Hepatitis B virus (HBV) infection has decreased in frequency in kidney transplant recipients (KTR) due to the reinforcement of vaccination policies in the Chronic Kidney Disease (CKD) population and increased precautions to prevent transmission of the HBV among dialysis patients.1 Reactivation of HBV infection in KTR is associated with important morbidity and mortality.2 Immunosuppressive (IS) drugs used to prevent graft rejection blunt B and T cell functions and that permits HBV replication and viral protein expression on the surface of the infected hepatocytes.3 Reactivation is more frequent in patients who are HBsAg-positive, but it can also occur in patients with resolved HBV infection (HBsAg-negative and anti-HBc-positive), since the virus can still replicate within the hepatocytes.4,5 Data are scarce and conflicting regarding the risk of HBV reactivation in this subset of patients. Reported rates of reactivation are variable; while some authors claim that the risk is negligible regardless of anti-HBs status,6 others have published rates ranging from 1 to 6.5%.7,8 It has been suggested that in these patients the presence of anti-HBs antibodies may provide protection against HBV reactivation8–10 but there are too few data about the proportion of renal transplant patients with resolved HBV infection and with positive anti-HBs titers that lose immunity during follow-up.11 Thus, it remains unclear regarding what kind of monitoring is needed and whether these patients would benefit from antiviral prophylaxis during the post-transplant period.

In this study we aim to retrospectively evaluate the risk of HBV reactivation in KTR with previously resolved infection in a Portuguese Kidney Transplant Centre.

HBV reactivation is a potentially fatal condition with mortality rates reported as high as 25%.4 In our study the rate of HBV reactivation in patients with previously resolved infection was approximately 2%, resulting in death in one patient. This highlights the importance of assessing potential risk factors for reactivation since prophylaxis can prevent its occurrence.

Only 4 retrospective studies addressed the risk of reactivation in HBsAg-negative and anti-HBc-positive KTR.7–9,13 The number of patients was small and reactivation rates varied from 0 to 6.5%. Risk factors for reactivation included older age, presence of rejection, use of rituximab and loss/absence of anti-HBs, but findings were not consistent among the 4 studies possibly due to the small number of cases in each study. We found that 13.9% of the patients with resolved HBV infection and positive anti-HBs titers lost immunity. In our series, older age and presence of BPAR were independent risk factors for loss of anti-HBs, which in its turn might increase the risk of reactivation. Age can be a risk factor since older patients tend to produce weaker immunological response and tend to have lower levels of anti-HBs.8 Acute rejection is thought to be a risk factor through an increase of immunosuppression used for its treatment and this has been confirmed in other solid-organ transplants (SOT).8

It is postulated that IS agents such as B-Cell depleting drugs like rituximab are associated with a high risk of HBV reactivation even in patients with resolved HBV infection.4,13,14 In our study, none of our patients had received rituximab. Relationship between other drugs used in kidney transplantation and reactivation is less consistent.8,15 We found no association between the type of IS drug used and loss of anti-HBs.

Our study is limited by its retrospective nature, and we are unaware of when the patients included in our study acquired HBV infection and the timing of their acquisition of positive anti-HBs titers after the infection. We were also unable to assess previous HBV vaccination history. Both could influence anti-HBs titers and the risk of HBV reactivation after renal transplantation, although there are no studies addressing this issue.

The retrospective nature of our study and the absence of HBV genotype testing in our reactivation cases do not allow us to completely rule out the possibility of re-infection instead of reactivation. However, both patients were diagnosed in an inpatient setting and none had recent history of high risk behavior or contact with blood products. Besides, both were highly immunosuppressed – one of the patients had a severe opportunistic infection and the other a high cumulative IS load given the history of 3 transplants, which favors the hypothesis of reactivation.

Our transplant center did not test HBV viral load in KTR with resolved HBV infection, and serological HBV testing did not follow a systematic protocol. This way, we cannot assure that asymptomatic reactivations might have been missed during the follow-up period, and this way we might have underestimated the reactivation rates in our population. At last, the small number of reactivation cases did not allow us to infer about potential risk factors for reactivation. Our study however has some specific strengths; in an era of declining HBV incidence in the Western Countries, we have managed to retrieve a fairly high number of patients and a long term follow-up.

The American Association for the Study of Liver Diseases recommends routine use of appropriate antiviral prophylaxis in all patients who are HBsAg-positive prior to or at the initiation of chemotherapy, immunosuppressive therapy, hematopoietic stem cell transplantation, or solid organ transplantation.12 When B-cell depleting agents like rituximab are used in patients with resolved infection (HBsAg-negative, anti-HBc-positive) antiviral prophylaxis can be anticipated to result in similar risk reduction of HBV reactivation as described for HBsAg-positive patients,14 otherwise recommendations regarding antiviral prophylaxis in KTR with resolved HBV infection are lacking. Current guidelines do not recommend using anti-HBs titer to guide initiation of prophylaxis since there is no threshold level that universally prevents HBV reactivation.10,12,14 However, anti-HBs titer is still believed to confer protection against reactivation.8,13,16 Considering that loss of anti-HBs increases the risk of reactivation,7,8,17,18 patients who are at increased risk of anti-HBs loss, such as older patients and those with BPAR as found in our study, might benefit from closer surveillance of HBV DNA levels4,10,19 or even antiviral prophylaxis. Although evidence is scarce regarding HBV DNA monitoring in patients with resolved HBV infection we suggest, as a cost-effective measure, a baseline measurement of HBV DNA levels for all candidates to kidney transplantation with resolved HBV infection (anti-HBc positive, HBsAg negative) to exclude occult viral replication. For those with positive HBV DNA we suggest antiviral prophylaxis starting from the time of transplantation and follow-up with periodical assessment of aminotransferases and HBV DNA levels. If the initial baseline HBV DNA is negative, we suggest serological HBV follow-up (HBsAg and anti-HBs) and close monitoring of aminotransferases levels. In case of HBsAg seroreversion or elevated aminotransferases, we suggest HBV DNA assessment. However, even with negative baseline negative HBV DNA; we acknowledge that some of these patients, especially if they are at higher risk of reactivation, might benefit from HBV DNA surveillance from the time of transplantation. In our study the small number of cases of HBV reactivation precludes any conclusion, and further studies are needed.

In conclusion, the risk of HBV reactivation in KTR with previous clinically resolved infection is not negligible at 2%. Older age and acute rejection were associated with loss of anti-HBs, and these patients might benefit from closer surveillance of HBV DNA level. Routine serological and/or HBV viral load monitoring in HBsAg-negative, anti-HBc-positive patients is recommended and should be emphasized in these patients.

Meng C: design of study, data collection, drafting article. Belino C, Pereira L, Sampaio S, Tavares: data analysis, drafting article. Pinho A: critical revision and statistical analysis. Bustorff M: design of study, drafting and critical revision. Sarmento A and Pestana M: critical revision.

The authors declare no conflict of interest.