Hepatitis B is an infection of the liver caused by the hepatitis B virus (HBV). The signs and symptoms can range from mild to severe and include anorexia, fatigue, abdominal pain, and jaundice. However, for some people, infection may be asymptomatic. The majority of immunocompetent adults who become acutely infected with hepatitis B are able to clear the infection. In contrast, people who are infected early in life tend to progress to chronic infection.
Hepatitis B reactivation refers to a sudden increase in HBV replication in a person with resolved or inactive chronic hepatitis B. While this can occur spontaneously, it is more commonly associated with the use of chemotherapy and other immunosuppressive therapies. This abrupt increase in viral replication can cause a severe disease flare, acute hepatitis, and even fulminant liver failure.
The risk of reactivation is dependent upon the degree and duration of immunosuppression, the type of medication and its mechanism of action, the underlying HBV disease activity and the extent of liver disease. Initiation of antiviral therapy once reactivation is established often leads to poor outcomes. Therefore, antiviral prophylaxis should be considered for susceptible patients. Evidence demonstrates that antiviral prophylaxis reduces rate of HBV-associated hepatitis, severe flares, and death.
The Therapeutic Guidelines provide the following recommendations for HBV testing to identify patients for antiviral prophylaxis:
- Test all patients for HBV prior to initiation of cancer chemotherapy or other significant immunosuppressive therapy;
- Routine testing is not required for patients prescribed short courses of low dose corticosteroids (equivalent to less than 20mg prednisolone daily);
- Testing should include hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc) and hepatitis B surface antibody (anti-HBs);
- Patients who test positive for hepatitis B surface antigen (HBsAg) are at risk of severe flare that could lead to liver failure. These patients should have their hepatitis B disease fully assessed and receive antiviral prophylaxis before beginning significant immunosuppressant therapy;
- Patients who are HBsAg negative but anti-HBc positive may require prophylaxis, depending upon the type of chemotherapy they receive;
- Patients who demonstrate no prior exposure to HBV do not require prophylaxis. However, hepatitis B vaccination should be considered;
If antiviral prophylaxis is considered necessary, it should ideally be initiated at least one week before starting significant immunosuppressive therapy. However, this may not be possible if urgent chemotherapy or immunosuppression is required. Entecavir and tenofovir are the first-line agents recommended for prophylaxis. These agents are preferred over other antivirals, such as lamivudine, due to their potency and low risk of resistance.
Entecavir is a nucleoside analogue that inhibits HBV polymerase. Following transformation to its active form, entecavir inhibits all three steps in the HBV replication process.
One randomised, open-label trial investigated the effectiveness of entecavir in HBsAg seropositive patients with lymphoma who were receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Entecavir demonstrated a lower risk of HBV reactivation (6.6% for entecavir and 30% for lamivudine), HBV-related hepatitis (0% vs 13.3%), and less chemotherapy interruption (1.6% vs 18.3%). A retrospective analysis of patients with solid tumours produced similar findings. In this study, the rate of HBV reactivation was 0% in the entecavir group compared to 7% in the lamivudine group. In addition, interruption of chemotherapy was only required in 2.9% of the entecavir group compared to 9.7% of the lamivudine group.
Entecavir is available as oral tablets. Food may reduce the rate and extent of absorption. Therefore, it is usually advised to take doses on an empty stomach at least two hours before or after a meal. Entecavir is predominantly eliminated by the kidneys and dose reduction is recommended for patients with a creatinine clearance <50mL/min.
The most common adverse effects associated with entecavir include headache, fatigue, nausea, and diarrhoea. Lactic acidosis is a serious but rare adverse effect associated with entecavir and other nucleoside analogues.
Tenofovir is a nucleotide analogue that inhibits the action of HBV polymerase and also has activity against HIV reverse transcriptase.
Tenofovir disoproxil is available in a number of different salt forms with the following equivalencies:
= 300mg tenofovir disoproxil fumarate
= 300mg tenofovir disoproxil maleate
= 291mg tenofovir disoproxil phosphate
All three of the above doses provide 245mg of tenofovir disoproxil and are considered bioequivalent.
Tenofovir is also available as tenofovir alafenamide. Tenofovir alafenamide is absorbed more quickly than disoproxil salts, achieving higher intracellular levels of the active drug, tenofovir diphosphate. This means that lower doses are required which may have safety benefits due to reduced drug exposure for the kidneys and other organs. However, no studies have investigated its use as a prophylactic agent and the guidelines currently recommend disoproxil salts for HBV prophylaxis.
Tenofovir is available as oral tablets which should be taken with food for optimal absorption. Tenofovir’s most common adverse effects include nausea, vomiting, headache, and hypophosphataemia. Nephrotoxicity is an infrequent adverse effect which may be reversible if identified early. Tenofovir alafenamide may have less renal toxicity compared to the disoproxil forms.
Both tenofovir and entecavir are first-line agents for antiviral prophylaxis. Entecavir is typically preferred for patients with pre-existing renal impairment and tenofovir is preferred for females of childbearing potential.
Duration of therapy
Patients should be advised to continue taking their HBV prophylaxis for the duration recommended by their prescriber. The usual duration is between six and 12 months after stopping immunosuppressive therapy. However, this should be increased to 18 to 24 months after stopping immunosuppressive therapy if the patient receives B-cell depleting, B-cell active or anti-CD20 medicines such as rituximab or is undergoing haematopoietic stem cell transplantation.
- Chen WC, Cheng JS, Chiang PH, Tsay FW, Chan HH, Chang HW, et al. A comparison of entecavir and lamivudine for the prophylaxis of hepatitis B virus reactivation in solid tumor patients undergoing systemic cytotoxic chemotherapy. PLoS One. 2015; 10(6): e0131545.
- Hepatitis B Management During Cancer Therapy Consensus Statement Group 2019. Hepatitis B management during immunosuppression for haematological and solid-organ malignancies: an Australian consensus statement 2019. Melbourne: Hepatitis B Management During Cancer Therapy Consensus Statement Group; 2019.
- Huang H, Li X, Zhu J, Ye S, Zhang H, Wang W, et al. Entecavir vs lamivudine for prevention of hepatitis B virus reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: a randomized clinical trial. JAMA. 2014; 312(23): 2521-30.
- Liver Disorders Expert Group. Therapeutic Guidelines: Liver Disorders. Melbourne: Therapeutic Guidelines; 2020.
- Myint A, Tong MJ, Beaven SW. Reactivation of hepatitis B virus: a review of clinical guidelines. Clinical Liver Disease 2020; 15(4): 162-7.
- Rossi S (editor). Australian Medicines Handbook. Adelaide: AMH; 2021.