Add on Lamivudine to Adefovir Monotherapy for the Treatment of Lamivudine-resistant Chronic Hepatitis B Patients

Young Ju Cho; Jae Youn Cheong; Myoung Hee Lee; Su Jin Jeon; Yoon Chul Lee; Sun Gyo Lim; Chang Joon Kang; Sung Won Cho

doi:10.4166/kjg.2010.56.2.83

Journal List > Korean J Gastroenterol > v.56(2) > 1006765

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Cho, Cheong, Lee, Jeon, Lee, Lim, Kang, and Cho: Add on Lamivudine to Adefovir Monotherapy for the Treatment of Lamivudine-resistant Chronic Hepatitis B Patients

Original Article

Korean J Gastroenterol 2010;56(2):83-89.

Published online: 21 February 2010

DOI: https://doi.org/10.4166/kjg.2010.56.2.83

Add on Lamivudine to Adefovir Monotherapy for the Treatment of Lamivudine-resistant Chronic Hepatitis B Patients

Young Ju Cho, M.D., Jae Youn Cheong, M.D., Myoung Hee Lee, M.D., Su Jin Jeon, M.D., Yoon Chul Lee, M.D., Sun Gyo Lim, M.D., Chang Joon Kang, M.D., Sung Won Cho, M.D.

Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea

Correspondence to: Sung Won Cho, M.D. Department of Gastroenterology, Ajou University School of Medicine, San-5, Woncheon-dong, Yeontong-gu, Suwon 442- 721, Korea Tel: +82-31-219-5999, Fax: +82-31-219-6939 E-mail: sung_woncho@hotmail.com

Received 8 February 2010 Accepted 3 June 2010

Abstract

Background/Aims

Add on adefovir (ADV) to ongoing lamivudine (LAM) has been recommended as a standard therapy for the treatment of LAM resistance. In the past, switch to ADV monotherapy was suggested as an option for the treatment of LAM resistance, leading to frequent development of ADV resistance. However, ADV monotherapy has been still used in LAM-resistant patients because of low cost in Korea. The aims of this study were to evaluate the virologic response and virologic breakthrough during adding on LAM in LAM-resistant patients receiving ADV monotherapy.

Methods

The study population comprised 99 patients with LAM-resistance. We divided them into 3 groups (Group 1: switch to ADV monotherapy, N=58, Group 2: add on ADV to ongoing LAM, N=25, Group 3: add on LAM to ADV monotherapy, N=16). HBV DNA levels were assessed at baseline and every 3 months during therapy. Serum HBV DNA levels were measured by bDNA assay or the COBAS TaqMan ^TM HBV test.

Results

The median treatment duration for group 1, group 2, and group 3 was 42.0, 20.6, and 31.8 (18.7 mon. of ADV＋13.1 mon. of LAM) months, respectively. Cumulative rate of virologic breakthrough in group 1 was 5.2%, 19.0%, and 25.9% at 12, 24, and 36 months of treatment, respectively. Virologic breakthrough was not detected in group 2 and group 3 (p=0.016, group 1 vs. group 2 or 3). In group 3, median serum HBV DNA levels were 4.22 log₁₀ copies/mL prior to LAM administration. Median serum HBV DNA changes from baseline (log₁₀ copies/mL) were −0.91, −1.93, −1.87 and −1.74 at week 12, 24, 36 and 48, respectively.

Conclusions

Later add on LAM to ADV monotherapy prevented the development of ADV resistance in patients with LAM resistance effectively, comparable to ADV add on to continuing LAM therapy.

Keywords: Lamivudine, Drug resistance, Adefovir, Chronic hepatitis B

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Fig. 1.

Incidence of virological breakthrough in LAM-resistant patients according to the therapy. Group 1, ADV monotherapy; Group 2, add on ADV to LAM; Group 3, add on LAM to ADV monotherapy. ADV, adefovir; LAM, lamivudine.

Fig. 2.

Change of serum HBV DNA after add on LAM to ADV monotherapy. ADV, adefovir; LAM, lamivudine.

Table 1.

Baseline Characteristics of 99 Lamivudine-resistant Patients

Patient features	Patients (n=99)
Mean age, years (SD)	45.26 (±8.4)
Male, n (%)	77 (77.8)
HBeAg-positive, n (%)	77 (77.8)
HBV DNA, log₁₀ copies/mL (SD)	7.49 (±0.97)
Mean ALT, IU/L (SD)	179.9 (±174.8)
Mean AST, IU/L (SD)	121.1 (±111.6)
Mean duration of ADV, months (SD)	35.01 (±12.45)
Liver cirrhosis, n (%)	31 (31.3)
YMDD mutation
rtM204I, n (%)	22 (22.2)
rtM204I+rtL180M, n (%)	28 (28.3)
rtM204V+rtL180M, n (%)	37 (37.4)
rtM204I+rtM204V+rtL180M, n (%)	10 (10.1)
Wild type, n (%)	2 (2.0)

HBeAg, hepatitis B e antigen; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HBV, hepatitis B virus; SD, standard deviation; ADV, adefovir; rtM204I, Methionine to isoleucine at codon 204; rtM204V, Methionine to valine at codon 204; rtL180M, leucine to methionine at codon 180.

Table 2.

Comparison of the Baseline Characteristics among 3 Groups

Patient features	Group 1 (n=58)	Group 2 (n=25)	Group 3 (n=16)	p-value
Patient features	Group 1 (n=58)	Group 2 (n=25)	Group 3 (n=16)	Group 1 vs. 2	Group 2 vs. 3
Mean age, years (SD)	43.84 (7.24)	48.84 (10.79)	44.81 (6.59)	0.033	0.278
Male, n (%)	47 (81)	20 (80)	10 (62.5)	1.000	0.287
HBeAg-positive, n (%)	46 (79.3)	19 (76)	12 (75)	0.737	1.000
HBV DNA, log₁₀ copies/mL (SD)	7.54 (0.96)	7.57 (0.67)	7.17 (1.34)	0.99	0.414
Mean AST, IU/L (SD)	142.16 (121.43)	127.00 (95.47)	141.69 (127.95)	0.824	0.676
Mean ALT, IU/L (SD)	208.96 (182.93)	185.96 (158.13)	349.12 (499.68)	0.839	0.223
Mean duration of ADV, months (SD)	42.05 (8.99)	20.68 (5.64)	31.87 (10.51)	0.14	0.11
Liver cirrhosis, n (%)	16 (27.6)	11 (44)	4 (25)	0.143	0.218
YMDD mutation, n (%)
rtM204I＋ rtL180M	18 (31)	6 (24)	4 (25)	0.504	0.793
rtM204V＋ rtL180M	21 (36.2)	13 (52)	3 (18.8)
rtM204V/I＋ rtL180M	3 (5.2)	2 (8)	5 (31.3)
Wild type	1 (1.7)	0 (0)	1 (6.3)

HBV, hepatitis B virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; rtM204I, Methionine to isoleucine at codon 204; rtM204V, Methionine to valine at codon 204; rtL180M, leucine to methionine at codon 180; IVR, initial virologic response.

Table 3.

Viologic Breakthrough Rate according to the HBeAg Positivity

Virologic breakthrough, n (%)	HBeAg (＋)	HBeAg (−)	Total	p-value
Within total	12/77	3/22	15/99	0.562
Within total	(15.6)	(13.6)	(15.2)
Within group 1^∗	12/46	3/12	15/58	0.627
Within group 1^∗	(26.1)	(25.0)	(25.9)

Group 1, ADV monotherapy group.

^∗ Group 2 & 3 had no virologic breakthrough patients.

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