Treatment strategies using adefovir dipivoxil for individuals with lamivudine-resistant chronic hepatitis B

Table 1 Baseline characteristics of patients with lamivudine-resistant chronic hepatitis B

	"Switch/combination" group2 (n = 75)	"Add-on" group3(n = 79)	P value1
Age (yr)	43.3 ± 10.2	47.6 ± 12.9	0.022
Male gender	56 (74.7)	53 (67.1)	0.301
BMI (kg/m2)	24.1 ± 5.1	23.8 ± 3.2	0.583
Positive for HBeAg	57 (76.0)	53 (67.1)	0.221
Positive for anti-HBe	19 (25.3)	25 (31.6)	0.386
HBV DNA (log10 IU/mL)	6.75 ± 0.93	6.94 ± 1.08	0.233
AST (IU/L)	148.7 ± 134.5	141.1 ± 148.3	0.742
ALT (IU/L)	230.1 ± 213.4	199.5 ± 191.8	0.351
Albumin (g/dL)	4.4 ± 0.5	4.3 ± 0.6	0.166
ALP (IU/L)	83.4 ± 37.6	76.8 ± 27.6	0.211
GGT (IU/L)	60.5 ± 42.9	67.1 ± 71.1	0.494
Total bilirubin (mg/dL)	1.2 ± 0.9	1.4 ± 1.9	0.425
Prothrombin time (INR)	1.16 ± 0.29	1.15 ± 0.19	0.825
Hemoglobin (g/dL)	14.5 ± 1.8	14.2 ± 1.7	0.345
WBC (/mm3)	5279 ± 1771	4972 ± 1374	0.233
Platelet (× 103/mm3)	156 ± 68	145 ± 69	0.283
BUN (mg/dL)	12.5 ± 3.1	13.1 ± 4.4	0.325
Creatinine (mg/dL)	0.97 ± 0.15	0.92 ± 0.20	0.110
Duration of prior lamivudine treatment (mo)	28.7 ± 13.6	28.3 ± 15.5	0.886
Cirrhosis	25 (33.3)	40 (50.6)	0.030

All values are expressed as mean ± SD or number of patients (%).

¹P values were calculated using the two-sample t test for continuous variables and the χ² test for categorical variables;

²Lamivudine was first switched to adefovir dipivoxil (adefovir), and then lamivudine was re-added later as needed in cases of primary non-response, inadequate response or virologic breakthrough;

³Adefovir was added to ongoing lamivudine treatment due to lamivudine resistance. BMI: Body mass index; HBeAg: Hepatitis B e Antigen; Anti-Hbe: Antibody to HBeAg; HBV DNA: Hepatitis B virus DNA; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; GGT: γ glutamyl transpeptidase; INR: International normalized ratio; WBC: White blood cell; BUN: Blood urea nitrogen.

Table 2 Multivariate analysis for factors of virologic response (undetectable in polymerase chain reaction assay)

Variables	HR	95%CI	P value1
Male gender	0.958	0.621-1.477	0.846
HBeAg (+)	0.668	0.415-1.077	0.098
HBV DNA (log10 IU/mL)	0.810	0.644-1.018	0.071
AST (IU/L)	1.000	0.998-1.002	0.955
ALT (IU/L)	1.000	0.999-1.002	0.606
Duration of prior lamivudine treatment (mo)	1.011	0.998-1.024	0.112
Inadequate response2	0.121	0.069-0.212	< 0.001
Treatment group3 "Add-on" vs "switch/combination"	1.646	1.080-2.510	0.021

¹P-values were calculated with the Cox’s proportional hazard model; Variables with a P < 0.1 in the univariate analysis were included in the multivariate analysis;

²Inadequate response was defined as serum HBV DNA levels of 2000 IU/mL or greater at 6 mo of treatment;

³Patients were divided into two treatment groups: the "add-on" group, in which adefovir dipivoxil (adefovir) was added to ongoing lamivudine treatment due to lamivudine resistance, and the "switch/combination" group, in which lamivudine was first switched to adefovir and then re-added later as needed. HBeAg: Hepatitis B e Antigen; HBV DNA: Hepatitis B virus DNA; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; HR: Hazard ratio.

Table 3 Multivariate analysis for risk factors of virologic breakthrough

	HR	95%CI	P value1
HBeAg (+)	3.251	0.400-26.403	0.270
Albumin (g/dL)	0.552	0.194-1.573	0.266
ALP (IU/L)	1.004	0.994-1.014	0.427
PT (INR)	1.269	0.186-8.648	0.808
Platelet (× 103/mm3)	0.997	0.986-1.007	0.519
Cirrhosis	1.016	0.243-4.448	0.983
Duration of prior lamivudine treatment (mo)	0.99	0.945-1.038	0.691
Inadequate response2	6.57	–1.517-28.458	0.012
Treatment groups3			0.029
Group B vs group A	0.668	0.149-2.984	0.597
Group C vs group A	0.096	0.015-0.629	0.015

¹P-values were calculated with Cox’s proportional hazard model; Variables with a P < 0.1 in the univariate analysis were included in the multivariate analysis;

²Inadequate response was defined as serum HBV DNA levels of 2000 IU/mL or greater at 6 mo of treatment;

³Treatment groups were divided into three groups according to the timing of the drug combination; groups A and B represent the patients who followed or violated the roadmap treatment strategy, respectively; group C included those participants who were treated by adding adefovir dipivoxil (adefovir) to ongoing lamivudine therapy. Roadmap treatment strategy was supposed to initiate adefovir monotherapy first and then add lamivudine later when serum HBV DNA levels were detectable (≥ 60 IU/mL) at six months of treatment. HBeAg: Hepatitis B e antigen; ALP: Alkaline phosphatase; PT: Prothrombin time; INR: International normalized ratio; HR: Hazard ratio.

Table 4 Patterns of genotypic resistance to adefovir dipivoxil in patients with lamivudine-resistant chronic hepatitis B

Mutation pattern	"Switch/combination" group1 (n = 75)	"Add-on" group2(n = 79)
rtA181V	2	0
rtA181T	3	1
rtA181V + rtA181T	0	1
rtN236T	3	0
rtA181V + rtN236T	1	0
rtA181T + rtN236T	1	0
Total, n (%)	10 (13.3)	2 (2.5)

rtA181V, alanine to valine substitution at rt181; rtA181T, alanine to threonine substitution at rt181; rtN236T, asparagine to threonine substitution at rt236.

¹Lamivudine was first switched to adefovir dipivoxil (adefovir), and then lamivudine was re-added later as needed in case of primary non-response, inadequate response, or virologic breakthrough;

²Adefovir was added to ongoing lamivudine treatment due to lamivudine resistance.