Long-term Renal Safety Between Patients With Chronic Hepatitis B Receiving Tenofovir vs. Entecavir Therapy

A Multicenter Study

Young Eun Chon; Soo Young Park; Seung Up Kim; Han Pyo Hong; Jae Seung Lee; Hye Won Lee; Mi Na Kim; Jun Yong Park; Do Young Kim; Sang Hoon Ahn; Beom Kyung Kim


J Viral Hepat. 2022;29(4):289-296. 

In This Article

Abstract and Introduction


Renal safety is a critical issue in chronic hepatitis B (CHB) patients receiving long-term entecavir (ETV) or tenofovir disofuroxil fumarate (TDF) therapy. We investigated their effects on estimated glomerular filtration rate (eGFR). Treatment-naive CHB patients receiving ETV or TDF for ≥1 year were recruited. The eGFR was assessed using the Chronic Kidney Disease Epidemiology Collaboration equation. We calculated average annual percent change (AAPC) in eGFR using Joinpoint regression. At the beginning of the observation, the ETV group had more unfavorable conditions than the TDF group: lower eGFR and higher FIB-4 and APRI than the TDF group (all p < .001). After 6 years of antiviral therapy, the mean eGFR in the ETV group (n = 1793) was maintained (96.0 at first year to 95.6 ml/min/1.73 m2 at sixth year; AAPC −0.09%; p = .322), whereas that in the TDF group (n = 1240) significantly decreased annually (101.9 at first year to 96.9 ml/min/1.73 m2 at sixth year; AAPC −0.88%; p < .001). Notably, in the TDF group, even patients without diabetes (AAPC −0.80%; p = 0.001) or hypertension (AAPC −0.87%; p = .001) experienced significant decrease in eGFR. Expectably, accompanying diabetes (AAPC −1.59%; p = .011) or hypertension (AAPC −1.00%; p = .002) tended to accelerate eGFR decrease. TDF treatment (odds ratio 1.66, p < .001), along with eGFR<60 ml/min/1.73 m2, serum albumin<3.5 mg/dl, and hypertension, were independently associated with ongoing renal dysfunction, defined as a negative slope of the mean eGFR change. In conclusion, compared with ETV, long-term TDF treatment induced slow, but progressive renal dysfunction. Although the annual eGFR change by TDF was small, careful monitoring is necessary, especially in patients requiring life-long therapy.


Chronic hepatitis B virus (HBV) infection is a major public health problem affecting approximately 257 million people worldwide.[1] Patients with high serum HBV-DNA levels are more likely to develop liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC).[2,3] Thus, suppression of HBV-DNA through antiviral therapy (AVT) using oral nucleos[t]ide analog (NUCs) has become the major basis for treatment of HBV infection.[4–8] Currently, two prominent oral NUCs with high antiviral efficacy and minimal resistance, entecavir (ETV), and tenofovir disoproxil fumarate (TDF), are recommended in the initial treatment of CHB according to the clinical guidelines.[4–6] Since oral NUCs can effectively suppress HBV replication, but not eradicate intra-hepatic virus itself, their use should be life-long in most patients. Therefore, along with the issue of antiviral efficacy, the long-term safety of oral NUCs has become a concern.

Of their potential adverse effects, renal safety is the most important given that the medications are known to be excreted by renal filtration. Furthermore, chronic kidney disease is more often associated with patients with CHB than with non-CHB controls.[9] For instance, CHB patients with cirrhosis are more likely to develop renal insufficiency, including acute kidney injury or hepatorenal syndrome, due to reduced renal blood flow and hemodynamic disturbances.[10] Furthermore, renal tubular dysfunction and Fanconi syndrome have been associated with TDF therapy for a decade.[11–13] Subsequently, several studies have reported the comparative analyses of renal function between patients receiving ETV and TDF; however, these studies had small sample sizes[14,15] and short follow-up periods.[16,17] Moreover, in most previous studies, renal dysfunction was defined at a cross-sectional level, that is, only a decrease in the estimated glomerular filtration rate (eGFR) at one or two time points.[13,18]

In this multicenter study, we aimed to investigate the long-term effects of ETV and TDF on renal function in a large-scale study population by assessing the serial changes in renal function in the long-term.