Published 23 November 2005

Recommendations

• Patients known to be HBsAg positive should receive lamivudine prophylaxis 100mg/day starting the week before chemotherapy and continuing until 8 weeks after the chemotherapy finishes.
• A Special Access Form must be completed for lamivudine to contribute to a patient's deductible. This is available at: https://www.healthservices.gov.bc.ca/exforms/pharmacare.html
• Decisions regarding baseline screening for HBsAg carrier status should take into account the patient's risk factors and the marked regional variation in HBsAg carrier rates.
• Patients with identifiable risk factors should be screened for HBsAg.  Screening is optional for patients from regions with low HBsAg prevalence and without known risk factors.
• Screening and the use of lamivudine for hepatitis C is not recommended

Risk Factors for HBV
1. Patients from endemic regions ¨CSoutheast Asia, China, Africa, and the Inuit
2. Sexual activity ¨C accounts for 50% cases in USA (esp. promiscuity/prostitution)
3. Percutaneous (IVDU, sharing razors/tooth brushes, tattoo, piercing, acupuncture)
4. Blood transfusion
5. Organ transplantation

Of note, there is no clear risk factor in 20-30% cases (possible under-reporting) (1)

Prevalence of HBsAg Positivity in Various Regions of BC

Based on a prenatal screen in 1215 BC women aged 15-44 years old the age-standard HBsAg positivity rate (active carriers) was 1.4% (2).  This was similar to the crude 1.0% rate for BC and the Yukon for 1996-2000 detected by Canadian Blood Services.  Results from Nova Scotia were 0.1% and Barrie Ontario 0.3%.  There is a marked regional variation amongst the 35,000 carriers in BC(3).  The extrapolated carrier rates are:  Interior BC 0.1%, Northern BC 0.15%, Vancouver Island 0.19%, Fraser Region 0.65%, Vancouver Coastal 1.94%.

HBV Review:   HBV is a partially double stranded, hepatotropic DNA virus that replicates through an RNA template using the enzyme DNA polymerase (1).  Approximately 350 million people worldwide are infected.  Eight percent of the population of Southeast Asia, China, and Africa, and 10% of the population of Hong Kong are chronic carriers of the virus.  These patients are serum-positive for Hepatitis B surface Antigen, HBsAg.

Life Cycle:  When an adult is infected with the virus there is a 2-4 week incubation period during which the patient has no symptoms and liver enzymes are normal as the virus itself is usually not cytopathic.  Hepatic inflammation and elevated liver enzymes are secondary to the patient developing an immune response to antigens presented on infected hepatocytes in an attempt to eradicate the virus.  Over 95% of infected adults will clear the virus and become HBsAg negative and develop antibodies to HBsAg. If this is unsuccessful the patient will remain HBsAg positive and will be a chronic carrier of the virus.  However, in endemic parts of the world the majority of infections occur in the perinatal period (vertical transmission to the neonate).  Unlike adults, most neonates do not clear the infection and 95% become chronic asymptomatic carriers of HBV.

Antibodies/Antigens
HBsAg - HBV surface antigen; patient is actively infected
Antibody to HBsAg - develops when patient clears the virus
Antibody to HBcAg - antibody to HBV core antigen; remains positive in all patients who were exposed to the virus (whether they clear it or not).  Patients who were vaccinated against HBV are negative for antibodies to HBcAg but are positive for antibodies to HBsAg.
HBeAg - marker of active viral replication

Chemotherapy and HBV
Patients who are HBsAg positive can have a flare of hepatitis while on chemotherapy. This is usually defined as a ≥ 3x increase in ALT (or an absolute ALT over 100 u/L) compared to baseline levels with a ≥10x increase in HBV DNA level (or an absolute DNA level > one million copies/ml). The severity of the hepatitis is graded as mild (ALT ≤2x ULN), moderate (ALT 2-5x ULN), or severe (>5xULN) (4) Hepatitis flares while on chemotherapy may result in delays of chemotherapy administration, permanent discontinuation, and even fatalities. (5) It is estimated that over 20-40% of patients who are HBsAg positive will have an HBV flare while on chemotherapy. (4, 6, 7)

Risk Factors for HBV Flare in HBsAg Positive Patients on Chemotherapy(8)
Detectable HBV DNA OR(odds ratio) = 8.4; use of steroids (for antiemetics or in CHOP) OR = 2.7; Lymphoma OR 5.0; Breast cancer OR = 4.2.  Other series have suggested that male sex, HBeAg positivity, and pre-chemotherapy liver enzyme levels are risk factors.

Prevention of Flares
Lamivudine is a nucleoside analogue that interferes with HBV replication.   In patients with detectable HBV DNA, almost 100% will have a temporary clearance of the virus after 4-12 weeks of lamivudine therapy (1).  However, this results in a sustained remission in less than 20%.  Initial studies showed lamivudine prophylaxis to be effective at preventing flares in HBsAg positive lymphoma patients (9).  Lamivudine has also been used to successfully treat established HBV flares in patients on chemotherapy.  However, treatment with lamivudine once the patient has flared is not always successful, and fatalities have been reported (5). 

Lamivudine prophylaxis has been studied in breast cancer patients using case-control series from Hong Kong.  The largest series confined to HBsAg positive, breast cancer patients was reported in 2004(4) and involved 92 patients.  The lamivudine (case) group received prophylactic lamivudine 100mg/d starting the week before chemotherapy and continuing for 2 months after chemotherapy ended. The control group did not receive lamivudine prophylaxis. The majority of patients were treated in the adjuvant setting, received anthracycline chemotherapy, and also received steroids as part of the anti-emetic regimen.  In this series no deaths were reported.  Lamivudine prophylaxis reduced the number of HBV flares from 31.1% to 6.5%, and reduced the number of delays/premature terminations of chemotherapy from 21.3% to 3.2%.
 
A second report, using an identical study design from the same Hong Kong investigators (6) included 258 cancer patients of which 81 had breast cancer.  In this case-control series lamivudine reduced the number of HBV flares from 24.4% to 4.6%, and reduced the number of delays/premature terminations of chemotherapy from 14.5% to 0%.

From these two reports it appears that lamivudine prophylaxis reduces the number of HBV flares on chemotherapy from 30% to 5% (24-31% to 4¨C6%).  The number needed to treat to prevent one flare is between 4 and 5.  The number needed to treat to avoid 1 delay/disruption in chemotherapy is approximately 6 (5.5 ¨C 7.1).

Lamivudine
The prophylactic dose is 100mg/day starting the week before chemotherapy and is continued until 8 weeks after chemotherapy finishes.  Lamivudine is an expensive medication with 30 tablets costing approximately $145.  It is covered by most extended health plans, but not by basic MSP until a patient reaches their deductible.  A Special Access Form must be filled out so that the medication contributes to the patient' s deductible. https://www.healthservices.gov.bc.ca/exforms/pharmacare.html

Hepatitis C
Hepatitis C is not associated with an appreciable risk for chemotherapy related flares. (10)  Lamivudine is not an effective method for suppression of hepatitis C. Thus, screening for hepatitis C, and the use of lamivudine are not recommended.

Recommendations

• Patients known to be HBsAg positive should receive lamivudine prophylaxis 100mg/day starting the week before chemotherapy and continuing until 8 weeks after the chemotherapy finishes.
• A Special Access Form must be completed for lamivudine to contribute to a patient's deductible. This is available at: https://www.healthservices.gov.bc.ca/exforms/pharmacare.html
• Decisions regarding baseline screening for HBsAg carrier status should take into account the patient's risk factors and the marked regional variation in HBsAg carrier rates.
• Patients with identifiable risk factors should be screened for HBsAg.  Screening is optional for patients from regions with low HBsAg prevalence and without known risk factors.
• Screening and the use of lamivudine for hepatitis C is not recommended

References

1. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337(24):1733-45.
2. Dawar M, Patrick DM, Bigham M, Cook D, Krajden M, Ng H. Impact of universal preadolescent vaccination against hepatitis B on antenatal seroprevalence of hepatitis B markers in British Columbia women. Cmaj 2003;168(6):703-4.
3. BC Centre for Disease Control:  2004 British Columbia Annual Summary of Reportable Diseases.
4. Yeo W, Ho WM, Hui P, et al. Use of lamivudine to prevent hepatitis B virus reactivation during chemotherapy in breast cancer patients. Breast Cancer Res Treat 2004;88(3):209-15.
5. Cainelli F, Longhi MS, Concia E, Vento S. Failure of lamivudine therapy for chemotherapy-induced reactivation of hepatitis B. Am J Gastroenterol 2001;96(5):1651-2.
6. Yeo W, Chan PK, Ho WM, et al. Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy. J Clin Oncol 2004;22(5):927-34.
7. Yeo W, Chan PK, Hui P, et al. Hepatitis B virus reactivation in breast cancer patients receiving cytotoxic chemotherapy: a prospective study. J Med Virol 2003;70(4):553-61.
8. Yeo W, Zee B, Zhong S, et al. Comprehensive analysis of risk factors associating with Hepatitis  virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer 2004;90(7):1306-11.
9. Shibolet O, Ilan Y, Gillis S, Hubert A, Shouval D, Safadi R. Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers. Blood 2002;100(2):391-6.
10. Persico M, De Marino F, Russo GD, et al. Efficacy of lamivudine to prevent hepatitis reactivation in hepatitis B virus-infected patients treated for non-Hodgkin lymphoma. Blood 2002;99(2):724-5.