Answers

Short answers

1 The diagnosis is severe life threatening reactivation of pre-existing chronic HBV infection, although drug induced liver injury and de novo autoimmune hepatitis should also be considered.

2 Severe reactivation is most often seen during chemotherapy, but it can also occur during immunosuppression—especially if biological agents such as monoclonal antibodies, or a combination of chemotherapy and biological agents, are used.

3 Immunosuppressive treatment leads to an increase in the replication of HBV, followed by severe hepatitis and a sharp decline in hepatic function.

4 Early antiviral treatment is important (if the viral load is high, entecavir 0.5 mg/day or tenofovir 300 mg/day), because delaying treatment may reduce survival if the patient has acute fulminant hepatitis or reactivating hepatitis.

5 Patients undergoing immunosuppressive treatment, especially chemotherapy, are tested for the hepatitis B surface antigen and antibody to hepatitis B core antigen. If the test for the hepatitis B surface antigen is positive, prophylactic antiviral treatment is indicated. If the test for the hepatitis B core antigen only is positive then close monitoring is needed. It is safer to prevent reactivation than to treat reactivation

Long answer 1. Diagnosis
Life threatening liver disease during treatment with anti-TNF monoclonal antibodies or other immunosuppressives can be caused by the reactivation of HBV infection, de novo autoimmune hepatitis, or drug induced liver injury; alternatively, it can be unrelated to treatment and may coincide with acute viral hepatitis.

HBV reactivation
The patient had not been tested serologically for HBV before treatment with efalizumab and adalimumab. Reactivation of HBV is the most common cause of severe hepatitis in patients treated with monoclonal antibodies.¹ Reactivation can to some degree be differentiated from acute infection by measuring serum antibodies to hepatitis B core antigen. This test is positive in acute infection but usually negative (or only low positive ) in cases of reactivation. However, hepatitis B surface antigen may be negative in acute HBV infection

De novo autoimmune hepatitis
Although anti-TNF monoclonal antibodies suppress the immune system, there is evidence that these agents can induce autoimmune disease.² The most commonly reported autoimmune diseases in this setting are vasculitis and systemic lupus erythematosus, but seven cases of autoimmune hepatitis have been described.² All occurred in women,³ and our patient is a man. It is unclear how anti-TNF leads to autoimmunity, but blocking TNF may interfere with the suppression of autoreactive CD8 T cells.⁴

Drug induced liver injury
This phenomenon is one of the most common reasons that drugs are withdrawn from the market or their development is halted, and it has become the most common cause of acute liver failure in the United States.⁵ However, no case of drug induced liver injury in relation to anti-TNF has been reported.

Long answer 2. When does HBV reactivation occur?
Reactivation of HBV infection during chemotherapy in carriers
This seems to be more common for certain malignancies and treatments. The risk has been reported to be higher in lymphomas than in other malignancies, and the highest risk is seen in bone marrow transplant recipients. Reactivation of HBV has been reported in 15-50% of hepatitis B surface antigen positive patients undergoing chemotherapy and up to 75% of those who have received a bone marrow transplant.

Several meta-analyses or systematic reviews support the effectiveness of a priori treatment with antivirals in hepatitis B surface antigen positive patients undergoing immunosuppressive chemotherapy.^{6 7} One review calculated that only 11 patients need to receive lamivudine prophylaxis to save one life.⁶ Recent guidelines recommend prophylactic antiviral treatment for hepatitis B surface antigen positive patients undergoing chemotherapy.^{1 8}

Reactivation of HBV after treatment with monoclonal antibody
Several fatal cases of severe HBV reactivation after treatment with monoclonal antibody have been reported, although reactivation does not occur in all cases.^{9 10 11} Treatment with anti-TNF antibodies, immunosuppressants, or prolonged high dose steroids in hepatitis B surface antigen positive patients carries a risk of reactivation, and antiviral prophylaxis is recommended.

Reactivation in resolved HBV infection
Hepatitis B surface antigen negative patients who are positive for antibodies to hepatitis B core antigen should be monitored for hepatitis B surface antigen seroreversion and viral replication.^{12 13 14} After clearance of hepatitis B surface antigen, antibodies to hepatitis B core antigen persist as a marker of past infection, even when antibodies to hepatitis B surface antigen have disappeared. This is considered to be resolved infection. Because HBV remains in the body in undetectable quantities, reactivation can occur when the immune system is impaired.^{15 16} Because patients who are hepatitis B surface antigen negative but positive for antibodies to hepatitis B core antigen have lower rates of reactivation, antiviral prophylaxis is not recommended, but hepatitis B surface antigen and HBV DNA should be regularly monitored to check for reactivation.^{1 8} If tests for hepatitis B surface antigen or HBV DNA become positive, pre-emptive antiviral therapy should be started. The optimal monitoring interval is currently unknown because no prospective studies exist. A retrospective study found that a 100-fold increase in HBV DNA preceded hepatitis B surface antigen seroreversion by eight to 12 weeks and hepatitis (as determined by an increase in alanine aminotransferase) by 12 to 28. The authors therefore suggested that HBV DNA should be monitored at least three-monthly with real time polymerase chain reaction.¹⁷

Pre-emptive treatment seems to be indicated in the absence of hepatitis B surface antigen in patients treated with chemotherapy plus monoclonal antibodies. A recent study reported a 25% reactivation rate in patients receiving CHOP-rituximab therapy, with one fatal case.¹⁸

Long answer 3. Why does HBV reactivation often occur suddenly?
In the past it was thought that patients with hepatitis B surface antigen in their serum and no signs of active hepatitis were healthy carriers, and that only the host immune response would lead to hepatic injury as indicated by raised transaminases. However, epidemiological prospective studies showed that viral load is associated with the development of cirrhosis and liver cancer in HBV infection,^{19 20} and that reducing viral load improves survival.^{21 22} Viral load often increases in patients who are immunosuppressed, and this is followed by hepatitis when immunity is restored.

Long answer 4. Treatment
Antiviral treatment has been reported to improve survival in patients with severe acute hepatitis.²³ Timely initiation seems crucial,²⁴ and recent guidelines recommend oral antiviral treatment in patients with acute HBV and an increased international normalised ratio.^{1 8} Given the potency of newer drugs, entecavir, telbivudine, or tenofovir are preferred because of their fast action on HBV DNA.

Because reactivation of pre-existing chronic hepatitis B may carry an even higher risk of death than is seen in patients who have hepatitis as a result of recent infection, early intervention is important. This is probably because patients with reactivation of chronic disease usually have a higher viral load than those who have acute HBV infection.²⁵

Long answer 5. Preventing HBV reactivation
Prophylaxis is clearly preferable to treating reactivation.^{26 27 28} Antiviral treatment should be started two weeks before, or at the beginning of, immunosuppressive chemotherapy or treatment with an anti-TNF antibody, and it should be continued for at least six months to a year after immunosuppressive treatment has finished. Patients should continue to be monitored closely (every three months) because fatal reactivations can occur several months after the end of immunosuppressive treatment.^{29 30}

A standard dose of lamividine is the prophylactic treatment of choice for reactivation of HBV because the risk of resistance is small when the viral load is low. As with fulminant acute HBV, lamivudine also decreases HBV related mortality in cases of reactivation.³¹ Some patients with reactivation may even be able to continue with cytotoxic chemotherapy while being treated with lamivudine.³²

In patients with high viral load, the substantial risk of resistance means that more potent antivirals such as entecavir or tenofovir may be of greater benefit.^{33 34 35 36} Such patients have only been treated with lamivudine in the past, however, and no evidence based data are available on more potent antiviral agents.

Summary
Patients undergoing immunosuppressive treatment should be routinely evaluated for their HBV status. This is particularly important for patients from areas where HBV is endemic, such as Asia and Africa. Patients who are positive for hepatitis B surface antigen should be given prophylactic antivirals. Patients whose tests are negative for hepatitis B surface antigen but positive for antibody to hepatitis B core antigen have a risk for reactivation. Such patients should be closely monitored for hepatitis B surface antigen and HBV DNA during immunosuppressive treatment or treatment with monoclonal antibodies such as anti-TNF.

Learning points

• Once people are infected with HBV, the virus persists in the body for life.
  
• Before patients are given immunosuppressive treatment (chemotherapy or monoclonal antibodies) they should be screened for hepatitis B surface antigen and antibodies to hepatitis B core antigen.
  
• Patients who are positive for hepatitis B surface antigen have a high risk of HBV reactivation on immunosuppressive therapy and should be treated pre-emptively. Lamivudine is sufficient for patients with a low viral load. If the viral load is >20 000 IU/ml, entecavir 0.5 mg/day or tenofovir 200 mg/day are recommended; this dose will need to be adapted in patients with renal insufficiency.
  
• Patients who are negative for hepatitis B surface antigen but positive for antibodies to hepatitis B core antigen have a lower, but still substantial, risk of HBV reactivation on immunosuppressive treatment. They should be monitored monthly for hepatitis B surface antigen and HBV DNA.
  
• Patients with HBV reactivation need immediate antiviral treatment and they should be managed in conjunction with a liver transplant centre.
  

Cite this as: BMJ 2009;338:b508