Objectives: Hepatitis B virus reactivation in HBsAg-positive kidney transplant recipients sometimes results in liver failure and death. Although current guidelines recommend continuing antiviral therapy for ≥6 months after the last dose of immunosuppressive therapy, in transplant recipients, duration is uncertain because immunosuppressive therapy is lifelong. Here, we evaluated the incidence and effects of hepatitis B virus reactivation in kidney transplant recipients with hepatitis B virus infection.
Materials and Methods: We reviewed patients who underwent kidney transplant between 2012 and 2023; we excluded patients with missing hepatitis B serology, those who were hepatitis B surface antigen negative/anti-HBc negative, those with total follow-up of <1 year, and those with coinfection. Hepatitis B virus reactivation was defined as at least a 100-fold increase in hepatis B virus DNA levels in patients with previously detectable or levels that were negative before becoming positive.
Results: In 21 hepatitis B surface antigen-positive kidney transplant recipients, mean age was 45.8 ± 8.5 years, 76% were male, and 62% had living donor transplant. Mean follow-up was 86 ± 32 months. Seven transplant recipients received antiviral treatment (3 with entecavir, 3 with tenofovir disoproxil fumarate, 1 with lamivudine). Among 14 patients without antiviral treatment, 7 had positive HBV DNA (>69 IU/mL) at time of transplant All recipients received prophylactic antiviral therapy (14 received entecavir, 4 received lamivudine, 3 received tenofovir disoproxil fumarate) concomitant with transplant. During follow-up, hepatitis B virus reactivation was observed in 25% of patients who received lamivudine. No serious adverse outcomes, including liver transplant or death, due to HBV reactivation were observed.
Conclusions: Although optimal duration of prophylactic antiviral therapy remains unclear, entecavir or tenofovir was the preferred antiviral therapy over lamivudine for hepatitis B virus reactivation prophylaxis. Close monitoring with antiviral prophylaxis is the optimal strategy to prevent hepatitis B virus reactivation during immunosuppressive therapy.

Key words : Antiviral prophylaxis, Immunosuppressive treatment, Renal transplant, Viral hepatitis

Introduction
Kidney transplantation (KT) is the gold standard treatment for patients with end-stage renal disease, improving both patient quality of life and survival. However, the lifelong immunosuppressive therapy required to prevent graft rejection makes transplant recipients more susceptible to infections. Hepatitis B virus (HBV) reactivation (HBVr) is a major complication that can lead to significant morbidity and even mortality. According to the World Health Organization, approximately 296 million people worldwide live with chronic HBV infection, posing an important health problem in the kidney transplant candidate population. In hepatitis B surface antigen (HBsAg)-positive patients, immunosuppressive therapy carries a risk of uncontrolled viral replication. This presentation can manifest with a clinical spectrum ranging from asymptomatic HBV DNA increase to fulminant liver failure and even death. This risk is even more pronounced in kidney transplant recipients (KTRs) receiving potent immunosuppressive agents, such as high-dose corticosteroids, B-cell-depleting antibodies, or calcineurin inhibitors. In HBsAg-positive KTRs, the incidence of HBVr ranges from 45% to 70%. Guidelines strongly recommend initiating prophylactic antiviral therapy before or in conjunction with immunosuppressive therapy in HBsAg-positive patients. However, this is not directly applicable to KTRs because, unlike limited-duration immunosuppressive therapies such as chemotherapy, this patient group requires lifelong immunosuppressive therapy. This requirement raises the question of how long prophylactic antiviral therapy should be continued and creates uncertainty in clinical management. Among antiviral treatment options, lamivudine, a first-generation nucleoside analog, has been used for many years because of its low cost and early efficacy. However, the development of resistance in more than 20% of patients receiving long-term therapy limits its reliability for long-term prophylaxis. In contrast, newer agents such as entecavir, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide offer superior long-term outcomes due to their high antiviral potency and high genetic barriers to resistance, and these are now recommended as first-line agents. In this study, we aimed to evaluate the incidence of HBVr in KTRs with HBV infection under prophylactic antiviral therapy, to compare the efficacy and safety of different antiviral agents (lamivudine, entecavir, TDF), and to contribute to the evidence base regarding optimal management strategies in this special patient population.

Materials and Methods
In this retrospective study, we reviewed patients who underwent KT between 2012 to 2023. We collected demographic characteristics, etiology of kidney disease, donor type, and duration of dialysis. Patients with missing hepatitis B serology, HBsAg positive, HBsAg negative/anti-HBc negative patients, patients with a total follow-up of <1 year, and patients with hepatitis C virus-HIV coinfection were excluded. We analyzed factors that could be associated with risk of HBVr, including age, sex, kind of donor (living or deceased), hepatitis viral marker of recipients and donors before KT, induction and immunosuppressive regimens, and use of rituximab. The primary outcome, HBVr, was defined as least a 100-fold increase in HBV DNA levels in patients with previously detectable or HBV DNA levels that were negative before becoming positive. Secondary outcomes of the study were hepatitis flare, liver failure, or mortality due to HBVr. Hepatitis flare was defined as an abrupt increase in alanine aminotransferase levels 3-fold above the upper limit of normal range. Hepatitis B virus-associated liver failure was defined as at least 1 of the following: development of severe liver injury with encephalopathy, ascites, impaired synthetic function (international normalized ratio of prothrombin time of ≥1.5 or total bilirubin >3 mg/dL), or death.

Statistical analyses
We analyzed patient data with Statistical Package for the Social Sciences (SPSS) for Windows version 29.0 (IBM). For descriptive values, we presented categorical data as frequency and percentage and continuous data as mean ± SD. For comparisons between groups, we used the independent sample t test to compare 2 groups and the Pearson χ test to compare categorical variables. P < .⁰⁵ was considered statistically significant.

Results
Our analyses included 21 HBsAg-positive KTRs. Mean age was 45.8 ± 8.5 years, 76% were male, and 62% had a living donor transplant. Mean follow-up period was 86 ± 32 months (Table 1). Of 21 KTRs, 7 received antiviral treatment (3 received entecavir, 3 received TDF, 1 received lamivudine) and 14 did not receive antiviral treatment before transplant. Among these, 7 had positive HBV DNA (>69 IU/mL) at the time transplant. All recipients received prophylactic antiviral therapy (14 received entecavir, 4 received lamivudine, 3 received TDF) concomitant with transplant. During the median follow-up, HBVr was observed in 25% of patients in lamivudine group. No serious adverse outcomes, including liver transplant or death, due to HBVr were observed (Table 2).

Discussion
This study is a retrospective analysis evaluating the long-term outcomes of prophylactic antiviral therapy in HBsAg-positive KTRs, with a mean follow-up of 86 months. Our main findings indicated that severe HBVr can be prevented with appropriate prophylaxis, but the choice of antiviral agent is the key determinant of this success. In particular, the 25% HBVr rate observed in the lamivudine-only group provides important clinical information when compared with the absence of reactivation in the other groups. In our study, the development of HBVr in patients receiving lamivudine prophylaxis alone is fully consistent with literature data demonstrating lamivudine’s weak genetic barrier and the high risk of developing resistance with long-term use. This observation clearly demonstrates that lamivudine alone is insufficient for long-term prophylaxis in these patients and is not a reliable option. Therefore, current guidelines no longer recommend lamivudine as a first-line option for this patient group. Similarly in a study that evaluated 94 HBV-positive patients who underwent KT and were followed-up for mean of 75.7 months, 56 received antiviral prophylaxis (51 with lamivudine and 5 with entecavir) and 38 did not. The investigators reported that lamivudine-based antiviral prophylaxis for HBV-positive KTRs showed no long-term clinical benefit. In contrast, no HBVr was observed during follow-up in patients who received entecavir and TDF. In a study from Yap and colleagues, 30 HBsAg-positive KTRs who received entecavir (18 were treatment naïve and 12 were lamivudine-resistant) were evaluated. The investigators reported that entecavir showed favorable long-term efficacy and tolerability in treatment-naïve KTRs, but one-third of lamivudine-resistant KTRs showed no response or viral breakthrough after entecavir treatment. In a study of 63 HBsAg-positive and 63 HBsAg-negative KTRs patients, 62% of patients who received initial treatment with lamivudine developed drug resistance after 4 years. In the study, treatment with nucleoside/nucleotide analogs provided a long-term survival advantage in HBsAg-positive KTRs and salvage therapy with adefovir or entecavir was effective and well-tolerated in KTRs who developed resistance to lamivudine. Thus, for patients under lifelong immunosuppression and at persistent risk of HBVr (that is, KTRs), the long-term safety and efficacy of agents with high antiviral potential, which have a high genetic barrier to the development of this resistance, make them an ideal choice. Although our study did not directly answer the question of the optimal duration of prophylaxis, our results offer important clues. Our patients were successfully controlled with entecavir/TDF for more than 7 years, highlighting the potential risks of discontinuing antiviral therapy in a population undergoing lifelong immunosuppression. Therefore, most centers are adopting lifelong prophylaxis as a practical approach for these patients.

Conclusions
Our study showed the critical importance of HBV prophylaxis in HBsAg-positive KTRs and emphasized the importance of choosing high-barrier antiviral agents such as entecavir and tenofovir over lamivudine. Multicenter studies with larger patient cohorts and prospective designs are needed to clarify the optimal duration of prophylaxis and to investigate potential strategies for safely discontinuing treatment in low-risk patients. However, based on current evidence, lifelong entecavir or TDF based prophylaxis with close monitoring is considered the safest and most effective treatment strategy.