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

Disclosures

J Viral Hepat. 2022;29(4):289-296.

Abstract and Introduction

Abstract

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%;

Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Clinical characteristics of patients at 1 year of AVT ( n = 3033)
Variables	All	ETV (n = 1793)	TDF (n = 1240)	p-value
Age (years)	48.8 ± 11.6	48.7 ± 11.4	48.9 ± 11.8	.735
Male gender	1936 (63.8)	1134 (63.2)	802 (64.7)	.442
Body mass index (kg/m²)	23.7 ± 3.7	23.8 ± 4.3	23.6 ± 2.8	.185
Diabetes mellitus	247 (8.1)	159 (8.9)	88 (7.1)	.091
Hypertension	271 (8.9)	174 (9.7)	97 (7.8)	.080
Liver cirrhosis	852 (28.1)	509 (28.4)	343 (27.7)	.681
HBeAg positivity	1501 (49.5)	891 (59.4)	610 (40.6)	.796
HBV-DNA (log_{10 IU}/ml)	5.8 ± 6.0	5.4 ± 5.9	5.9 ± 5.8	.890
AST (IU/L)	30 ± 30	31 ± 36	29 ± 17	.038
ALT (IU/L)	30 ± 24	29 ± 27	29 ± 17	.394
Albumin (g/dl)	4.3 ± 0.5	4.3 ± 0.5	4.3 ± 0.5	.647
Total bilirubin (g/dl)	0.9 ± 0.8	0.9 ± 0.9	0.8 ± 0.5	.003
Gamma-glutamyl transpeptidase (IU/L)	77 ± 99	79 ± 100	66 ± 96	.027
Platelet count (×10⁹/L)	165 ± 79	160 ± 86	171 ± 69	<.001
Prothrombin time (INR)	165 ± 79	1.0 ± 0.2	0.9 ± 0.2	.320
Serum Na (mM)	141 ± 3	140 ± 3	141 ± 3	.322
Creatinine (mg/dl)	0.9 ± 0.3	0.9 ± 0.3	0.8 ± 0.2	<.001
eGFR by CKD-EPI equation (ml/min/1.73 m²)	98.4 ± 20.9	96.0 ± 20.3	101.9 ±21.3	<.001
FIB−4 index	2.38 ± 2.28	2.57 ± 2.74	2.10 ± 1.80	<.001
APRI score	0.63 ± 1.26	0.70 ± 1.38	0.54 ± 0.47	<.001

Note: Variables are expressed as mean ± standard deviation or no. (%).
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; AVT, antiviral therapy; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration equation; ETV, entecavir; HBeAg; HBV, hepatitis B virus; hepatitis B e antigen; INR, international normalized ratio; TDF, tenofovir disoproxil fumarate.

Table 2. Changes in eGFR in chronic hepatitis B patients treated with ETV or TDF ( n = 3033)
Antiviral regimen	Time after starting AVT	eGFR (ml/min/1.73 m²)	95% CI
ETV (n = 1793)	1 year	96.0 ± 20.3	(94.8–97.2)
	2 years	96.3 ± 19.9	(95.1–97.5)
	3 years	96.7 ± 20.9	(95.5–97.9)
	4 years	96.5 ± 19.9	(95.3–97.7)
	5 years	96.1 ± 19.9	(94.9–97.3)
	6 years	95.6 ± 19.7	(94.3–96.8)
TDF (n = 1240)	1 year	101.9 ±21.3	(99.3–104.4)
	2 years	100.3 ± 21.7	(97.6–102.9)
	3 years	99.4 ± 22.0	(96.7–102.1)
	4 years	99.4 ± 21.5	(96.8–102.0)
	5 years	98.3 ± 21.0	(95.6–100.9)
	6 years	96.9 ± 19.1	(94.2–99.6)

Note: Variables are expressed as mean ±standard deviation.
Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate; ETV, entecavir; TDF, tenofovir disoproxil fumarate.

Table 3. Comparison of patients with and without ongoing renal dysfunction
Variables	Preserved renal function (n = 2352)	Ongoing renal dysfunction (n = 681)	p-value
Age (years)	47.2 ± 10.9	48.7 ± 11.2	.019
Male gender	1505 (64.0)	456 (37.0)	.312
Body mass index (kg/m2)	23.7 ± 3.1	23.6 ± 2.7	.693
Diabetes mellitus	186 (7.9)	81(11.9)	.030
Hypertension	186 (7.9)	88 (12.9)	.007
Liver cirrhosis	611 (26.0)	219 (32.2)	.026
HBeAg positivity	1220 (51.9)	317 (46.5)	.082
HBV- DNA (log_{10 IU}/ml)	5.2 ± 6.7	5.1 ± 4.2	.890
AST (IU/L)	30 ± 24	30 ± 18	.866
ALT (IU/L)	32 ± 40	30 ± 23	.566
Serum albumin (g/dl)	4.4 ± 0.4	4.3 ± 0.4	<.001
Total bilirubin (g/dl)	0.9 ± 0.4	0.8 ± 0.7	.060
Gamma-glutamyl transpeptidase (IU/L)	79 ± 95	77 ± 90	.320
Platelet count (×10⁹/L)	166 ± 75	165 ± 70	.741
Prothrombin time (INR)	1.0 ± 0.2	0.9 ± 0.2	.017
Serum Na (mM)	140 ± 3	141 ± 3	.411
Creatinine (mg/dl)	0.9 ± 0.2	0.8 ± 0.2	<.001
eGFR by CKD-EPI (ml/min/1.73 m²)	100.0 ± 18.9	92.6 ±17.5	<.001
TDF (vs. ETV)	2116 (9.1)	154 (22.6)	<.001

Note: Variables are expressed as mean ± standard deviation or no. (%).
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration equation; ETV, entecavir; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; INR, international normalized ratio; TDF, tenofovir disoproxil fumarate.

Table 4. Risk factors of ongoing renal dysfunction
Variables	Univariate analysis		Multivariate analysis
Variables	OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value
Male	1.140 (0.896–1.450)	.285
Age >60 years	1.557 (1.169–2.075)	.002	1.249 (0.925–1.688)	.147
Hypertension	2.667 (1.931–3.684)	<.001	2.356 (1.664–3.334)	<.001
Diabetes mellitus	1.861 (1.292–2.681)	.001	1.387 (0.934–2.059)	.105
Liver cirrhosis	1.286 (0.999–1.654)	.051
eGFR <60 ml/min/1.73m² at 1 year of AVT	1.963 (1.285–2.996)	.002	1.823 (1.179–2.821)	.007
Albumin <3.5 mg/dl at 1 year of AVT	2.128 (1.453–3.117)	<.001	2.023 (1.370–2.988)	<.001
TDF (vs. ETV)	1.572 (1.242–1.989)	<.001	1.656 (1.303–2.107)	<.001

Abbreviations: AVT, antiviral therapy; CI, confidence interval; eGFR, estimated glomerular filtration rate; ETV, entecavir; OR, odds ratio; TDF, tenofovir disoproxil fumarate.