Brief Article
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Hepatol. Dec 27, 2012; 4(12): 389-393
Published online Dec 27, 2012. doi: 10.4254/wjh.v4.i12.389
Efficacy of 3 years of adefovir monotherapy in chronic hepatitis B patients with lamivudine resistance
Min-Ning Song, Mei-Zhu Hong, Dan-Qing Luo, Wen-Qi Huang, Feng Min, Rong-Hua Fan, Wei-Bing Wu, Li Zhang
Min-Ning Song, Mei-Zhu Hong, Wen-Qi Huang, Feng Min, Rong-Hua Fan, Wei-Bing Wu, Li Zhang, Department of Infectious Diseases, the Affiliated Success Hospital/the 174th Hospital of PLA, Xiamen University, Xiamen 361003, Fujian Province, China
Dan-Qing Luo, School of Management, Xiamen University, Xiamen 361005, Fujian Province, China
Author contributions: Song MN generated the study concept and design; Song MN, Hong MZ, Huang WQ, Min F, Fan RH, Wu WB and Zhang L provided the material; Song MN drafted the manuscript; Luo DQ analyzed and interpreted the data and performed the statistical analysis.
Correspondence to: Min-Ning Song, MD, Department of Infectious Diseases, the Affiliated Success Hospital/the 174th Hospital of PLA, Xiamen University, Xiamen 361003, Fujian Province, China. luodqluojzsongmn2004@126.com
Telephone: +86-592-6335715 Fax: +86-592-6335530
Received: August 14, 2012
Revised: October 13, 2012
Accepted: November 25, 2012
Published online: December 27, 2012

Abstract

AIM: To study the effect of rescue monotherapy with adefovir (ADV) in patients with chronic hepatitis B (CHB) who developed drug resistance to lamivudine (LAM).

METHODS: A total of 76 treated CHB patients with resistance to LAM were enrolled in the present study. The patients’ baseline characteristics, such as age, gender, blood tests and hepatitis B virus (HBV) DNA were collected; therapy duration and the response of each patient were also recorded. ADV monotherapy was set as the observation group A. Twenty-four patients with LAM resistance, who were set as group B, accepted combined therapy with LAM + ADV. Patients were followed up at 0, 12, 24, 52, 104 and 156 wk. Hepatitis B surface antigen status, hepatitis B e antigen (HBeAg)/anti-HBe status, HBV DNA level and biochemical indexes were monitored. Sequencer of HBV polymerase gene was performed on the ABI 3730 automated sequencer. If no desired effects had been achieved during the course of treatment, patients’ choices were also taken into account. The control group was tested at the same time.

RESULTS: In the two groups, 27 cases developed viral breakthrough after LAM treatment response. The remaining 49 cases underwent biochemical rebound accompanied by rtM204I/V or rtL180M mutation. In group A, 52 cases finished 156 wk of ADV monotherapy; of whom, 36 cases were HBeAg positive and 16 HBeAg negative. In patients whose baseline HBV DNAs were 103-105 copies/mL, 88.8% of patients’ HBV DNAs were lower than the lower test limit (103 copies/mL) after 12 to 156 wk of ADV treatment. In patients whose baseline HBV DNAs were ≥ 106 copies/mL, 41.1%-47.0% of patients’ HBV DNAs were lower than the lower test limit after the same course of ADV therapy (χ2 were 4.35-5.4, 41.1%-47.0% vs 88.8% group 103-105 copies/mL, P < 0.01). In group A, seroconversion of HBeAg developed in 8 of 36 cases (22.2%). In group B, 24 cases finished 156 wk of LAM + ADV; of whom, 17 cases were HBeAg positive and 7 HBeAg negative. In patients whose baseline HBV DNAs were 103-105 copies /mL, 81.8% of patients’ HBV DNAs were lower than the lower test limit (103 copies/mL) after 12 to 156 wk of treatment. In the patients whose baseline HBV DNAs were ≥ 106 copies/mL, 46.1%-53.8% of patients’ HBV DNAs were lower than the lower test limit after the same course of LAM + ADV therapy (χ2 were 4.1-5.0, 46.1%-53.8% vs 81.8% group 103-105 copies/mL, P < 0.05-0.01). In group B, 4 of 17 cases (23.5%) developed seroconversion of HBeAg. Treatment outcomes in groups A and B were comparable.

CONCLUSION: In both group A and B, the ratios of virological response have similar efficacy in patients with lower baseline HBV DNAs.

Key Words: Adefovir, Lamivudine, Drug resistance, Chronic hepatitis B, Antiviral therapy, Monotherapy



INTRODUCTION

The main treatment for chronic hepatitis B (CHB) is antiviral therapy. Nucleoside analogues are one of the major choices. However, drug resistance hinders nucleoside analogues from a wide application, especially in cases of long-term oral administration. When multiple drugs are used, the occurrence of single or multiple drug resistance is an issue that cannot be neglected. Considering the need for nucleoside administration in the long run, an appropriate strategy is necessary so that multiple drug resistance can be avoided.

Lamivudine (LAM) resistance is fairly common in clinical practice. The present study was performed in order to evaluate the efficacy of single rescue therapy with adefovir (ADV). We hope to determine (1) the feasibility of single agent salvage therapy with ADV in LAM resistant cases; and (2) whether a predicted efficacy can be derived from the baseline hepatitis B virus (HBV) DNA load.

MATERIALS AND METHODS
Patients

During the period between April 2006 and March 2007, there were 85 cases of patients who failed the initial LAM treatment in our hospital. Among those cases, 27 cases developed viral breakthrough after LAM treatment response. Viral breakthrough was defined as serum HBV DNAs rebound greater than 102 copies/mL. The remaining 49 cases underwent biochemical rebound accompanied by rtM204I/V or rtL184M mutation. In group A, 52 cases were employed and oral ADV in 10 mg/d was given for 8 wk before the cessation of LAM. In group B (24 cases), ADV of 10 mg/d and LAM of 100 mg/d were administered. Diamine glycyrrhizin or silymarin was used for patients with elevated alanine aminotransferase (ALT). Patients were excluded if they had the following: interferon administration in the last 6 mo; combined infection of HCV or HDV; autoimmune hepatitis; elevated confirmed liver cancer or suspected liver cancer; decompensated liver disease; and a history of alcohol abuse, pregnancy or breast-feeding. The diagnosis was made according to the guidelines[1]. There was no history of immunomodulatory agent administration in the last 6 mo. All patients gave informed consent before treatment. Finally, 52 patients were enrolled in ADV single drug and 24 patients were enrolled ADV plus LAM in this prospective research. In patients with HBeAg-positive CHB, combined response was defined as ALT levels returning to normal, accompanied by undetectable HBV DNA and HBeAg seroconversion; partial response was defined as ALT levels returning to normal, HBV DNA < 103 copies/mL with no seroconversion.

Monitoring of patients

Patients were followed up at 12, 24, 52, 104 and 156 wk. Hepatitis B surface antigen status, hepatitis B e antigen (HBeAg)/anti-HBe status, HBV DNA level and biochemical indexes were monitored. If no desired effects had been achieved during the course of treatment, patients’ choices were also taken into account. Group B was tested at the same time.

Sequencing of HBV polymerase gene and assay of HBV DNA

Sera from patients on presentation were taken for the following tests: (1) sequencing of HBV polymerase gene, which was performed on the ABI 3730 automated sequencer; and (2) assay of HBV DNAs, which was determined by quantitative fluorescence polymerase chain reaction (PCR) on the ABI 7000 (Applied Biosystems) with a lower limit of detection of 1000 copies/mL. HBV DNAs levels lower than the detection limit were regarded as negative for statistical calculations.

RESULTS
Demographics

A total of 76 CHB patients were enrolled. The baseline demographics, liver function tests, liver biochemistry, HBV Gene sequencing determination data and HBV DNAs levels are listed in Table 1.

Table 1 Baseline demographic and virological data of the study population.
FactorA groupn (range)B groupn (range)
Sex (M:F)38:1418:6
Age (yr)27.6 (19-60)25.7 (18-59)
ALT (U/L)165 (44-1000)230 (110-640)
HbeAg positive/HBeAg negative36:1617:7
HBV DNA (log copies/mL)7.35 (3.00-9.0)7.5 (3.0-9.0)
LAM-induced mutation of HBV DNA and rebound40:1220:4
Baseline characteristics and treatment outcomes

At 12, 24, 52, 104 and 156 wk, there was no statistical difference in the number of patients who achieved virological response (VR, defined as HBV DNA < lower detection limit) or biochemical response (defined as ALT < lower detection limit) between the two groups with a baseline of HBeAg positive and HBeAg-negative. More than that, there was also no statistical difference between the two groups with a baseline ALT < 2 × upper limit of normal (ULN) and ALT > 2 × ULN. However, patients with a lower baseline HBV DNA level tended to have a higher VR ratio. Baseline HBV DNAs, HBeAg status, ALT and their relationship to treatment outcomes of each group are shown in Table 2.

Table 2 Control of the therapeutic effect in the two groups.
GroupBaselinen12 wk24 wk52 wk104 wk156 wk
(copies/mL)VR1BR2VR1BR2VR1BR2VR1BR2VR1BR2
A103-1051816 (88.8)116 (88.8)16 (88.8)116 (88.8)16 (88.8)316 (88.8)16 (88.8)116 (88.8)16 (88.8)116 (88.8)
A≥ 1063414 (41.1)24 (70.5)15 (44.1)30 (88.2)16 (47.0)22 (64.7)16 (47.0)26 (76.4)16 (47.0)18 (52.9)
B103-105119 (81.8)49 (81.8)9 (81.8)410 (90.9)9 (81.8)410 (90.9)8 (72.7)9 (81.8)9 (81.8)49 (81.8)
B≥ 106136 (46.1)10 (76.9)6 (46.1)10 (76.9)6 (46.1)9 (69.2)7 (53.8)9 (69.2)6 (46.1)9 (69.2)
AHBeAg positive3618 (50.0)26 (72.2)20 (55.5)30 (83.3)20 (55.5)26 (72.2)22 (61.1)26 (72.2)20 (55.5)22 (61.1)
AHBeAg negative1612 (75.0)14 (87.5)14 (87.5)16 (100.0)12 (75.0)12 (75.0)14 (87.5)16 (100.0)12 (75.0)6 (75.0)
BHBeAg positive178 (47.8)12 (70.5)9 (52.9)15 (88.2)9 (52.9)15 (88.2)9 (52.9)13 (76.4 )10 (58.8)11 (64.7)
BHBeAg negative75 (71.4)6 (85.7)5 (71.4)6 (85.7)6 (85.7)6 (85.7)5 (71.4)6 (85.7)5 (71.4)6 (85.7)
AALT < 2 × ULN2017 (85.0)18 (90.0)16 (80.0)18 (90.0)14 (70.0)14 (70.0)14 (70.0)18 (90.0)14 (70.0)14 (70.0)
AALT > 2 × ULN3218 (56.2)22 (68.7)18 (56.2)28 (87.5)18 (56.2)26 (81.2)22 (68.7)24 (75.0)18 (56.25)20 (62.5)
BALT < 2 × ULN108 (80.00)9 (90.0)8 (80.0)10 (100.0)8 (80.0)10 (100.0)8 (80.0)10 (100.0)8 (80.0)9 (90.0)
BALT > 2 × ULN148 (57.1)10 (71.4)8 (57.1)12 (85.7)10 (71.4)12 (85.7)10 (71.4)12 (85.7)10 ( (71.4)12 (85.7)
HBeAg seroconversion state in treatment course with ADV monotherapy

As shown in Table 3, after 12 wk of treatment, HBeAg seroconversion was 0/36 cases in group A. At 24 and 52 wk, it was 4/36 cases (11.1%). After 104 and 156 wk of treatment, the HBeAg seroconversion ratio rose in 8/36 cases (22.2%). After 12 to 52 wk of treatment, HBeAg turned negative in 2/36 cases (5.5%). After 156 wk of treatment, HBeAg turned negative in 6/36 cases (16.6%). The ratio of HBV DNAs lower than 103 copies/mL gradually increased with the treatment course when compared with the baseline (χ2 were 6.4-11.0, 23.05% vs 65.4%, P < 0.01). After treatment, the ratio of HBV DNAs > 107 copies/mL decreased gradually with the treatment course (χ2 were 4.07-10.8, 3.8% vs 34.6%, P < 0.05-0.01). No significant difference was observed in either group.

Table 3 Response to adefovir salvage therapy n (%).
ProjectHBV DNA (copies/mL)HBeAg positivertA181V/S variation
103103-106107HBeAg seroconversionHBeAg eliminationChange drug
Baseline levelA12 (23.0)22 (42.43)18 (34.6)36
B5 (20.8)11 (45.8)8 (33.3)17
12 wkA30 (57.7)118 (34.6)4 (7.6)20 (0)2 (5.5)
B14 (58.3)48 (33.3)2 (8.3)51 (5.8)1 (5.8)
24 wkA32 (61.5)420 (38.4)0 (0)34 (11.1)2 (5.5)2 (5.5)
B15 (62.5)48 (33.3)1 (4.1)52 (11.7)2 (11.7)1 (5.8)
52 wkA34 (65.4)118 (34.6)0 (0)34 (11.1)2 (5.5)2 (5.5)
B16 (66.6)48 (33.3)0 (0)54 (23.5)2 (11.7)1 (5.8)
104 wkA36 (69.2)116 (30.7)0 (0)38 (22.2)4 (11.1)2 (5.5)
B16 (66.6)48 (33.3)0 (0)54 (23.5)2 (11.7)1 (5.8)
156 wkA34 (65.4)116 (30.7)2 (3.8)38 (22.2)6 (16.6)4 (11.1)
B15 (62.5)48 (33.3)1 (4.1)54 (23.5)2 (11.7)2 (11.7)
The handling of poor effect and viral rebound

During treatment, 10 cases underwent poor response or viral rebound. The rtA181V/I/S loci variation was detected in 4 cases (7.6%). Entecavir (ETV) was added at 52 and 108 wk. After one year, the 2nd HBV polymerase gene sequencing was performed and rtM204I variation persisted in 2 cases (2/10). Although ALT turned to normal, HBV DNAs were higher than 103 copies /mL in the time course. Six patients shifted to ETV at 24 wk. At 104 wk, 10 patients’ ALT turned normal with HBV DNAs < 103 copies/mL. However, after self-withdrawal at 4-12 wk, ALT became abnormal. In group B, 3 patients (12%) at 104 and 156 wk respectively were detected with rtA181V/I/S and rtM204I, rtL180M sites of variation.

DISCUSSION

In the treatment of chronic hepatitis B, ADV tends to induce mutations of the HBV genome that are different from that of LAM. Thus, ADV may serve as an alternative for the patients with LAM resistance. Due to the earlier entry of LAM into China’s market, ADV used to act as a salvage therapy in patients who could not gain a satisfying response or have resistance to LAM. Several reports have indicated that combined use of ADV and LAM surpasses single salvage treatment with ADV[2-6]. However, the enrolled patients were limited. More than that, expenditure and multi-drug resistance are worthy of care[7,8]. Thereupon, we executed single salvage treatment of ADV in 2006 in patients who developed resistance to LAM. Similarly to the observation of Shin et al[9], Lee et al[10] and Kim et al[11] patients who have a lower viral load tended to have a higher response ratio to ADV monotherapy. We also observed that patients who have a higher viral load usually have a poor response, which agreed with Idilman et al[12], Chen et al[13] and Aizawa et al[14]. Unauthorized withdrawal of drugs would lead to the rebound of HBV DNA. In the cases where HBV DNAs cannot return to normal, the ratio of ALT normalization was also low. After 156 wk of treatment, the ratio of HBeAg seroconversion was 22.2% (8/36 cases), which was similar to both Aizawa et al[15], Ryu et al[16] and Heo et al[17] of single rescue therapy of ADV in patients who developed drug resistance to LAM and the ratio of HBeAg seroconversion in patients who accepted single ADV treatment for the first time. After ADV salvage therapy, the proportion of patients whose HBV DNAs were lower than 103 copies/mL increased gradually with time compared with the baseline. The number of patients whose HBV DNAs were higher than 107 copies/mL decreased gradually with time compared with the baseline (Table 2). The overall decline of HBV DNA load was similar to that in the initial treatment with ADV[18]. Variation of rtA181V/I/S loci was detected in 4 cases (7.6%) after 104 wk of treatment. Among them, 2 cases (3.8%) remained with rtM204I loci variation after 52 wk of ADV treatment. Meanwhile, the cases remained in a state of low HBV DNAs load and ALT were stable. Mutation rate was similar to that in the report of initial treatment of ADV. No multiple resistance sites were screened out. In group A, HBV DNA was slightly higher than group B. However, it was more difficult to deal with multiple points of resistance.

Our results showed that single salvage therapy of ADV has a certain effect on patients who developed resistance to LAM. We think it is suitable to initiate ADV salvage therapy in patients whose HBV DNA is in 103-105 copies/mL, although timely monitoring on HBV DNA load is needed. It is sagacious to adopt combination therapy if no satisfying effect is achieved. Chen et al[19] has also observed that no additional benefit may be gained in initiating combination therapy at the very beginning[20,21]. HBV DNA load at 24 wk or 12 mo may serve as a predictor of ADV resistance[22-25]. Single salvage therapy with ADV is conducive to reducing non-individualized combination therapy, the potential hazards of multiple drug resistance, the financial burden and mental stress of patients due to long-term additional medication and to enhance compliance. ADV rescue treatment cannot gain a satisfying effect in LAM resistant cases which may stem from the limitation of ADV in patients with high HBV DNA loads. No significant difference was observed in the two groups. Timely detection of HBV DNA load, virological breakthrough and genome variation are necessary for the achievement of a preferable response. In the patients who do not have desired outcome, combined therapy may be a suitable strategy.

ACKNOWLEDGMENTS

We are much indebted to Dr. Jin-Shui Pan for comments and checking the interpretation of the manuscript.

COMMENTS
Background

The greatest challenge in the treatment of hepatitis B with a nucleoside was drug resistance after long-term treatment. At the same time, with the multi-drug combination, resistance to the multi-drug is also a matter of time. Due to the earlier entry of resistance to lamivudine (LAM) into China’s market, adefovir (ADV) is used as a salvage therapy in patients who cannot gain a satisfying response or have resistance to LAM. Several reports have indicated that the combined use of ADV and LAM surpasses single salvage treatment with ADV. However, hepatitis B virus (HBV) DNA may have a significant influence on the antiviral effect of ADV. The present research aims at evaluating the effect of ADV monotherapy on LAM resistant patients with diverse levels of HBV DNA.

Research frontiers

How to control and reduce the occurrence of nucleoside resistance is a current difficulty and hot issue. Particularly, it is great challenge when multiple drug and long term administration are needed. To date, there is no satisfying solution for this issue.

Innovations and breakthroughs

Although there is debate on whether ADV or ADV plus LAM should be used for the rescue treatment on LAM resistance, HBV DNA level may have a significant effect on the efficacy of salvage therapy. Sagacious and individualized choice should be made for patients with different HBV DNA levels.

Applications

Although multicenter and randomized observations are needed, the present research may shed light on the strategy of rescue therapy on LAM resistance.

Terminology

Salvage therapy: A therapeutic approach, involving chemotherapy, radiation therapy or surgery, after initial regimens have failed to lead to improvement in a patient’s condition. Salvage therapy is most often used for neoplastic diseases; Drug resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug.

Peer review

The authors’ aim is important, although it is difficult to understand how the authors selected observation and control groups among chronic hepatitis B patients. The authors prospectively evaluated the effectiveness of ADV vs ADV + LAM treatment in patients with lamivudine resistance. They concluded that combination therapy should be used in patients with high DNA levels. This conclusion has practical implications.

Footnotes

Peer reviewer: Yasemin Hatice Balaban, MD, Professor, Medical Faculty Internal Medicine Department, Gastroenterology Unit, Hacettepe University, 06100 Ankara, Turkey

S- Editor Song XX L- Editor Roemmele A E- Editor Li JY

References
1.  Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association. The guideline of prevention and treatment for chronic hepatitis B (2010 version). Zhonghua Ganzangbing Zazhi. 2011;19:13-24.  [PubMed]  [DOI]
2.  Chung GE, Kim W, Lee KL, Hwang SY, Lee JH, Kim HY, Jung YJ, Kim D, Jeong JB, Kim BG. Add-on adefovir is superior to a switch to entecavir as rescue therapy for Lamivudine-resistant chronic hepatitis B. Dig Dis Sci. 2011;56:2130-2136.  [PubMed]  [DOI]
3.  Sheng YJ, Liu JY, Tong SW, Hu HD, Zhang DZ, Hu P, Ren H. Lamivudine plus adefovir combination therapy versus entecavir monotherapy for lamivudine-resistant chronic hepatitis B: a systematic review and meta-analysis. Virol J. 2011;8:393.  [PubMed]  [DOI]
4.  Vassiliadis TG, Giouleme O, Koumerkeridis G, Koumaras H, Tziomalos K, Patsiaoura K, Grammatikos N, Mpoumponaris A, Gkisakis D, Theodoropoulos K. Adefovir plus lamivudine are more effective than adefovir alone in lamivudine-resistant HBeAg- chronic hepatitis B patients: a 4-year study. J Gastroenterol Hepatol. 2010;25:54-60.  [PubMed]  [DOI]
5.  Kim HJ, Park JH, Park DI, Cho YK, Sohn CI, Jeon WK, Kim BI. Rescue therapy for lamivudine-resistant chronic hepatitis B: comparison between entecavir 1.0 mg monotherapy, adefovir monotherapy and adefovir add-on lamivudine combination therapy. J Gastroenterol Hepatol. 2010;25:1374-1380.  [PubMed]  [DOI]
6.  Pellicelli AM, Barbaro G, Francavilla R, Romano M, Barbarini G, Mazzoni E, Mecenate F, Paffetti A, Barlattani A, Struglia C. Adefovir and lamivudine in combination compared with adefovir monotherapy in HBeAg-negative adults with chronic hepatitis B virus infection and clinical or virologic resistance to lamivudine: a retrospective, multicenter, nonrandomized, open-label study. Clin Ther. 2008;30:317-323.  [PubMed]  [DOI]
7.  Liu Y, Wang C, Zhong Y, Chen L, Li X, Ji D, Wang H, Xin S, Zoulim F, Xu D. Evolution and suppression of HBV strains with multidrug resistance to lamivudine, adefovir dipivoxil and entecavir in a patient with chronic hepatitis B. Antivir Ther. 2010;15:1185-1190.  [PubMed]  [DOI]
8.  Yang HJ, Lee JH, Kim YJ, Yoon JH, Lee HS. Antiviral efficacy of combination therapy with entecavir and adefovir for entecavir/lamivudine-resistant hepatitis B virus with or without adefovir resistance. J Med Virol. 2012;84:424-430.  [PubMed]  [DOI]
9.  Shin SR, Koh KC, Gwak GY, Choi MS, Lee JH, Paik SW, Yoo BC. A low viral load predicts a higher initial virologic response to adefovir in patients with Lamivudine-resistant chronic hepatitis B. J Gut Liver. 2010;4:530-536.  [PubMed]  [DOI]
10.  Lee JM, Park JY, Kim do Y, Nguyen T, Hong SP, Kim SO, Chon CY, Han KH, Ahn SH. Long-term adefovir dipivoxil monotherapy for up to 5 years in lamivudine-resistant chronic hepatitis B. Antivir Ther. 2010;15:235-241.  [PubMed]  [DOI]
11.  Kim SS, Cheong JY, Lee D, Lee MH, Hong SP, Kim SO, Cho SW. Adefovir-based combination therapy with entecavir or lamivudine for patients with entecavir-refractory chronic hepatitis B. J Med Virol. 2012;84:18-25.  [PubMed]  [DOI]
12.  Idilman R, Kaymakoglu S, Oguz Onder F, Ahishali E, Bektas M, Cinar K, Pinarbasi B, Karayalcin S, Badur S, Cakaloglu Y. A short course of add-on adefovir dipivoxil treatment in lamivudine-resistant chronic hepatitis B patients. J Viral Hepat. 2009;16:279-285.  [PubMed]  [DOI]
13.  Chen EQ, Wang LC, Lei J, Xu L, Tang H. Meta-analysis: adefovir dipivoxil in combination with lamivudine in patients with lamivudine-resistant hepatitis B virus. Virol J. 2009;6:163.  [PubMed]  [DOI]
14.  Aizawa M, Tsubota A, Fujise K, Tatsuzawa K, Kono M, Hoshina S, Tajiri H. Clinical course and predictive factors of virological response in long-term lamivudine plus adefovir dipivoxil combination therapy for lamivudine-resistant chronic hepatitis B patients. J Med Virol. 2011;83:953-961.  [PubMed]  [DOI]
15.  Aizawa M, Tsubota A, Fujise K, Sato K, Baba M, Takamatsu M, Namiki Y, Ohkusa T, Tajiri H. Overlap/switch to adefovir monotherapy for lamivudine-resistant patients who responded to combination therapy: a pilot controlled study. Intern Med. 2010;49:1067-1072.  [PubMed]  [DOI]
16.  Ryu HJ, Lee JM, Ahn SH, Kim do Y, Lee MH, Han KH, Chon CY, Park JY. Efficacy of adefovir add-on lamivudine rescue therapy compared with switching to entecavir monotherapy in patients with lamivudine-resistant chronic hepatitis B. J Med Virol. 2010;82:1835-1842.  [PubMed]  [DOI]
17.  Heo NY, Lim YS, Lee HC, Chung YH, Lee YS, Suh DJ. Lamivudine plus adefovir or entecavir for patients with chronic hepatitis B resistant to lamivudine and adefovir. J Hepatol. 2010;53:449-454.  [PubMed]  [DOI]
18.  Okuse C, Yotsuyanagi H, Yamada N, Okamoto M, Ikeda H, Kobayashi M, Fukuda Y, Takahashi H, Nagase Y, Suzuki Y. Effect of nucleoside analog-interferon sequential therapy on patients with acute exacerbation of chronic hepatitis B. Hepatol Res. 2010;40:461-469.  [PubMed]  [DOI]
19.  Chen CH, Wang JH, Lu SN, Hu TH, Hung CH, Chang MH, Changchien CS, Lee CM. Characteristics of adefovir resistance in patients with or without lamivudine-resistant hepatitis B virus treated with adefovir: a 4-year experience. Liver Int. 2011;31:206-214.  [PubMed]  [DOI]
20.  Wu S, Fukai K, Imazeki F, Arai M, Kanda T, Yonemitsu Y, Yokosuka O. Initial virological response and viral mutation with adefovir dipivoxil added to ongoing Lamivudine therapy in Lamivudine-resistant chronic hepatitis B. Dig Dis Sci. 2011;56:1207-1214.  [PubMed]  [DOI]
21.  Yatsuji H, Suzuki F, Sezaki H, Akuta N, Suzuki Y, Kawamura Y, Hosaka T, Kobayashi M, Saitoh S, Arase Y. Low risk of adefovir resistance in lamivudine-resistant chronic hepatitis B patients treated with adefovir plus lamivudine combination therapy: two-year follow-up. J Hepatol. 2008;48:923-931.  [PubMed]  [DOI]
22.  Kim MC, Jung SW, Shin JW, Park NH. The level of HBV DNA at month 12 is an important predictor of virological breakthrough during adefovir monotherapy in chronic hepatitis B patients with lamivudine resistance. Dig Dis Sci. 2011;56:1215-1221.  [PubMed]  [DOI]
23.  Ong A, Wong VW, Wong GL, Chan HY, Tse CH, Chan HL. Management options for lamivudine-resistant chronic hepatitis B patients with suboptimal virological suppression by adefovir. Aliment Pharmacol Ther. 2011;34:972-981.  [PubMed]  [DOI]
24.  Shim JH, Suh DJ, Kim KM, Lim YS, Lee HC, Chung YH, Lee YS. Efficacy of entecavir in patients with chronic hepatitis B resistant to both lamivudine and adefovir or to lamivudine alone. Hepatology. 2009;50:1064-1071.  [PubMed]  [DOI]
25.  Jeon JW, Shin HP, Lee JI, Joo KR, Cha JM, Park JJ, Lim JU, Lim K, Kim S. Efficacy of entecavir and adefovir combination therapy for patients with lamivudine- and entecavir-resistant chronic hepatitis B. Dig Dis Sci. 2012;57:1358-1365.  [PubMed]  [DOI]