Safety and efficacy of tenofovir alafenamide in liver transplant recipients: A single center experience

Tenofovir disoproxil fumarate (TDF) is frequently used for treatment of and prophylaxis against reactivation of hepatitis B virus (HBV) after liver transplant (LT). Because TDF can lead to renal impairment and a decrease in bone mineral density (BMD), the prodrug tenofovir alafenamide (TAF) may be considered a viable alternative with fewer adverse effects. Only limited information is available about the use of TAF for LT recipients. We report a European single‐center experience with TAF as treatment for LT patients.


| INTRODUC TI ON
Nucleotide analogues (NAs) are the most important agents used to treat chronic hepatitis B virus (HBV) infection. 1,2 The NA tenofovir is frequently used because of its high efficacy and barrier to resistance. 3,4 The prodrug tenofovir disoproxil (TDF) has been used most frequently, although it carries potential concerns related to adverse effects, particularly a decrease in bone mineral density (BMD) and impairment of renal function. The prodrug tenofovir alafenamide (TAF) was approved for HBV patients in 2017. 5 For this patient group, the antiviral efficacy of TAF is equal to that of TDF, 6 but the plasma stability of TAF is known to be better, resulting in more efficient delivery to hepatocytes. 7 Therefore, TAF can achieve therapeutic concentrations at lower dosages, thereby reducing the potential for adverse effects. 6,8,9 Chronic HBV infection is still one of the most important causes of liver cirrhosis and consecutive liver transplant (LT) in the world. 10 In many countries, allocation for LT is based on the Model for End-Stage Liver Disease (MELD) score, which uses the serum creatinine level as a measure of renal dysfunction. For this reason, many LT patients exhibit impaired renal function at the time of transplant. After LT, most patients must maintain lifelong immunosuppression, which frequently involves the administration of calcineurin inhibitors.
The most frequently used such immunosuppressant is tacrolimus (TAC), 11 which can be associated with a variety of adverse effects, including severe nephrotoxicity. 12,13 After patients with chronic HBV undergo LT, or after the transplantation of a liver from an HBV-positive donor, prophylaxis against HBV recurrence is recommended for most patients. 1 Reactivation prophylaxis is mostly achieved by the administration of NAs and HBV immunoglobulin (Ig). 1,2 TDF is applied for a large percentage of LT patients, but impaired renal function evokes limitations, since TDF is eliminated by renal clearance and accumulates in these patients. 14 Additionally, TDF is associated with low but still clinically significant nephrotoxicity. 15 In the case of renal insufficiency, TDF dosing must be adjusted to renal function; thus, patients may take TDF every other day or every third day, for example, a dosing schedule resulting in variable and possibly insufficient serum levels of the antiviral drug. 14,16 Furthermore, irregular intake of medication may impair medication adherence.
TAF can be considered a viable alternative for prophylaxis against HBV reactivation because there is no need for dosage adjustment related to renal function. This more regular dosing results in reliable and stable serum levels and may be associated with fewer adverse effects.
Although TAF is established as a treatment for HBV patients, the availability of data regarding the efficacy and safety of administering TAF to LT recipients is still limited. Here, we present our experience with 29 patients treated with TAF for prophylaxis against HBV recurrence after LT.

| Patients
This study retrospectively analyzed data from 29 patients who were treated with TAF as prophylaxis against HBV recurrence. One patient began TAF treatment directly after LT. Three patients had not previously been treated with NAs but began recurrence prophylaxis with TAF because of insufficient HBV antibody (anti-HBs) titers. The remaining 25 patients were switched from another NA to TAF. TAF was administered at a dosage of 25 mg once daily. Demographic and clinical data were documented. Renal function was determined by the estimated glomerular filtration rate (eGFR) as measured by the Modification of Diet in Renal Disease equation. Additionally, clinical findings (adverse effects, cause of therapy interruption) were documented at baseline (initiation of TAF treatment) and every 3 months thereafter for the first year (months 3, 6, 9, and 12). The analysis was conducted in accordance with the Helsinki Declaration of 1975 and was approved by the ethics committee of the University Hospital Essen.

| Statistical analysis
Nominal data were displayed as absolute numbers and relative pro-

| Study cohort
Demographic data, baseline characteristics, and median laboratory values are depicted in Table 1. In total, the study included 29 patients who were treated with TAF as prophylaxis against HBV recurrence ( Figure 1). The cohort consisted of 21 men (72%) and 8 women (28%) with a median age of 54 years. The median MELD score at the time of transplant was 16. The median time between LT and TAF initiation was 8 years. All patients exhibited impaired renal function (elevated serum creatinine level, impaired eGFR) at the time of therapy conversion, and most patients suffered from renal insufficiency grade 3 (62%, Table 1). Liver function was stable before the switch to therapy with TAF. Before the switch, most patients were being treated with an NA: entecavir (38%), lamivudine (28%), or TDF (14%). For most patients, immunosuppressive therapy consisted of monotherapy with TAC (45%), combination therapy with TAC and mycophenolate mofetil (31%), or combination therapy with TAC and everolimus (EVR) (17%). Three patients (10%) were also receiving treatment with prednisolone (Table 1).

Most patients (19, 66%) underwent LT because of HBV infection.
The remaining patients received prophylactic treatment because they had received a LT from an anti-HBc-positive donor (Table 1).
Most patients (22, 76%) completed 1 year of HBV prophylaxis with TAF. Four patients (14%) discontinued therapy because of adverse effects (headache/fatigue, two patients; nausea/vomitus/ diarrhea, two patients); three of these patients experienced these adverse effects 4 weeks after the initiation of TAF therapy, whereas the other experienced the adverse effect 3 months after initiation.
All four patients resumed therapy with their previous medications (entecavir, three patients; lamivudine, one patient) after discontinuing TAF therapy. Two of the 29 patients were lost to follow-up and one died of multiorgan dysfunction (the initial hospitalization was because of worsening of known heart failure).
At the time of the switch to TAF, 25 patients (86%) tested seronegative for HBsAg; the other four (14%) tested seropositive. Amongst

| No significant impact of TAF on immunosuppressive medication
To

| TAF does not impair liver or renal function
The serum levels of aspartate aminotransferase, alanine aminotransferase (ALT), direct bilirubin, creatinine, cystatin C and the eGFR were  (Table 2).

F I G U R E 3
Influence of switch to tenofovir alafenamide on hepatic and renal function. Liver function is displayed as boxplots with medians and 95% confidence intervals (CIs) showing laboratory values of aspartate aminotransferase (AST, A), alanine aminotransferase (ALT, B) and direct bilirubin (C) at the time of the switch to tenofovir alafenamide (baseline, B) and at 3, 6, 9, and 12 mo after the switch. Renal function is depicted as boxplots with medians and 95% CIs of serum levels of creatinine (D), cystatin c (E), and estimated glomerular filtration rate (eGFR) as determined by the modification of diet in renal disease score (F) at baseline (B) and at 3, 6, 9, and 12 mo after the switch. Variables were analyzed with one-way ANOVA with the statistical significance assigned at the level of P ≤ .05 The risk of HBV recurrence after LT is strongly reduced by the administration of NAs and of HB Ig; the risk is now estimated to be 5%. 22 Tenofovir is a potent NA used to treat LT patients, and TAF has been found to be non-inferior to TDF in suppressing viral replication among non-LT patients. 6 Regarding LT patients, Sripongpun Tenofovir alafenamide is known to be associated with less deterioration of kidney function than is TDF in non-LT patients. 6,8,9 Renal safety is always an important problem for LT recipients; renal insufficiency is common among these patients because of MELD-based selection, liver-associated kidney problems before LT, and the nephrotoxic effects of calcineurin inhibitors. 12,13 Previous studies of TAF administration to LT patients found stable 23 or even slightly ameliorated 19 renal function, without any statistically significant differences. We did not observe any statistically significant differences in eGFR or serum creatinine levels in our cohort 1 year after the initiation of TAF administration.
Still, five patients exhibited worsening of renal function, whereas two exhibited improved renal function. Because our study lacked a control group, our findings cannot be compared to those of stud- experienced fatigue, and 5% experienced nausea [9]. Although these symptoms were not serious, it still is interesting that the rate of discontinuation of therapy in our study is quite high in comparison to that found in a study involving non-LT patients (1%). 9 Because the other studies involving LT patients did not report adverse events associated with TAF treatment, further evaluation is needed. One patient died during the study, but this event was deemed to be unrelated to TAF administration because the patient had been experiencing multiple severe diseases for years.
Of course, our study has some limitations. As it is the case for almost all retrospective analyses, potential bias cannot be excluded, and the lack of a control group impedes the interpretation of the data. Still, our study contributes an analysis regarding administration of TAF to a homogenous, single-center cohort of LT patients, including safety, efficacy, and possible interactions with immunosuppressive medications, and data concerning this questioning are still scarce. For this reason, our study can be beneficial for LT patients in whom switch of therapy is planned. However, long-term prospective studies are needed for careful assessment of the administration of TAF to LT patients. In particular, those studies should compare long-term impairment of renal function of patients receiving TAF with that of patients receiving TDF.
In conclusion, switching LT patients to HBV therapy and prophylaxis with TAF is effective in suppressing viral replication and is safe because it neither influences serum levels of immunosuppressants nor impairs graft function. In addition, adverse events in LT patients are neither more severe nor more frequent than those reported in non-LT patients.

CO N FLI C T O F I NTE R E S T
All the authors declare no conflict of interest.

ACK N OWLED G M ENT
Open access funding enabled and organized by Projekt DEAL.