Renal safety of tenofovir and/or entecavir in patients with chronic HBV monoinfection

Figures & data

Figure 1 Flowchart of the study selection process.

Abbreviations: ETV, entecavir; HBV, hepatitis B virus; TDF, tenofovir disoproxil fumarate.

Table 1 Main characteristics of included studies

Study	Sites	Study design	Sample size, n	Gender, n (M/F)	Age, mean (SD) or median (range), years	Duration of follow-up, mean (SD) or median (range), months	HBV DNA at baseline, mean (SD or IQR) or median (range)	HBeAg-positive, n (%)	Status	Treatment regimens
Riveiro-Barciela et al, 2017^Citation15	Spain	Observational study	611	Total: 444/167; TDF-containing: 305/119; ETV: 139/48	Total: 50 (13); TDF-containing: 50 (13); ETV: 50 (13)	TDF-containing: 49 (29); ETV: 55 (22)	Total: 4.0 (2.4) log10 IU/mL; TDF-containing: 3.8 (2.3) log10 IU/mL; ETV: 4.9 (2.4) log10 IU/mL	Total: 101 (16.5); TDF-containing: 67 (15.8); ETV: 34 (18.2)	TN, TE, cirrhosis	TDF: 245 mg/day; ETV: 0.5 or 1 mg/day
Koksal et al, 2016^Citation16	Turkey	Prospective cohort study	120	TDF: 19/25; ETV: 17/15; control: 21/23	TDF: 36 (29–43.7); ETV: 40 (27.2–46.5); control: 37.5 (29–42.2)	48	TDF: 6.8 (1.0) log10 IU/mL; ETV: 7.0 (1.2) log10 IU/mL; control: NR	TDF: 7 (15.9); ETV: 8 (25); control: NR	TN	NR
López Centeno et al, 2016^Citation17	Spain	Retrospective cohort study	64	TDF-containing: 25/7; ETV: 23/9	TDF-containing: 50.15 (16.17); ETV: 49.22 (15.26)	12	TDF-containing: 1,127.4 (19–2,463,121.4) copies/mL; ETV: 29,311.4 (376.2–4,660,135.2) copies/mL	TDF-containing: 13 (40.6); ETV: 5 (15.6)	TN, TE	NR
Rodríguez-Nóvoa et al, 2016^Citation3	Spain	Cross-sectional study	280	TDF: 38/31; ETV: 70/19; control: 58/64	TDF: 48 (12); ETV: 49 (12); control: 47 (10)	TDF: 35 (9); ETV: 43 (13)	NR	TDF: 6 (8.8); ETV: 11 (12.5); control: 2 (1.7)	TN	NR
Zoulim et al, 2016^Citation18	Poland, Germany, France, Italy, the Netherlands, Romania	Prospective clinical trial	92	TDF/ETV: 69/23	TDF/ETV: 43.6 (1.55)a	24	TDF/ETV: 4.4 (0.23)a log10 IU/mL	TDF/ETV: 56 (62.2)	TE	NR
Sriprayoon et al, 2017^Citation19	Thailand	Randomized controlled trial	400	TDF: 113/87; ETV: 121/79	TDF: 41.2 (11.6); ETV: 41.6 (11.5)	36	TDF – HBeAg (+): 7.0 (1.4) log10 IU/mL – HBeAg (−): 5.0 (1.3) log10 IU/mL ETV – HBeAg (+): 7.1 (1.5) log10 IU/mL – HBeAg (−): 4.9 (1.3) log10 IU/mL	TDF: 92 (46.0); ETV: 95 (47.5)	TN	TDF: 300 mg/day; ETV: 0.5 mg/day
Tsai et al, 2016^Citation20	Taiwan	Retrospective–prospective cohort study	141	Total: 108/33; TDF: 32/5; ETV: 46/16; LdT: 30/12	Total: 55.2 (12.2); TDF: 53.6 (12.6); ETV: 55.2 (11.5); LdT: 56.6 (12.9)	NR	Total: 6.3 (1.3) log10 copies/mL; TDF: 6.3 (1.3) log10 copies/mL; ETV: 6.4 (1.2) log10 copies/mL; LdT: 6.0 (1.4) log10 copies/mL	Total: 37 (26); TDF: 10 (27); ETV: 18 (29); LdT: 9 (21)	Cirrhosis	NR
Park et al, 2016^Citation21	Korea	Prospective clinical trial	64	TDF/ETV: 52/12	TDF/ETV: 47 (9.8)	12	TDF/ETV: 4.29 (1.23) log10 IU/mL	TDF/ETV: 57 (89.1)	TE, MDR CHB	TDF: 300 mg/day; ETV: 1.0 mg/day
Wang et al, 2016^Citation22	Taiwan	Retrospective clinical trial	236	TDF – TN: 100/31 – TE: 83/22	TDF – TN: 48.9 (12.9) – TE: 48.9 (13.4)	38.5 (13–49)	TDF – TN: 6.9 (1.5) log10 copies/mL – TE: 6.2 (1.9) log10 copies/mL	TDF – TN: 42 (32.1) – TE: 51 (48.6)	TN, TE, cirrhosis	NR
Tsai et al, 2016^Citation23	Taiwan	Retrospective cohort study	587	TDF: 121/49; ETV: 168/65; LdT: 132/52	TDF: 51.8 (11.9); ETV: 52.8 (12.4); LdT: 54.2 (14.6)	TDF: 12 (12–24); ETV: 36 (12–84); LdT: 36 (12–60)	TDF: 6.4 (1.9) log10 copies/mL; ETV: 6.2 (1.5) log10 copies/mL; LdT: 5.7 (1.8) log10 copies/mL	TDF: 39 (22.9); ETV: 61 (26.2); LdT: 33 (17.9)	TN, cirrhosis	NR
Koklu et al, 2015^Citation24	Turkey	NR	857	TDF: 183/90; ETV: 197/85; LAM: 185/117	TDF: 47.74 (12.45); ETV: 49.86 (13.35); LAM: 49.21 (13.17)	24	TDF: 6.69 (1.79) log10 copies/mL; ETV: 6.54 (1.74) log10 copies/mL; LAM: 5.27 (1.63) log10 copies/mL	TDF: 68 (27.8); ETV: 68 (27.1); LAM: 33 (11.5)	TN, cirrhosis	NR
Kim et al, 2015^Citation25	Korea	NR	52	Total: 38/14; TDF/ETV: 22/5; TDF/LAM: 16/9	Total: 53.5 (9.9); TDF/ETV: 52.6 (9.6); TDF/LAM: 54.4 (10.3)	Total: 16 (8–22); TDF/ETV: 16 (10–22); TDF/LAM: 16 (8–17)	Total: 3.69 (1.57) log10 IU/mL; TDF/ETV: 4.14 (1.64) log10 IU/mL; TDF/LAM: 3.22 (1.38) log10 IU/mL	Total: 48 (92.3); TDF/ETV: 24 (88.9); TDF/LAM: 24 (96.0)	TE, cirrhosis	TDF: NR; ETV: 1 mg/day; LAM: 100 mg/day
Ha et al, 2015^Citation26	USA (all Asians)	Matched case–cohort study	206	TDF: 65/38; ETV: 65/38	TDF: 43.5 (10.4); ETV: 43.8 (10.7)	TDF: 24 (6–66); ETV: 18 (6–54)	TDF: 5.3 (1.5) log10 IU/mL; ETV: 6.15 (1.9) log10 IU/mL	TDF: 34 (35.4); ETV: 46 (44.7)	TN, cirrhosis	TDF: 300 mg/day; ETV: 0.5 or 1.0 mg/day
Lim et al, 2016^Citation27	Korea	Randomized open-label trial	102	Total: 88/14; TDF→TDF: 42/8; TDF/ETV→TDF: 46/6	Total: 50 (26–70); TDF→TDF: 49 (28–68); TDF/ETV→TDF: 50 (26–70)	24 (TDF or TDF/ETV for 12, then TDF for 12)	Total: 3.38 (1.78–9.00) log10 IU/mL; TDF→TDF: 3.27 (1.78–9.00) log10 IU/mL; TDF/ETV→TDF: 3.50 (2.04–8.79) log10 IU/mL	Total: 90 (88.2); TDF→TDF: 44 (88); TDF/ETV→TDF: 46 (88.5)	TE, cirrhosis, ADV-resistant	TDF: 300 mg/day; ETV: 1 mg/day
Hung et al, 2015^Citation28	Taiwan	NR	189	TDF: 30/11; ETV: 106/42	TDF: 49.8 (13.1); ETV: 50.6 (14.7)	6	TDF: 7.0 (1.9) log10 copies/mL; ETV: 6.5 (1.9) log10 copies/mL	TDF: 14 (34); ETV: 42 (28)	TN, cirrhosis, severe acute exacerbation	TDF: 300 mg/day; ETV: 0.5 mg/day
Lim et al, 2016^Citation29	Korea	Randomized open-label trial	90	Total: 68/22; TDF: 32/13; TDF/ETV: 36/9	Total: 51 (9); TDF: 51 (9); TDF/ETV: 52 (10)	12	Total: 4.02 (3.08–5.24)b log10 IU/mL; TDF: 4.09 (3.07–5.47)b log10 IU/mL; TDF/ETV: 3.74 (3.10–4.95)b log10 IU/mL	Total: 80 (88.9); TDF: 40 (88.9); TDF/ETV: 40 (88.9)	TE, cirrhosis, ETV-resistant	TDF: 300 mg/day; ETV: 1 mg/day
Qi et al, 2015^Citation30	China	Prospective cohort study	275	Untreated: 27/9; LAM: 25/25; ADV: 49/11; LdT: 54/14; ETV: 46/15	Untreated: 31 (21–59); LAM: 53.5 (23–66); ADV: 49 (24–70); LdT: 33.5 (21–64); ETV: 42 (19–64)	Untreated: 23 (12–46); LAM: 24 (11–36); ADV: 24 (8–47); LdT: 23 (12–45); ETV: 24 (11–47)	Untreated: 5.5 (2.9–8.1) log10 copies/mL; LAM: 6.1 (4.2–8.9) log10 copies/mL; ADV: 6.4 (3.8–9.9) log10 copies/mL; LdT: 7.4 (3.2–9.8) log10 copies/mL; ETV: 6.7 (4.1–8.9) log10 copies/mL	Untreated: 18 (50); LAM: 24 (48); ADV: 31 (52); LdT: 59 (87); ETV: 46 (75)	TN, TE, cirrhosis	LAM: 100 mg/day; ADV: 10 mg/day; LdT: 600 mg/day; ETV: 0.5 mg/day
Tien et al, 2015^Citation31	USA (all Asians)	Cross-sectional study	146	Total: 78/68; untreated: 24/36; TDF: 29/13; ETV: 25/19	Total: 48 (11); untreated: 46 (12); TDF: 49 (12); ETV: 51 (9)	Total: 29 (19); untreated: NR; TDF: 26 (13); ETV: 32 (24)	NR	Total: 27 (18); untreated: 8 (13); TDF: 11 (26); ETV: 8 (18)	TN, TE, cirrhosis	NR
Lok et al, 2012^Citation32	USA, Argentina, Australia, Brazil, Canada, France, India, Italy, Mexico, Poland, Russian Federation, South Africa, Turkey	Randomized open-label trial	379	TDF/ETV: 146/51; ETV: 116/66	TDF/ETV: 39 (1.0)a; ETV: 40 (1.1)a	25	TDF/ETV: 7.5 (0.10)a log10 IU/mL; 7.5 (0.11)a log10 IU/mL	TDF/ETV: 138 (70.1); ETV: 126 (69.2)	TN	TDF: 300 mg/day; ETV: 0.5 mg/day
Gish et al, 2012^Citation33	USA	Retrospective cohort study	160	TDF: 52/28; ETV: 52/28	TDF: 54.5 (13); ETV: 55.1 (12)	TDF: 19.8 (2.1–45.5); ETV: 29.3 (1.1–55.1)	TDF: 6.99 log10 IU/mL; ETV: 7.36 log10 IU/mL	NR	NR	TDF: 300 mg/day; ETV: 0.5 or 1 mg/day
Liaw et al, 2011^Citation34	Taiwan	Randomized double-blind trial	112	TDF: 37/8; TDF/FTC: 40/5; ETV: 17/5	TDF: 52 (48–57)b; TDF/FTC: 50 (42–58)b; ETV: 54 (47–58)b	12	TDF: 5.70 (4.9–6.6)b log10 copies/mL; TDF/FTC: 6.28 (4.5–7.3)b log10 copies/mL; ETV: 5.93 (4.2–7.4)b log10 copies/mL	TDF: 14 (31.1); TDF/FTC: 18 (40.0); ETV: 7 (31.8)	TN, TE (but, excluded for prior TDF or ETV and ADV ≥24 months)	TDF: 300 mg/day; ETV: 0.5 or 1 mg/day; FTC: 200 mg/day

Notes:

a This indicates standard error (SE).

b This indicates median (IQR).

Abbreviations: ADV, adefovir dipivoxil; CHB, chronic hepatitis B; ETV, entecavir; FTC, emtricitabine; F, female; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; IQR, interquartile range; LAM, lamivudine; LdT, telbivudine; M, male; MDR, multidrug-resistant; NR, not reported; SD, standard deviation; TDF, tenofovir disoproxil fumarate; TN, treatment-naïve; TE, treatment-experienced.

Table 2 Summary of renal safety evaluation provided by included studies

Study	Renal safety evaluation	Summary
Riveiro-Barciela et al, 2017^Citation15	Mean eGFR by MDRD, mL/min	TDF-containing	BL: 90.8, 12th MO: 90.3, 36th MO: 88.9, 60th MO: 85.1
		ETV	BL: 81.2, 12th MO: 79.0, 36th MO: 84.8, 60th MO: 90.7
	Mean creatinine, mg/dL	TDF-containing	BL: 0.9, 12th MO: 0.9, 36th MO: 0.91, 60th MO: 0.95
		ETV	BL: 0.99, 12th MO: 1.0, 36th MO: 1.0, 60th MO: 0.9
Koksal et al, 2016^Citation16	eGFR by CKD-EPI-CysC, mean (SD), mL/min/1.73 m^2	TDF	BL: 84.7 (29.6), 3rd MO: 82.8 (45.9), 12th MO: 79.7 (36.3), 24th MO: 76.9 (30.8); p=0.004
		ETV	BL: 90.0 (24.1), 3rd MO: 96.6 (81.6), 12th MO: 92.9 (43.3), 24th MO: 84.5 (29.5); p=0.46
	eGFR by CKD-EPI-Cr-CysC, mean (SD), mL/min/1.73 m^2	TDF	BL: 90.6 (22.5), 3rd MO: 82.7 (31.2), 12th MO: 83.1 (32.2), 24th MO: 73.6 (34.7); p=0.05
		ETV	BL: 93.5 (19.6), 3rd MO: 95.6 (41.1), 12th MO: 88.7 (31.2), 24th MO: 82.3 (23.7); p=0.17
	Creatinine, mean (SD), mg/dL	TDF	BL: 0.76 (0.16), 3rd MO: 0.86 (0.19), 12th MO: 0.81 (0.24), 24th MO: 0.85 (0.26); p=0.08
		ETV	BL: 0.83 (0.18), 3rd MO: 0.84 (0.14), 12th MO: 0.82 (0.13), 24th MO: 0.80 (0.16); p=0.16
López Centeno et al, 2016^Citation17	eGFR <60 mL/min/1.73 m^2, n (%)	TDF-containing	BL: 4 (12.5), 12th MO: 6 (19.4)
		ETV	BL: 5 (15.6), 12th MO: 5 (15.6)
	Creatinine ≥1.4 mg/dL, n (%)	TDF-containing	BL: 3 (9.4), 12th MO: 4 (12.9)
		ETV	BL: 2 (6.3), 12th MO: 2 (6.3)
Rodríguez-Nóvoa et al, 2016^Citation3	Creatinine, median (SD), mg/dL	TDF	0.95 (0.15)
		ETV	1.02 (0.20)
		Control	0.93 (0.16)
	Phosphate, median (SD), mg/dL	TDF	3.18 (0.55)
		ETV	3.19 (0.54)
		Control	3.28 (0.45)
	eGFR by MDRD4, median (SD), mL/min	TDF	83 (15)
		ETV	81 (14)
		Control	83 (14)
	Ratio protein/creatinine, median (SD), mg/g	TDF	80 (43)
		ETV	66 (59)
		Control	63 (28)
	Ratio retinol-binding protein/creatinine, median (SD), μg/mL	TDF	104 (112)
		ETV	71 (62)
		Control	72 (49)
Zoulim et al, 2016^Citation18	Creatinine increase from BL ≥0.3 mg/dL, n (%)	TDF/ETV	24th MO: 1 (1.1)
	Creatinine increase from BL ≥0.5 mg/dL, n (%)	TDF/ETV	24th MO: 1 (1.1)
	Creatinine clearance <50 mL/min, n (%)	TDF/ETV	24th MO: 1 (1.1)
	Phosphate <2.0 mg/dL, n (%)	TDF/ETV	24th MO: 2 (2.2)
	Phosphate <2.3 mg/dL, n (%)	TDF/ETV	24th MO: 8 (8.9)
Sriprayoon et al, 2017^Citation19	eGFR at BL, mean (SD), mL/min/1.73 m^2	TDF	106.7 (20.6)
		ETV	105.3 (22.3)
	eGFR decrease ≥20%, n (%)	TDF	12th MO: 18 (9.4), 24th MO: 33 (17.3), 36th MO: 32 (16.8)
		ETV	12th MO: 6 (3.1), 24th MO: 13 (6.7), 36th MO: 29 (14.9)
	Phosphorus <2.0 mg/dL, n (%)	TDF	12th MO: 0 (0.0), 24th MO: 0 (0.0), 36th MO: 0 (0.0)
		ETV	12th MO: 0 (0.0), 24th MO: 0 (0.0), 36th MO: 0 (0.0)
	Fractional excretion of phosphate, mean (SD)	TDF	24th MO: 9.4 (3.7), 36th MO: 9.6 (3.8)
		ETV	24th MO: 8.9 (3.6), 36th MO: 8.7 (3.5)
Tsai et al, 2016^Citation20	eGFR by MDRD, mean (SD), mL/min/1.73 m^2	TDF	Prior 12th MO: 80.1 (13.3), BL: 78.3 (11.6), 24th MO: 73.0 (13.1)
		ETV	Prior 12th MO: 76.2 (11.3), BL: 75.6 (9.5), 24th MO: 79.3 (14.2)
	Rise in CKD category with ≥25% increase in eGFR, n (%)	TDF	0 (0.0)
		ETV	0 (0.0)
	Rise in CKD category with <25% rise in eGFR, n (%)	TDF	1 (2.7)
		ETV	1 (1.6)
	No change in CKD category, n (%)	TDF	34 (91.9)
		ETV	57 (91.9)
	Drop in CKD category with <25% decrease in eGFR, n (%)	TDF	1 (2.7)
		ETV	4 (6.5)
	Drop in CKD category with ≥25% decrease in eGFR, n (%)	TDF	1 (2.7)
		ETV	0 (0.0)
Park et al, 2016^Citation21	Creatinine, median (range), mg/dL	TDF/ETV	BL: 0.87 (0.38–1.30), 12th MO: 0.90 (0.57–1.28)
	Creatinine increase from BL >0.5 mg/dL, n (%)	TDF/ETV	1 (1.56) (BL: 0.60 mg/dL, 9th MO: 1.36 mg/dL, 12th MO: 0.58 mg/dL)
Wang et al, 2016^Citation22	eGFR, mean (SD), mL/min/1.73 m^2	TDF (TN)	BL: 98.9, 6th MO: 94.5, 12th MO: 90.5, 24th MO: 90.5, 36th MO: 90.9
		TDF (TE)	BL: 92.2, 6th MO: 87.3, 12th MO: 86.7, 24th MO: 85.3, 36th MO: 84.3
	eGFR decrease >20%, n (%)	TDF (TN, TE)	38 (16.89)
	Creatinine increase from BL ≥0.5 mg/dL, n (%)	TDF (TN, TE)	8 (3.56)
	Phosphate <2.5 mg/dL, n (%)	TDF (TN, TE)	14 (8.28)
Tsai et al, 2016^Citation23	eGFR by MDRD, mean (SD), mL/min/1.73 m^2	TDF	BL: 92, 12th MO: 85.6, 24th MO: 86.3
		ETV	BL: 86.1, 12th MO: 92.6, 24th MO: 94.4, 36th MO: 97, 48th MO: 100.8, 60th MO: 100.4
		LdT	BL: 81.1, 12th MO: 81.8, 24th MO: 79.3, 36th MO: 81.1, 48th MO: 84.7, 60th MO: 87.6
	Phosphate <2.5 mg/dL, n (%)	TDF	4 (8.2)
		ETV	1 (1.8)
		LdT	1 (5.3)
Koklu et al, 2015^Citation24	eGFR by MDRD, mean (SD), mL/min/1.73 m^2	TDF	BL: 100.72 (25.19), 1st MO: 96.44 (24.27), 6th MO: 97.13 (23.95), 12th MO: 96.11 (24.42), 24th MO: 96.72 (25.67); p=0.001
		ETV	BL: 96.20 (22.53), 1st MO: 96.37 (21.01), 6th MO: 95.87 (21.84), 12th MO: 94.30 (23.80), 24th MO: 95.94 (23.85); p=0.535
		LAM	BL: 96.91 (25.17), 1st MO: 96.00 (25.28), 6th MO: 95.34 (26.78), 12th MO: 97.50 (25.39), 24th MO: 96.23 (24.07); p=0.490
	Creatinine, mean (SD), mg/dL	TDF	BL: 0.85 (0.42), 1st MO: 0.90 (0.56), 6th MO: 0.89 (0.51), 12th MO: 0.89 (0.42), 24th MO: 0.90 (0.58); p=0.001
		ETV	BL: 0.86 (0.19), 1st MO: 0.85 (0.18), 6th MO: 0.86 (0.19), 12th MO: 0.88 (0.21), 24th MO: 0.87 (0.22); p=0.500
		LAM	BL: 0.84 (0.17), 1st MO: 0.85 (0.18), 6th MO: 0.88 (0.42), 12th MO: 0.84 (0.19), 24th MO: 0.85 (0.21); p=0.111
	Phosphate, mean (SD), mg/dL	TDF	BL: 3.23 (0.45), 1st MO: 3.21 (0.49), 6th MO: 3.21 (0.46), 12th MO: 3.15 (0.53), 24th MO: 3.23 (0.62); p=0.810
		ETV	BL: 3.38 (0.36), 1st MO: 3.47 (0.36), 6th MO: 3.39 (0.38), 12th MO: 3.39 (0.36), 24th MO: 3.45 (0.43); p=0.358
		LAM	BL: 3.08 (0.81), 1st MO: 3.17 (0.89), 6th MO: 3.28 (1.04), 12th MO: 3.22 (0.98), 24th MO: 2.98 (0.70); p=0.121
Kim et al, 2015^Citation25	Creatinine increase from BL >0.5 mg/dL, n (%)	TDF/ETV	0 (0.0)
		TDF/LAM	0 (0.0)
	Creatinine increase from BL >0.3 mg/dL, n (%)	TDF/ETV	5 (18.52)
		TDF/LAM	5 (20.00)
	Creatinine clearance <50 mL/min, n (%)	TDF/ETV	0 (0.0)
		TDF/LAM	0 (0.0)
	Phosphate <2.0 mg/dL, n (%)	TDF/ETV	0 (0.0)
		TDF/LAM	0 (0.0)
	Phosphate <2.7 mg/dL, n (%)	TDF/ETV	2 (7.41)
		TDF/LAM	3 (12.00)
	Change in creatinine, mean (IQR), mg/dL	TDF/ETV	6th MO: −0.03 (−0.25 to 0.23), 12th MO: 0.11 (−0.11 to 0.38), 18th MO: 0.21 (−0.08 to 0.42)
		TDF/LAM	6th MO: −0.04 (−0.21 to 0.24), 12th MO: 0.08 (−0.28 to 0.25), 18th MO: 0.19 (−0.02 to 0.43)
	Change in creatinine clearance, mean (IQR), mL/min	TDF/ETV	6th MO: 0.7 (−60.9 to 16.9), 12th MO: −12.5 (−63.2 to 7.3), 18th MO: −22.1 (−64.3 to 6.9)
		TDF/LAM	6th MO: 2.4 (−26.5 to 16.4), 12th MO: −7.5 (−31.9 to 33.4), 18th MO: −21.3 (−37.0 to −8.9)
Ha et al, 2015^Citation26	Patients reclassified to a higher category of renal impairment classification, n (%)	TDF	16 (15.5)
		ETV	18 (17.5)
	% change in eGFR from BL in patients reclassified to a more severe renal classification on treatment, n (%)	TDF	<10%: 3 (19), 10%–19.99%: 4 (25), 20%–29.99%: 7 (44), 30%–39.99%: 2 (13), >40%: 0 (0)
		ETV	<10%: 2 (11), 10%–19.99%: 9 (50), 20%–29.99%: 6 (33), 30%–39.99%: 0 (0), >40%: 1 (6)
Lim et al, 2016^Citation27	Creatinine increase from BL ≥0.5 mg/dL, n (%)	TDF→TDF	0 (0.0)
		TDF/ETV→TDF	0 (0.0)
	eGFR <50 mL/min/1.73 m^2, n (%)	TDF→TDF	0 (0.0)
		TDF/ETV→TDF	0 (0.0)
	Phosphate <2.0 mg/dL, n (%)	TDF→TDF	0 (0.0)
		TDF/ETV→TDF	0 (0.0)
Hung et al, 2015^Citation28	Creatinine increase from BL ≥0.5 mg/dL at 6 MO, n (%)	TDF	2 (6.67)
		ETV	2 (2.02)
	Mean eGFR by MDRD, mL/min/1.73 m^2	TDF	BL: 108, 6th MO: 87; p=0.001
		ETV	BL: 92, 6th MO: 84; p=0.001
Lim et al, 2016^Citation29	Creatinine increase from BL ≥0.5 mg/dL, n (%)	TDF	0 (0.0)
		TDF/ETV	0 (0.0)
	eGFR <50 mL/min/1.73 m^2, n (%)	TDF	1 (2.22)
		TDF/ETV	0 (0.0)
	Phosphate <2.0 mg/dL, n (%)	TDF	0 (0.0)
		TDF/ETV	1 (2.22)
Qi et al, 2015^Citation30	Change in creatinine, mg/dL	Untreated	12th MO: 0.004, 24th MO: 0.012, 36th MO: 0.030
		LAM	12th MO: 0.018, 24th MO: 0.047, 36th MO: 0.082
		ADV	12th MO: 0.071, 24th MO: 0.128, 36th MO: 0.314
		LdT	12th MO: −0.066, 24th MO: −0.100, 36th MO: −0.135
		ETV	12th MO: 0.006, 24th MO: −0.023, 36th MO: 0.007
	Change in eGFR by CG, mL/min	Untreated	12th MO: −0.665, 24th MO: −0.892, 36th MO: −1.047
		LAM	12th MO: −4.530, 24th MO: −8.817, 36th MO: −11.637
		ADV	12th MO: −5.623, 24th MO: −11.260, 36th MO: −13.720
		LdT	12th MO: 8.232, 24th MO: 14.998, 36th MO: 23.619
		ETV	12th MO: −0.001, 24th MO: 1.806, 36th MO: −1.358
	Change in eGFR by MDRD, mL/min	Untreated	12th MO: −0.692, 24th MO: −1.071, 36th MO: −1.799
		LAM	12th MO: −4.715, 24th MO: −10.166, 36th MO: −12.410
		ADV	12th MO: −6.922, 24th MO: −11.637, 36th MO: −15.381
		LdT	12th MO: 9.570, 24th MO: 15.428, 36th MO: 26.236
		ETV	12th MO: −0.002, 24th MO: 1.988, 36th MO: −1.284
Tien et al, 2015^Citation31	eGFR by CG, mean (SD), mL/min	Untreated	118 (36)
		TDF	108 (29)
		ETV	103 (26)
	eGFR by MDRD, mean (SD), mL/min	Untreated	118 (28)
		TDF	103 (26)
		ETV	102 (22)
	Phosphate, mean (SD), mg/dL	Untreated	3.4 (0.5)
		TDF	3.4 (0.5)
		ETV	3.5 (0.5)
	Phosphate <2.8 mg/dL, n (%)	Untreated	5 (8)
		TDF	6 (14)
		ETV	2 (4)
	Creatinine, mean (SD), mg/dL	Untreated	0.65 (0.17)
		TDF	0.79 (0.22)
		ETV	0.76 (0.19)
	Creatinine >1.5 mg/dL, n (%)	Untreated	0 (0)
		TDF	0 (0)
		ETV	0 (0)
Lok et al, 2012^Citation32	Creatinine increase from BL ≥0.3 mg/dL, n (%)	TDF/ETV	4 (2.0)
		ETV	6 (3.3)
	Creatinine increase from BL ≥0.5 mg/dL, n (%)	TDF/ETV	0 (0.0)
		ETV	3 (1.6)
Gish et al, 2012^Citation33	Creatinine increase from BL ≥0.2 mg/dL, n (%)	TDF	22 (27.5)
		ETV	23 (28.8)
	Creatinine increase from BL ≥0.5 mg/dL, n (%)	TDF	3 (3.8)
		ETV	11 (13.8)
	eGFR decrease ≥20% (CG), n (%)	TDF	28 (35.0)
		ETV	29 (36.3)
	eGFR decrease ≥20% (MDRD), n (%)	TDF	33 (41.3)
		ETV	35 (43.8)
Liaw et al, 2011^Citation34	Creatinine increase from BL ≥0.5 mg/dL, n (%)	TDF	4 (8.9)
		TDF/FTC	1 (2.2)
		ETV	1 (4.5)
	Phosphate <2.0 mg/dL, n (%)	TDF	1 (2.2)
		TDF/FTC	2 (4.4)
		ETV	0 (0.0)

Notes: The change in eGFR was calculated by (2nd year eGFR – baseline eGFR)/baseline eGFR ×100%. Categories of CKD were defined based on eGFR: ≥90, 60–89, 59–30, and <30 mL/min/1.73 m², respectively. Classification of eGFR is as follows: unimpaired (eGFR >80 mL/min), mildly impaired (50 mL/min ≤ eGFR ≤80 mL/min), moderately impaired (30 mL/min ≤ eGFR <50 mL/min), and severely impaired (eGFR <30 mL/min).

Abbreviations: BL, baseline; CKD-EPI-CysC, Chronic Kidney Disease Epidemiology Collaboration and cystatin C; CKD-EPI-Cr-CysC, Chronic Kidney Disease Epidemiology Collaboration and creatinine plus cystatin C; CG, Cockcroft–Gault; eGFR, estimated glomerular filtration rate; ETV, entecavir; FTC, emtricitabine; IQR, interquartile range; LAM, lamivudine; LdT, telbivudine; MDRD, modification of diet in renal disease; MDRD4, modification of diet in renal disease 4-variable version; MO, month; SD, standard deviation; TDF, tenofovir disoproxil fumarate; TN, treatment-naïve; TE, treatment-experienced.

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