The host immune response plays a major role in the course and outcome of acute HBV infection. Thus, most adults with acute HBV infection recover uneventfully, and probably fewer than 5% fail to clear HBsAg and develop chronic hepatitis B.11
In contrast, newborns and immunocompromised adults usually do not recover, but develop chronic infection with variable degrees of chronic inflammation and injury.12
Persons with acute HBV infection who recover often have symptomatic and icteric disease, while those with acute infection who evolve into chronic hepatitis typically have subclinical, anicteric disease and may not be aware of having acquired the infection.12
Although patients who clear HBsAg and HBV DNA from serum are often referred to as having ‘recovered’ from HBV infection, this is a misnomer. In such cases the immune system has successfully suppressed viral replication, however HBV persists in the liver, and possibly in other tissues. Small quantities of HBV remain in infected cells in a form known as covalently closed circular or cccDNA. This is an episomal form of the viral genome, which intermittently can become transcriptionally active. With normal immune function, viral replication is immediately suppressed by circulating HBV-specific immune cells. However if immune surveillance is lost, due to either natural or treatment-induced immunosuppression, HBV can once again replicate with the potential for chronic liver damage and, as shown here, disease transmission. Indeed, molecular analysis of liver tissue from patients who have recovered from acute or chronic hepatitis B has revealed the presence of low levels of HBV DNA in liver.13-17
Most convincing for the persistence of HBV despite recovery, however, have been the “experiments in nature,” including liver and stem cell transplantation. Patients without hepatitis B who receive a donor liver from a person with serological markers of recovery from hepatitis B (anti-HBc with or without anti-HBs but with no detectable HBsAg or HBV DNA in serum) almost invariably develop hepatitis B after transplantation.18-21
The source of the hepatitis B appears to be the donor liver graft rather than a pre-existing “occult” hepatitis B in the recipient. For these reasons, donors with anti-HBc are generally excluded from use, although studies have shown that these livers can be used if prophylaxis is given against reactivation of hepatitis B or if the liver is given to a patient who has pre-existing hepatitis B infection.22-26
HBV reactivation can also occur due to “escape” mutants, which can cause clinical hepatitis in the presence of anti-HBs because of a mutation in the major antigenic determinant of the HBsAg.27
None of our cases suggested this phenomenon.
Stem cell transplantation represents the converse of liver transplantation in regards to reactivation of hepatitis B. In stem cell transplantation, the source of the hepatitis B is not the donor graft but rather the liver of the stem cell transplant recipient.4, 6, 28-32
In this situation, the profound immunosuppression and loss of pre-existing HBV-specific immunity allows for HBV reactivation in the recovered liver and return of active viral replication. Because stem cell and liver transplant patients receive long-term immunosuppressive therapy, they are prone to develop chronic infection once the virus is reactivated.18, 20, 33
Reactivation after stem cell transplantation is actually an extreme example of reactivation that can occur with any form of severe immunosuppression, such as with chemotherapy for leukemia or solid tumors,3, 10, 34-36
immunomodulation in autoimmune disease,37-39
and spontaneously with progression of acquired immunodeficiency syndrome5, 7, 40-43
Summary of Clinical Data from Published Case Reports of HBV Reverse Seroconversiona
The six cases presented in this report represent the spectrum of manifestations, underlying conditions and outcomes of reactivation with reappearance of HBsAg. The risk of reactivation probably relates both to the degree of immune suppression (being profound after stem cell transplantation and of mild to moderate severity with chemotherapy and use of immunomodulatory agents) as well as the state of HBV replication in the liver. Thus, reactivation or at least an increase in viral replication can be expected in most persons who are HBsAg positive and have low levels of HBV DNA in serum.10, 35, 44
Several studies have shown that patients with HBsAg and inactive liver disease can suffer severe clinical reactivation of hepatitis B after cancer chemotherapy and many studies have demonstrated the efficacy of prophylaxis with nucleoside analogue anti-HBV therapy against such reactivation.44-51
Reactivation with reappearance of HBsAg is less common after standard chemotherapy for cancer, but can occur35, 52, 53
and is probably even more frequent with more rigorous forms of immune suppression such as stem cell transplantation (in which the immune system that has successfully held HBV replication under control is ablated and a donor immune system is substituted).54-59
Four cases, #1,#2,#3 & #6, were examples of reactivation with reappearance of HBsAg in recipients of stem cell transplants. In each case, the recipient had serological markers of previous HBV infection before transplant; whereas only one of the donors had such serological markers. The onset of the reactivation was minimally or not symptomatic and all four patients were found to have become HBsAg and HBV DNA positive almost incidentally, either from routine testing or, in two instances, after spouses developed acute, self-limited hepatitis B infection. In all four cases, the recurrent hepatitis B became chronic and in one instance the recurrent disease was severe and progressive, leading to cirrhosis, end-stage liver disease and death within 4 years of the stem cell transplant. In all four, HBV DNA levels were high and sustained, even though immunosuppression was given only intermittently in most cases.
One case (5) represented reactivation caused by marked immune suppression from therapy (antithymocyte globulin, cyclosporine and mycophenolate) for aplastic anemia. He was found to have chronic hepatitis B when serum aminotransferase levels were persistently elevated approximately two years after initial immunosuppressive therapy. Notably this patient was initially positive only for anti-HBs, having presumably lost anti-HBc over time. This highlights the importance of considering ‘recovered’ HBV infection in patients who are positive for only anti-HBs but have no history of HBV vaccination. This is particularly relevant in patients from areas with high HBV prevalence.
Finally, in one case, #4, reactivation with reappearance of HBsAg occurred in a patient with HIV infection and progressive immunodeficiency. In this patient, hepatitis B was not suspected and the disease arose when lamivudine therapy was withdrawn as a part of the routine modification of drug regimens in managing chronic HIV infection. This instance reinforces the need to provide anti-HBV activity in the antiretroviral regimen in patients with anti-HBc even in the absence of HBsAg. Alternatives to lamivudine in this situation include tenofovir and emtracitabine. Other antiretroviral agents have little or no activity against HBV.
These six examples of reactivation and reappearance of HBsAg in patients with serological evidence of previous infection underscore the need to screen patients routinely for markers of HBV infection before embarking upon chemotherapy or immune suppression as in stem cell or even solid organ transplantation. Because the onset of recurrent hepatitis B can be subclinical and insidious, this problem may not always be apparent and the consequences of the reactivation may not appear until long after the patient is no longer followed for the treatment of cancer or autoimmune disease. Routine testing should include anti-HBc, HBsAg and anti-HBs, as patients with immune deficiencies may lose antibody reactivity to HBV antigens. Patients with markers of previous HBV infection should receive prophylaxis using either lamivudine or other anti-HBV nucleoside analogues (adefovir, tenofovir, emtracitabine, telbivudine, or entecavir). The duration of such antiviral prophylaxis has not been defined, but therapy may be needed life long in the situation of sustained immune alteration such as stem cell transplantation. Prospective studies of prophylaxis in these situations are needed, not to demonstrate so much the need for prophylaxis as the optimal antiviral regimen and whether prophylaxis can safely be stopped. Sex partners and close household contacts of patients with markers of previous HBV infection who are at risk for reverse seroconversion should be screened and preemptively vaccinated against HBV.