Reply to “Concerns Regarding the Paradoxical Renal Outcomes in Patients Switching From Entecavir to Tenofovir Alafenamide”

We appreciate the insightful comments of Drs. Ge and Wang [1] on our recent paper [2]. They raised concerns that prior entecavir (ETV) treatment contributed to poorer long-term renal outcomes after switching to tenofovir alafenamide (TAF) in patients with chronic hepatitis B. Indeed, the decline in estimated glomerular filtration rate (eGFR) was greater in the prior ETV group than in the prior tenofovir disoproxil fumarate (TDF)/combination (Combo) group after switching to TAF [2]; however, this finding likely reflects the fact that a substantial decline in eGFR had occurred during the prior TDF/Combo treatment [3]. Although we were unable to provide longitudinal eGFR data prior to switching to TAF in this study, our results indicate that the eGFR decline observed during the prior TDF/Combo therapy was partially reversible when switching to TAF. To clarify this issue, because a longer duration of TDF/Combo therapy may influence the degree of renal function recovery, further detailed analyses are warranted to address this issue. Similarly, because declines in eGFR are strongly influenced by age [4], the extent of eGFR decline observed in this study, which included a relatively large proportion of older patients, may be greater than that reported in other studies. Because the nonchronic kidney disease (CKD) group included a higher proportion of younger patients, propensity score-matched analysis was performed using variables including age, sex, and cirrhosis. Although traditional lifestyle-related diseases, including diabetes and hypertension, have been reported to influence the development of CKD, their distribution did not differ significantly between the two groups. As a result, this analysis demonstrated virological/biochemical outcomes and longitudinal eGFR trends comparable to those observed in the primary analysis. In addition, as shown in Figure 4, the absolute decline in eGFR was greater in the non-CKD group than in the CKD group [2]. This finding is likely attributable to the higher baseline eGFR in the non-CKD group. Importantly, when eGFR decline was evaluated as a percentage change, no significant difference was observed between the two groups. We also recognize that there are three main reasons for switching to TAF [5]. The first involves older patients at high risk of CKD or osteomalacia. The second is when sufficient antiviral efficacy cannot be achieved with ETV therapy. The third involves cases in which adherence to ETV is suboptimal due to the requirement for fasting administration. In our study, we did not have sufficiently detailed data to determine which cases applied to each of these categories. It is important to note that when adequate efficacy and safety are achieved with ETV monotherapy, patients are not routinely or forcibly switched to TAF. We also agree that incorporating detailed factors beyond age, sex, race, and treatment history would help mitigate residual confounding. Overall, we believe that our findings demonstrate that sequential TAF therapy provides robust virological and biochemical efficacy, as well as excellent renal safety, over 5 years, even in patients with CKD. Further studies are warranted to elucidate liver-related and extrahepatic complications, as well as mortality outcomes. The author received research grants from Gilead Sciences.