with associated abnormal electromyography consistent with a bilateral asymmetric lumbosacral radiculopathy. There was concern for neoplasm, so he underwent CT-guided biopsy — small core and fine-needle aspiration — of a retroperitoneal lymph node, and it was consistent with classical Hodgkin’s lymphoma.

Cerebrospinal fluid was negative for malignant cells. A staging PET/CT showed lymphoma involving predominantly the left cervical, paraesophageal and para-aortic nodal chains, with indeterminate non-FDG avid left lower lobe pulmonary nodule. Bone marrow biopsy was negative for lymphoma involvement. The patient was started on chemotherapy with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD).

After two cycles of ABVD, routine blood work showed he had elevated liver enzymes. Further investigation revealed labs consistent with an acute hepatitis B virus (HBV) infection. The patient did not have any symptoms associated with the infection. He had no nausea or vomiting, fever or chills, but his wife reported that his eyes had become more yellow than usual.

The patient’s ABVD was held. He was started on entecavir (Baraclude, Bristol-Myers Squibb) 0.5 mg orally once per day, and he was referred to the hepatology clinic.

His initial viral load was 603 million IU/mL. This trended down with initiation of his entecavir, and it declined to 930,000 IU/mL within 2 weeks, and 15,000 IU/mL after 1 month.

His alanine aminotransferase level peaked at 2,015 IU/L, but had decreased to 74 IU/L a month after initiation of entecavir. His total bilirubin peaked at 6.2 mg/dL a week after initiation of entecavir and was 2.1 mg/dL a month later. His international normalized ratio remained normal. His hepatitis B e antigen was negative and his hepatitis B e antibody was positive. He had not been tested for hepatitis B before initiation of treatment; however, he was negative for hepatitis C and HIV.

The source of hepatitis B infection was unknown. The patient denied known risk factors for hepatitis infection — including use of IV drugs or intranasal cocaine — and had no history of blood transfusions. He had no known family history of liver disease. He denied knowledge of positive sexual contacts and had been in a monogamous relationship with his wife for more than 10 years. She reported being vaccinated against hepatitis B and had been tested in the past as part of her job.

The third cycle of ABVD was started after a delay of 4 weeks. His interim-PET scan after two cycles was positive, but the decision was made to continue him on ABVD due to his multiple comorbidities, including active hepatitis B. The patient currently has received five of his planned six cycles of ABVD. The patient will be treated to complete six cycles of ABVD and repeat PET/CT. He is continuing entecavir and showing improvement in liver tests, including decrease in transaminases and bilirubin and a decrease in viral load. He has been continued on entecavir 0.5 mg daily.

Case discussion

This case demonstrates a significant complication during cytotoxic chemotherapy, that of reactivation of hepatitis.

HBV persists in the body after serologic recovery from acute disease. Replication of the virus is balanced by the host’s immune response. Therefore, when the host experiences immune suppression, such as in the case of cytotoxic chemotherapy, there is the potential for reactivation or a flare of HBV.

Reactivations often occur in patients who are carriers of HBV infection; however, they also may occur in patients with resolved infection showing positive hepatitis B surface antigen (HBsAg). Reactivation also may occur in patients with resolved infection who are HbsAg-negative, anti-HBs–positive and anti-hepatitis B core positive.

Risk factors

Risk factors associated with an increased risk for HBV reactivation among HBV carriers include a diagnosis of lymphoma or breast cancer, male gender, young age or pre-existing hepatitis. Choice of chemotherapy also may play a role, with treatment using anthracyclines, vincristine, rituximab (Rituxan, Genentech/Idec Pharmaceuticals) and glucocorticoids showing increased risk for recurrence. In addition, an initial high HBV DNA level (>105 copies/mL) before treatment with cytotoxic chemotherapy has been reported as the most important risk factor for HBV reactivation.

Prevention

The use of prophylactic antiviral treatment for those at high risk for reactivation of HBV has been shown to help prevent possible reactivation. In a meta-analysis of 14 studies that involved 275 patients receiving chemotherapy, preventive lamivudine treatment was found to reduce the risk for HBV reactivation and HBV-related hepatitis by 80% to 100%.

Outside of their use in primary prevention, antiviral medications also may be used to treat a flare of HBV. Several reports have demonstrated the efficacy of treatment with antivirals and associated clinical improvement in patients who have developed a flare of HBV during chemotherapy.

There have been multiple published guidelines from major societies and organizations, including the American Association for the Study of Liver Diseases, ASCO, the NIH and the CDC.

Most of these statements recommend serologic testing for hepatitis B before initiation of cytotoxic chemotherapy. The ASCO statement suggests that HBV screening requires clinical judgment and may be considered in patients with an increased risk for chronic HBV or if highly immunosuppressive therapy is planned. There is no uniform consensus regarding duration of treatment; however, multiple guidelines report treatment should be maintained for at least 6 months after withdrawal of chemotherapy. In patients who have a high baseline serum HBV DNA level, treatment should be continued until a therapeutic endpoint. In addition, it is recommended that treatment should be continued for at least 12 months after withdrawal of rituximab.

Lamivudine 100 mg to 150 mg daily, thus far, has been the antiviral agent used most extensively for prophylactic treatment in clinical studies. Newer antivirals such as entecavir and adefovir (Hepsera, Gilead) also may be considered as alternative treatments either in the setting of lamivudine resistance or as first-line drugs in both primary prophylaxis and treatment of HBV reactivation.

As this case demonstrates, reactivation of hepatitis B during cytotoxic chemotherapy may present significant clinical challenges in the treatment of patients with various types of cancer. Through screening — when appropriate — and treatment, we can hope to prevent complications of HBV reactivation while minimizing delay to chemotherapy treatment of the patients underlying cancer.

References:

Kohrt HE. Aliment Pharmacol Ther. 2006;24:1003-1016.

Loomba R. Ann Intern Med. 2008;148:519-528.

Mindikoglu A. Clin Gastroenterol Hepatol. 2006;4:1076-1081.

Yeo W. J Med Virol. 2000;62:299-307.

For more information:

Tim McCarthy, MD, is a fellow in hematology and oncology at the University of North Carolina at Chapel Hill. He may be reached at Physicians Office Building, 170 Manning Drive, Third floor, CB# 7305, Chapel Hill, NC 27599.

Disclosure: McCarthy reports no relevant 
financial disclosures.

Tim McCarthy, MD 

Tim McCarthy

A 59-year-old man with a medical history significant for hypertension became symptomatic with subacute onset of lower extremity weakness and sharp pain.

He was seen in consultation by neurology, which performed several tests. A spinal MRI showed marked aortocaval adenopathy from L2-L4 with associated abnormal electromyography consistent with a bilateral asymmetric lumbosacral radiculopathy. There was concern for neoplasm, so he underwent CT-guided biopsy — small core and fine-needle aspiration — of a retroperitoneal lymph node, and it was consistent with classical Hodgkin’s lymphoma.

Cerebrospinal fluid was negative for malignant cells. A staging PET/CT showed lymphoma involving predominantly the left cervical, paraesophageal and para-aortic nodal chains, with indeterminate non-FDG avid left lower lobe pulmonary nodule. Bone marrow biopsy was negative for lymphoma involvement. The patient was started on chemotherapy with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD).

After two cycles of ABVD, routine blood work showed he had elevated liver enzymes. Further investigation revealed labs consistent with an acute hepatitis B virus (HBV) infection. The patient did not have any symptoms associated with the infection. He had no nausea or vomiting, fever or chills, but his wife reported that his eyes had become more yellow than usual.

The patient’s ABVD was held. He was started on entecavir (Baraclude, Bristol-Myers Squibb) 0.5 mg orally once per day, and he was referred to the hepatology clinic.

His initial viral load was 603 million IU/mL. This trended down with initiation of his entecavir, and it declined to 930,000 IU/mL within 2 weeks, and 15,000 IU/mL after 1 month.

His alanine aminotransferase level peaked at 2,015 IU/L, but had decreased to 74 IU/L a month after initiation of entecavir. His total bilirubin peaked at 6.2 mg/dL a week after initiation of entecavir and was 2.1 mg/dL a month later. His international normalized ratio remained normal. His hepatitis B e antigen was negative and his hepatitis B e antibody was positive. He had not been tested for hepatitis B before initiation of treatment; however, he was negative for hepatitis C and HIV.

The source of hepatitis B infection was unknown. The patient denied known risk factors for hepatitis infection — including use of IV drugs or intranasal cocaine — and had no history of blood transfusions. He had no known family history of liver disease. He denied knowledge of positive sexual contacts and had been in a monogamous relationship with his wife for more than 10 years. She reported being vaccinated against hepatitis B and had been tested in the past as part of her job.

The third cycle of ABVD was started after a delay of 4 weeks. His interim-PET scan after two cycles was positive, but the decision was made to continue him on ABVD due to his multiple comorbidities, including active hepatitis B. The patient currently has received five of his planned six cycles of ABVD. The patient will be treated to complete six cycles of ABVD and repeat PET/CT. He is continuing entecavir and showing improvement in liver tests, including decrease in transaminases and bilirubin and a decrease in viral load. He has been continued on entecavir 0.5 mg daily.

Case discussion

This case demonstrates a significant complication during cytotoxic chemotherapy, that of reactivation of hepatitis.

HBV persists in the body after serologic recovery from acute disease. Replication of the virus is balanced by the host’s immune response. Therefore, when the host experiences immune suppression, such as in the case of cytotoxic chemotherapy, there is the potential for reactivation or a flare of HBV.

Reactivations often occur in patients who are carriers of HBV infection; however, they also may occur in patients with resolved infection showing positive hepatitis B surface antigen (HBsAg). Reactivation also may occur in patients with resolved infection who are HbsAg-negative, anti-HBs–positive and anti-hepatitis B core positive.

PAGE BREAK

Risk factors

Risk factors associated with an increased risk for HBV reactivation among HBV carriers include a diagnosis of lymphoma or breast cancer, male gender, young age or pre-existing hepatitis. Choice of chemotherapy also may play a role, with treatment using anthracyclines, vincristine, rituximab (Rituxan, Genentech/Idec Pharmaceuticals) and glucocorticoids showing increased risk for recurrence. In addition, an initial high HBV DNA level (>105 copies/mL) before treatment with cytotoxic chemotherapy has been reported as the most important risk factor for HBV reactivation.

Prevention

The use of prophylactic antiviral treatment for those at high risk for reactivation of HBV has been shown to help prevent possible reactivation. In a meta-analysis of 14 studies that involved 275 patients receiving chemotherapy, preventive lamivudine treatment was found to reduce the risk for HBV reactivation and HBV-related hepatitis by 80% to 100%.

Outside of their use in primary prevention, antiviral medications also may be used to treat a flare of HBV. Several reports have demonstrated the efficacy of treatment with antivirals and associated clinical improvement in patients who have developed a flare of HBV during chemotherapy.

There have been multiple published guidelines from major societies and organizations, including the American Association for the Study of Liver Diseases, ASCO, the NIH and the CDC.

Most of these statements recommend serologic testing for hepatitis B before initiation of cytotoxic chemotherapy. The ASCO statement suggests that HBV screening requires clinical judgment and may be considered in patients with an increased risk for chronic HBV or if highly immunosuppressive therapy is planned. There is no uniform consensus regarding duration of treatment; however, multiple guidelines report treatment should be maintained for at least 6 months after withdrawal of chemotherapy. In patients who have a high baseline serum HBV DNA level, treatment should be continued until a therapeutic endpoint. In addition, it is recommended that treatment should be continued for at least 12 months after withdrawal of rituximab.

Lamivudine 100 mg to 150 mg daily, thus far, has been the antiviral agent used most extensively for prophylactic treatment in clinical studies. Newer antivirals such as entecavir and adefovir (Hepsera, Gilead) also may be considered as alternative treatments either in the setting of lamivudine resistance or as first-line drugs in both primary prophylaxis and treatment of HBV reactivation.

As this case demonstrates, reactivation of hepatitis B during cytotoxic chemotherapy may present significant clinical challenges in the treatment of patients with various types of cancer. Through screening — when appropriate — and treatment, we can hope to prevent complications of HBV reactivation while minimizing delay to chemotherapy treatment of the patients underlying cancer.

References:

Kohrt HE. Aliment Pharmacol Ther. 2006;24:1003-1016.

Loomba R. Ann Intern Med. 2008;148:519-528.

Mindikoglu A. Clin Gastroenterol Hepatol. 2006;4:1076-1081.

Yeo W. J Med Virol. 2000;62:299-307.

For more information:

Tim McCarthy, MD, is a fellow in hematology and oncology at the University of North Carolina at Chapel Hill. He may be reached at Physicians Office Building, 170 Manning Drive, Third floor, CB# 7305, Chapel Hill, NC 27599.

Disclosure: McCarthy reports no relevant 
financial disclosures.