Subclinical proximal tubulopathy in hepatitis B: The roles of nucleot(s)ide analogue treatment and the hepatitis B virus

Table 1 Characteristics of the patients with no subclinical proximal tubulopathy at on day 0

Variables	Global (n = 138); n (%) ou; median (Q1; Q3); (n) (min-max)		ETV (n = 28); n (%) ou; median (Q1; Q3) (n) (min-max)	Naive (n = 84); n (%) ou; median (Q1; Q3) (n) (min-max)	TDF (n = 26); n (%) ou; median (Q1; Q3) (n) (min-max)	P value; ETV vs naive	P value; TDF vs naive
Male	72 (52.2%)		19 (67.9%)	39 (46.4%)	14 (53.8%)	0.051	0.511
Age in yr	37.5 (29; 47); (n = 138); (18-74)		45.5 (31; 57.5); (n = 28); (18-66)	36.5 (29; 45); (n = 84); (18-74)	35.5 (24; 42) (n = 26); (21-56)	0.082	0.222
BMI in kg/m2	24.5 (21.3; 27.8); (n = 115); (16.6-38.8)		25 (22.2; 29); (n = 24); (16.6-36.3)	24.8 (21.7; 28.7); (n = 71); (17.8-38.8)	21.8 (19; 26.5); (n = 20); (18-35.2)	0.912	0.022
Ethnicity
-African	65 (47.1%)		7 (25.0%)	44 (52.4%)	14 (53.8%)	0.0033	0.053
-Asian	16 (11.6%)		7 (25.0%)	4 (4.8%)	5 (19.2%)
-White	57 (41.3%)		14 (50.0%)	36 (42.9%)	7 (26.9%)
Phases of infection
-HbeAg + chronic infection	6 (4.3%)		3 (10.7%)	3 (3.6%)	0 (0.0%)	< 0.00013	< 0.00013
-HbeAg + chronic hepatitis	15 (10.9%)		6 (21.4%)	3 (3.6%)	6 (23.1%)
-HbeAg-chronic infection	60 (43.5%)		1 (3.6%)	57 (67.9%)	2 (7.7%)
-HbeAg-chronic hepatitis	57 (41.3%)		18 (64.3%)	21 (25.0%)	18 (69.2%)
Diabetes	9 (6.5%)		5 (17.9%)	4 (4.8%)	0 (0.0%)	0.043	0.573
High blood pressure	25 (18.1%)		9 (32.1%)	12 (14.3%)	4 (15.4%)	0.041	1.003
Renal insufficiency	1 (0.7%)		0 (0%)	1 (1.2%)	0 (0%)	1.003	1.003
Viral load
-PCR < 2000 UI/mL	69 (61.6%)		3 (15.8%)	60 (77.9%)	6 (37.5%)	< 0.00013	< 0.00013
-PCR ≥ 2000 et < 20000 UI/mL	22 (19.6%)		6 (31.6%)	16 (20.8%)	0 (0%)
-PCR ≥ 20000 UI/mL and < 7 (log)	13 (11.6%)		6 (31.6%)	1 (1.3%)	6 (37.5%)
PCR > 7 (log)	8 (7.1%)		4 (21.1%)	0 (0%)	4 (2.5%)	< 0.00012	< 0.00013
ALAT UI/L	25 (17; 36); (n = 133); (7-214)		40 (25; 57); (n = 27); (17-148)	19 (15; 26); (n = 83); (7-89)	46 (28; 70); (n = 23); (10-214)
Fibrosis4
-F0/F15	103 (84.4%)		13 (56.5%)	73 (94.8%)	17 (77.3%)	< 0.00013	0.00673
-F2	5 (4.1%)		2 (8.7%)	2 (2.6%)	1 (4.5%)
-F2/F3	8 (6.6%)		6 (26.1%)	2 (2.6%)	0 (0%)
-F3	1 (0.8%)		0 (0.0%)	0 (0%)	1 (4.5%)
-F3/F4
-F4	5 (4.1%)		2 (8.7%)	0 (0%)	3 (13.6%)
Fibrosis F0/F1 vs F2
-F0/F1	103 (84.4%)		13 (56.5%)	73 (94.8%)	17 (77.3%)	< 0.00013	0.023
-≥ F2	19 (15.6%)		10 (43.5%)	4 (5.2%)	5 (22.7%)
Previous HBV therapy	14 (10.1%)		5 (17.9%)	0 (0.0%)	9 (34.6%)	0.00073	< 0.00013
Nephrotoxic drugs	12 (6.1%)		4 (10.5%)	6 (5.2%)	2 (4.8%)	0.223	1.003

¹Chi² test.

²Mann-Whitney test.

³Fisher’s exact test.

⁴Evaluated by liver biopsy or FibroScan.

⁵METAVIR classification. BMI: Body mass index; ALAT: Alanine aminotransferase; ETV: Entecavir; HbeAG: Hepatitis B e-antigen; HBV: Hepatitis B virus; Max: Maximum; Min: Minimum; Q1: First quartile; Q3: Third quartile; TDF: Tenofovir disoproxil.

Table 2 Clinical characteristics of the patients with no subclinical proximal tubulopathy at on day 0

	Global population (n = 138); median (Q1; Q3); (n) (min-max)	ETV group; (n = 28); median (Q1; Q3); (n) (min-max)	Naive group; (n = 84); median (Q1; Q3); (n) (min-max)	TDF group; (n = 26); median (Q1; Q3); (n) (min-max)	P value; ETV vs naive	P value; TDF vs naive
Phosphatemia, mmoL/L	1.1 (1.0; 1.2); (n = 135); (0.6-1.4)	1.1 (1.0; 1.1); (n = 26); (0.9-1.3)	1.0 (1.0; 1.2); (n = 83); (0.7-1.4)	1.0 (0.9; 1.2); (n = 26); (0.6-1.2)	0.401	0.981
Plasma creatinine, μmoL/L	73 (58; 85); (n = 137); (37.5-114.9)	78.4 (66; 84); (n = 28); (51-114.9)	71 (58; 87); (n = 83); (37.5-113)	76.9 (57.5; 87); (n = 26); (38-98)	0.232	0.772
eGFR (MDRD), mL/min/1.73 m²	94.5 (82.6; 107.6); (n = 137); (58.6-169.1)	91 (84.2; 101); (n = 28); (62.7-141.3)	94.8 (80.7; 108.1); (n = 83); (58.6-151.1)	95.4 (84.3; 108.4); (n = 26); (70.2-169.1)	0.372	0.652
25(OH)D3, ng/mL	15.9 (9.9; 22.2); (n = 130); (3.1-55.2)	16.8 (12.6; 24.8); (n = 26) (5-55.2)	14.8 (9.4; 21); (n = 81); (4-42.1)	15.3 (9.8; 22.7); (n = 23); (3.1-36.9)	0.272	0.952
TmPi/eGFR, mmoL/L	1 (0.9; 1.1); (n = 181); (0.4-1.9)	1 (0.9; 1.2); (n = 34); (0.7-1.8)	1 (0.9; 1.1); (n = 111); (0.4-1.9)	1 (0.8; 1.2); (n = 36); (0.6-1.5)	0.242	0.862
FEUA, %	5.8 (4.5; 7.1); (n = 112); (2.2-9.7)	5.9 (4.7; 7.5); (n = 23); (2.7-9.1)	5.8 (4.4; 7); (n = 69); (2.2-9.3)	5.5 (4.5; 6.7); (n = 20); (3.8-9.7)	0.641	0.951

¹Student’s test.

²Mann-Whitney test. 25(OH)D3: 25-hydroxyvitamin D3; eGFR: Estimated glomerular filtration rate; ETV: Entecavir; FEUA: Fractional excretion rate of uric acid; Max: Maximum; Min: Minimum; Q1: First quartile; Q3: Third quartile; TDF: Tenofovir disoproxil.

Table 3 Subclinical proximal tubulopathy prevalence at month 24 in the entecavir, naive and tenofovir disoproxil groups

	Global (n = 138); n (%); (95%CI)	ETV (n = 28); n (%); (95%CI)	Naive (n = 84); n (%); (95%CI)	TDF (n = 26); n (%); (95%CI)	P value; ETV vs naive		P value; TDF vs naive
Missing values	45	9	22	14
SPT prevalence at M24; (n = 93)	29 (31.2%); (22.0-41.6)	4 (21.1%); (6.1-45.6)	19 (30.7%); (19.6-43.7)	6 (50.00%); (21.1-78.9)	0.421	0.322

¹Chi² test.

²Fisher’s exact test. CI: Confidence interval; ETV: Entecavir; SPT: Subclinical proximal tubulopathy; TDF: Tenofovir disoproxil.

Table 4 Potential confounding factors at baseline susceptible to influence the prevalence of subclinical proximal tubulopathy at month 24 between the different groups in univariate analysis

		HR (95%CI)	P value	Global P value
Fibrosis	≥ F2 vs F0/F1	1.09 (0.32-3.67)	0.89	0.89
Group	ETV vs naive	0.41 (0.09-1.83)	0.24	0.043
	TDF vs naive	2.28 (0.98-5.30)	0.05
Sex	Female vs male	0.85 (0.38-1.87)	0.68	0.68
Ethnicity	African vs White	0.91 (0.41-2.04)	0.83	0.63
	Asian vs White	0.36 (0.05-2.84)	0.33
Diabetes	Yes vs no	0.63 (0.08-4.67)	0.65	0.65
Previous hypertension	Yes vs no	1.26 (0.50-3.17)	0.63	0.63
Viral load	Low vs very low	0.94 (0.30-2.89)	0.91	0.46
	Elevated vs very low	2.38 (0.77-7.34)	0.13
	Very elevated vs very low	1.40 (0.40-4.93)	0.60
Previous HBV therapy	Yes vs no	1.11 (0.33-3.74)	0.86	0.86
Age at inclusion		1.02 (0.98-1.05)		0.35
BMI at inclusion		0.98 (0.89-1.08)		0.67
ALAT at inclusion		1.00 (0.99-1.01)		0.67

ALAT: Alanine aminotransferase; BMI: Body mass index; ETV: Entecavir; HBV: Hepatitis B virus; HR: Hazard ratio; TDF: Tenofovir disoproxil.