Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies

Table 1 Baseline characteristics of the patients n (%)

Variables	Total (n = 50)
Age (yr)1	46.5 (22-74)
Male	37 (74)
HBeAg-positive	47 (94)
Cirrhosis	12 (24)
Antiviral history before ETV (naïve/clevudine/LMV)	2/2/46 (4/4/92)
Duration of ETV (mo)1	24 (13-58)
Serum ALT (IU/L)1	31 (5-1704)
Serum total bilirubin level (mg/dL)1	0.84 (0.28-4.30)
Serum albumin level (g/dL)1	4.2 (3.6-5.1)
INR1	1.01 (0.87-1.30)
Serum HBV DNA level (log10 IU/mL)1	5.53 (2.81-7.63)
Duration of ADV combination therapy (mo)1	27 (12-45)
Site of ETV-resistant mutations added on rtM204V/I
rt184	19 (38)
rt202	22 (44)
rt173	1 (2)
rt169 + rt184	1 (2)
rt184 + rt202	6 (12)
rt184 + rt250	1 (2)
Patients with elevated ALT level above ULN	18 (36)
Rescue therapy regimens [(ADV + LMV)/(ADV + ETV)]	27/23 (54/46)

¹Data are expressed as median (range). ADV: Adefovir; ALT: Alanine aminotransferase; ETV: Entecavir; HBeAg: Hepatitis B e antigen; HBV: Hepatitis B virus; INR: International normalized ratio; LMV: Lamivudine; ULN: Upper limit of normal.

Table 2 Comparison of clinical features between groups according to 1-year virologic response n (%)

	Patients without VR (n = 32)	Patients with VR (n = 18)	P value
Age (yr)1	47 (22-70)	42.5 (33-74)	0.413
Male	22 (68.8)	15 (83.3)	0.328
HBeAg-positive	31 (96.9)	16 (88.9)	0.291
Cirrhosis	8 (25)	4 (22.2)	1.000
Duration of ETV therapy (mo)1	24 (13-48)	36 (17-58)	0.003
Serum ALT level (IU/L)1	34.5 (12-918)	29 (5-1704)	0.210
Serum total bilirubin level (mg/dL)1	0.84 (0.31-1.99)	0.79 (0.28-4.30)	0.869
Serum albumin level (g/dL)1	4.2 (3.6-5.1)	4.3 (3.6-4.9)	0.691
INR1	1.01 (0.93-1.23)	1.02 (0.87-1.30)	0.848
Serum HBV DNA level (log10 IU/mL)1	6.16 (3.85-7.63)	4.24 (2.81-7.08)	< 0.001
Site of ETV-resistant mutations			0.441
rt184	12 (37.5)	7 (38.9)
rt202	14 (43.8)	8 (44.4)
rt173	0 (0)	1 (5.6)
rt169 + rt184	0 (0)	1 (5.6)
rt184 + rt202	5 (15.6)	1 (5.6)
rt184 + rt250,	1 (3.1)	0 (0)
Presence of IVR-3	7 (21.9)	17 (94.4)	< 0.001
Rescue therapy regimens (ADV/LMV vs ADV/ETV)	19 vs 13 (59.4 vs 40.6)	8 vs 10 (44.4 vs 55.6)	0.382

¹Data are expressed as median (range). ADV: Adefovir; ALT: Alanine aminotransferase; ETV: Entecavir; HBeAg: Hepatitis B e antigen; HBV: Hepatitis B virus; INR: International normalized ratio; IVR-3: Initial virologic response at 3 mo; LMV: Lamivudine; VR: Virologic response.

Table 3 Multivariate analyses of clinical factors affecting one-year virologic response

	RR	95%CI	P value
Duration of ETV therapy (mo)	1.039	0.936-1.153	0.473
Serum HBV DNA level (< 5.2 log10 IU/mL)	7.614	1.160-49.986	0.034
Presence of IVR-3	24.862	2.398-257.781	0.007

ETV: Entecavir; HBV: Hepatitis B virus; IVR-3: Initial virologic response at 3 mo.

Table 4 Univariate and multivariate analyses of factors affecting long-term virologic response

	Univariate analysis			Multivariate analysis
	RR	95%CI	P value	RR	95%CI	P value
Age (yr)	1.011	0.973-1.050	0.586
Sex (male)	1.156	0.488-2.740	0.741
HBeAg positivity (-)	1.905	0.568-6.383	0.296
Disease status (LC)	0.775	0.293-2.054	0.609
Duration of ETV (mo)	1.077	1.036-1.119	< 0.001	1.022	0.970-1.076	0.419
Serum ALT (IU/L)	1.000	0.998-1.002	0.976
Serum total bilirubin level (mg/dL)	1.405	0.774-2.550	0.264
Serum albumin level (g/dL)	1.214	0.384-3.836	0.741
INR	0.137	0.001-22.543	0.445
Serum HBV DNA level (< 5.2 log10 IU/mL)	5.084	2.231-11.581	< 0.001	2.870	1.049-7.854	0.040
Type of ETV-resistant mutation (rtT184 )	0.780	0.359-1.693	0.529
Presence of IVR-3	8.822	3.228-24.114	< 0.001	4.417	1.402-13.918	0.011
Rescue therapy regimens (ADV/ETV)	2.007	0.928-4.338	0.077	1.678	0.683-4.119	0.259

ADV: Adefovir; ALT: Alanine aminotransferase; CHB: Chronic hepatitis B; ETV: Entecavir; HBeAg: Hepatitis B e antigen; HBV: Hepatitis B virus; INR: International normalized ratio; IVR-3: Initial virologic response at 3 mo; LC: Liver cirrhosis; LMV: Lamivudine.