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Cho EY, Yim HJ, Jung YK, Suh SJ, Seo YS, Kim JH, Kim HS, Lee SH, Ahn SH, Lee JI, Jeong SH, Kim JW, Lee JW, Kim IH, Kim HS, Park SJ, Lee JM, Hwang SG. Management of Clevudine-Resistant Chronic Hepatitis B: A Multicenter Cohort Study. Gut Liver 2017; 11:129-135. [PMID: 27538443 PMCID: PMC5221870 DOI: 10.5009/gnl15597] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 01/24/2016] [Accepted: 03/22/2016] [Indexed: 12/14/2022] Open
Abstract
Background/Aims Data are lacking regarding the management of chronic hepatitis B (CHB) with resistance to clevudine (CLV). This study evaluated the efficacy of different rescue therapies for CLV-resistant CHB. Methods Patients with CLV-resistant CHB were enrolled in the cohort, and all patients developed virologic breakthrough during CLV therapy and had confirmed-genotypic resistance to CLV (rtM204I mutation) before enrollment. Results Of the 107 patients, 12 received adefovir (ADV), 21 received a CLV plus ADV combination (CLV+ADV), 34 received a lamivudine plus ADV combination (LAM+ADV), and 40 received entecavir (ETV) therapy for 48 weeks. The CLV+ADV group had the lowest hepatitis B virus (HBV) DNA level (p<0.0001) and showed the greatest reduction of HBV DNA levels from baseline compared to all other groups (p=0.004) at week 48. HBV DNA was undetectable (<70 IU/mL) in 0%, 57.1%, 21.2%, and 27.5% (p=0.003) of the patients in each group, respectively, at week 48. At the end of the study, the mean alanine transaminase (ALT) level, rate of ALT normalization, and rate of hepatitis B envelope antigen loss or seroconversion did not differ between groups. Conclusions CLV+ADV combination therapy in patients with CLV-resistant CHB more effectively suppresses HBV replication than ETV, ADV, or LAM+ADV therapy.
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Affiliation(s)
- Eun Young Cho
- Department of Internal Medicine, Wonkwang University School of Medicine, Iksan, Korea
| | - Hyung Joon Yim
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
| | - Sang Jun Suh
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jeong Il Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University College of Medicine, Seongnam, Korea
| | - Jin-Wook Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seongnam, Korea
| | - Jin-Woo Lee
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - In Hee Kim
- Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea
| | - Hyoung Su Kim
- Department of Internal Medicine, Hallym University College of Medicine, Seoul, Korea
| | | | - Jeong Mi Lee
- Department of Public Health, Wonkwang University Graduate School, Iksan, Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
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Lee JW, Lee YJ, Lee JJ, Kim JH, Jung YK, Kwon OS, Choi DJ, Kim YS, Kim JH. [Efficacy of entecavir switching therapy in chronic hepatitis B patients with clevudine-induced myopathy]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2013; 61:30-6. [PMID: 23354347 DOI: 10.4166/kjg.2013.61.1.30] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND/AIMS Clevudine is a potent antiviral agent against HBV. However, long-term clevudine therapy may cause myopathy. This study was carried out to identify the efficacy of entecavir switching therapy in chronic hepatitis B patients experiencing clevudine-induced myopathy. METHODS One hundred forty six patients with chronic hepatitis B treated with 30 mg of clevudine per day for 73 weeks (range, 36-132 weeks) were enrolled. Among them, clevudine-induced myopathy occurred in 21 patients (14.4%) which was diagnosed if the patients had symptoms related to myopathy with concurrent CK and AST elevation. All the patients who were diagnosed as clevudine-induced myopathy stopped the therapy, and 17 patients (81%) were switched to entecavir 0.5 mg. RESULTS The patients with clevudine-induced myopathy were switched to entecavir 0.5 mg for median 68 weeks, and all of them showed disappearance of clinical myopathic symptoms and normalization of CK and AST level within median 2.2 months. Eight patients (47%) were HBeAg positive before entecavir treatment, and HBeAg seroconversion was achieved in 2 patients (25%). HBV DNA level was elevated in 3 patients (17.6%) at the time when the patients were diagnosed as myopathy, all of them achieved virological response with entecavir switching therapy. ALT level was elevated in 3 patients (17.6%) before entecavir treatment, all of them showed normalization of ALT level. During entecavir therapy, genotypic resistance to entecavir or virological breakthrough was not noted. CONCLUSIONS In chronic hepatitis B patients experiencing clevudine-induced myopathy, switching to entecavir 0.5 mg per day showed a resolution of myopathy and adequate viral suppression.
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Affiliation(s)
- Ji Won Lee
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University of Medicine and Science, Incheon, Korea
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Kim BK, Ko SY, Kwon SY, Park E, Kim JH, Choe WH, Lee CH. Virological Response and Muscular Adverse Events during Long-Term Clevudine Therapy in Chronic Hepatitis B Patients. HEPATITIS MONTHLY 2013; 13:e6056. [PMID: 23805155 PMCID: PMC3693539 DOI: 10.5812/hepatmon.6056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2012] [Revised: 05/24/2012] [Accepted: 05/26/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recently, several reports issued clevudine induced myopathy in the long term use. OBJECTIVES The aim of this study was to investigate antiviral effects and adverse events of clevudine monotherapy in patients with chronic hepatitis B (CHB). PATIENTS AND METHODS The subjects were 110 treatment-naïve CHB patients. They were treated with 30 mg clevudine/day for more than six months. Virological and biochemical tests, including that for serum creatine kinase (CK), were monitored at baseline and at 3-month intervals during treatment period. RESULTS In HBeAg-positive patients, the cumulative rates of virological response were 74.0 %, 68.5 %, and 67.3 % after one, two, and three years of clevudine treatment, respectively. Cumulative rates of HBeAg loss or seroconversion were 17.8 %, 30 %, and 31.5 % after one, two and, three years of clevudine treatment, respectively. In HBeAg-negative patients, the cumulative rates of virological response were 97.3 %, 100 %, and 94.6 %, respectively. Virological breakthrough occurred in 27 patients. The rtM204I mutation in HBV polymerase was predominantly detected. Muscular adverse events were observed in 15 patients. All patients with myopathy recovered after the cessation of clevudine monotherapy. Fluctuations in CK level during the clevudine treatment period were frequently observed irrespective of development of myopathy. Multiple episodes of CK elevation were significantly related to the development of myopathy. CONCLUSIONS Long-term clevudine monotherapy is effective for suppression of serum HBV DNA level and normalization of serum alanine amino transaminase levels, but associated with occurrence of rtM204I mutation. Clevudine-induced muscular adverse events are not uncommon, although they are totally reversible after cessation of the treatment. Muscular adverse events and serum CK level should be carefully monitored during long-term treatment with clevudine.
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Affiliation(s)
- Byung Kook Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 143-729, Korea
| | - Soon Young Ko
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 143-729, Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 143-729, Korea
- Corresponding author: So Young Kwon, Department of Internal Medicine, Konkuk University School of Medicine, Konkuk University Medical center, 4-12 Hwayang-dong, Gwangjin-gu, Seoul, 143-729, Korea. Tel.: +82-220305010, Fax: +82-220305029, E-mail:
| | - Eugene Park
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 143-729, Korea
| | - Jeong Han Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 143-729, Korea
| | - Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 143-729, Korea
| | - Chang Hong Lee
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 143-729, Korea
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Kim SB, Song IH, Kim YM, Noh R, Kang HY, Lee HI, Yang HY, Kim AN, Chae HB, Lee SH, Kim HS, Lee TH, Kang YW, Lee ES, Kim SH, Lee BS, Lee HY. Long-term treatment outcomes of clevudine in antiviral-naive patients with chronic hepatitis B. World J Gastroenterol 2012; 18:6943-50. [PMID: 23322992 PMCID: PMC3531678 DOI: 10.3748/wjg.v18.i47.6943] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Revised: 10/22/2012] [Accepted: 10/30/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the treatment outcomes of clevudine compared with entecavir in antiviral-naive patients with chronic hepatitis B (CHB).
METHODS: We retrospectively analyzed the clinical data of CHB patients treated with clevudine 30 mg/d and compared their clinical outcomes with patients treated with entecavir 0.5 mg/d. The biochemical response, as assessed by serum alanine aminotransferase (ALT) activity, virologic response, as assessed by serum hepatitis B virus DNA (HBV DNA) titer, serologic response, as assessed by hepatitis B e antigen (HBeAg) status, and virologic breakthrough with genotypic mutations were assessed.
RESULTS: Two-hundred and fifty-four patients [clevudine (n = 118) vs entecavir (n = 136)] were enrolled. In clevudine-treated patients, the cumulative rates of serum ALT normalization were 83.9% at week 48 and 91.5% at week 96 (80.9% and 91.2% in the entecavir group, respectively), the mean titer changes in serum HBV DNA were -6.03 and -6.55 log10 copies/mL (-6.35 and -6.86 log10 copies/mL, respectively, in the entecavir group), and the cumulative non-detection rates of serum HBV DNA were 72.6% and 83.1% (74.4% and 83.8%, respectively, in the entecavir group). These results were similar to those of entecavir-treated patients. The cumulative rates of HBeAg seroconversion were 21.8% at week 48 and 25.0% at week 96 in patients treated with clevudine, which was similar to patients treated with entecavir (22.8% and 27.7%, respectively). The virologic breakthrough in the clevudine group occurred in 9 (7.6%) patients at weeks 48 and 15 (12.7%) patients at week 96, which primarily corresponded to genotypic mutations of rtM204I and/or rtL180M. There was no virologic breakthrough in the entecavir group.
CONCLUSION: In antiviral-naive CHB patients, long-term treatment outcomes of clevudine were not inferior to those of entecavir, except for virologic breakthrough.
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Choung BS, Kim IH, Jeon BJ, Lee S, Kim SH, Kim SW, Lee SO, Lee ST, Kim DG. Long-term treatment efficacy and safety of clevudine therapy in naïve patients with chronic hepatitis B. Gut Liver 2012; 6:486-92. [PMID: 23170155 PMCID: PMC3493731 DOI: 10.5009/gnl.2012.6.4.486] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2012] [Revised: 05/01/2012] [Accepted: 05/14/2012] [Indexed: 01/03/2023] Open
Abstract
Background/Aims Clevudine (CLV) has potent antiviral activity against chronic hepatitis B (CHB) virus infection. The long-term efficacy and safety of CLV therapy in naïve patients with CHB were investigated. Methods In this retrospective study, 152 naïve Korean patients with CHB who received 30 mg of CLV once daily for at least 12 months were investigated. Results The cumulative rates at months 12, 24, and 36, respectively, were 65.8%, 74.7%, and 74.7% for undetectable serum hepatitis B virus (HBV) DNA (<12 IU/mL); 77.6%, 86.2%, and 86.2% for normalization of serum alanine aminotransferase (<40 IU/L); 17.6%, 23.5%, and 23.5% for hepatitis B e antigen (HBeAg) loss or seroconversion; and 6.6%, 22.5%, and 30.0% for viral breakthrough. HBeAg positivity (p=0.010), baseline serum HBV DNA level ≥6 log10 IU/mL (p=0.032) and detectable serum HBV DNA (≥12 IU/mL) at week 24 (p=0.023) were independently associated with the development of viral breakthrough. During follow-up, CLV-induced myopathy developed in 5.9% of patients. Conclusions The results of long-term CLV therapy for the treatment of naïve patients with CHB showed a high frequency of antiviral resistance and substantial associated myopathy. Therefore, we advise that CLV should not be used as a first-line treatment for naïve patients given the availability of other more potent, safer antiviral agents.
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Affiliation(s)
- Bum Su Choung
- Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
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Shin SR, Yoo BC, Choi MS, Lee DH, Song SM, Lee JH, Koh KC, Paik SW. A comparison of 48-week treatment efficacy between clevudine and entecavir in treatment-naïve patients with chronic hepatitis B. Hepatol Int 2011; 5:664-70. [PMID: 21484144 DOI: 10.1007/s12072-010-9238-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2010] [Accepted: 12/11/2010] [Indexed: 12/24/2022]
Abstract
PURPOSE Clevudine and entecavir are currently available in Korea as antiviral drugs against chronic hepatitis B (CHB). We aimed to compare the efficacy of clevudine and entecavir therapy. METHODS Treatment-naïve CHB patients who received 30 mg of clevudine or 0.5 mg of entecavir a day were analyzed. Mean reduction of hepatitis B virus (HBV) DNA levels, complete virological response (cVR, undetectable HBV DNA by real-time PCR), biochemical response (recovery to normal ALT level), and hepatitis B e antigen (HBeAg) seroconversion rate at the 48th week of treatment were assessed. RESULTS A number of 59 patients in clevudine group and 61 patients in entecavir group were included. Mean HBV DNA reductions from baseline were similar in the clevudine and entecavir groups, -6.4 versus -6.8 log(10) copies/mL in HBeAg-positive (p = 0.417) and -6.9 versus -7.0 log(10) copies/mL in HBeAg-negative patients (p = 0.640). The proportion of patients who achieved cVR was not different between the two groups, 53 versus 55% in HBeAg-positive (p = 1.000) and 100 versus 95% in HBeAg-negative patients (p = 0.452). Biochemical response rates and HBeAg seroconversion rates were also similar in both the groups. Two (3.4%) patients in clevudine group showed virologic breakthrough with rtM204I mutation using direct sequencing analysis. Clinical myopathy occurred in two (3.4%) patients in clevudine group. CONCLUSION Mean reduction of viral loads was similar between clevudine and entecavir groups during 48 weeks. However, virologic breakthrough and significant myopathy were noted only in clevudine-treated patients. Therefore, more attention should be paid to patients receiving clevudine.
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Affiliation(s)
- Su Rin Shin
- Department of Medicine, Kangnam Sacred Heart Hospital, Hallym University, Seoul, Korea
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Yang HW, Lee BS, Lee TH, Lee HY, Nam KW, Kang YW, Chae HB, Kim SH, Kim SB, Lee HI, Kim AN, Song IH, Lee SH, Kim HS. Efficacy of initial treatment with clevudine in naive patients with chronic hepatitis B. Korean J Intern Med 2010; 25:372-6. [PMID: 21179274 PMCID: PMC2997965 DOI: 10.3904/kjim.2010.25.4.372] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2009] [Revised: 01/22/2010] [Accepted: 09/14/2010] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND/AIMS Clevudine, a pyrimidine nucleoside analogue, has potent antiviral effects in patients with chronic viral hepatitis B (CHB). We report the efficacy of initial treatment with clevudine in naïve patients with CHB living in Daejeon and Chungcheong Province, South Korea. METHODS One hundred five adults with CHB were administered 30 mg of clevudine per day for an average of 51 weeks. We evaluated viral markers and liver biochemistry retrospectively every 3 months. RESULTS Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatitis B virus (HBV) DNA before the treatment were 184 ± 188 IU/L, 150 ± 138 IU/L, and 7.1 ± 1.2 log copies/mL, respectively. Undetectable rates (< 60 IU/mL) of DNA were 36.2%, 68.9%, 83.6%, 76.2%, and 75.8% at 12, 24, 36, 48, and 60 weeks, respectively. Seroconversion rates were 9.1%, 13.6%, 24.6%, 26.5%, and 26.1% and ALT normalization rates were 64.5%, 78.1%, 87.9%, 90.0% at 12, 24, 36, and 48 weeks, respectively. Six patients (5.7%) had a viral breakthrough. CONCLUSIONS Clevudine is a useful drug in the initial treatment of patients with CHB, with a potent antiviral effect and low incidence of viral breakthrough.
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Affiliation(s)
- Hyeon Woong Yang
- Department of Internal Medicine, Eulji University School of Medicine, Daejeon, Korea
| | - Byung Seok Lee
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Tae Hee Lee
- Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea
| | - Heon Young Lee
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Kwan Woo Nam
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Young Woo Kang
- Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea
| | - Hee Bok Chae
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Seok Hyun Kim
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Seok Bae Kim
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
| | - Hyang Ie Lee
- Department of Internal Medicine, Eulji University School of Medicine, Daejeon, Korea
| | - An Na Kim
- Department of Internal Medicine, Eulji University School of Medicine, Daejeon, Korea
| | - Il Han Song
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Hong Su Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
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Kim HJ, Park DI, Park JH, Cho YK, Sohn CI, Jeon WK, Kim BI. Comparison between clevudine and entecavir treatment for antiviral-naïve patients with chronic hepatitis B. Liver Int 2010; 30:834-40. [PMID: 20408946 DOI: 10.1111/j.1478-3231.2010.02245.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIMS There has been no study comparing the clinical efficacy of clevudine and entecavir in antiviral-naïve patients with chronic hepatitis B (CHB). METHODS A total of 128 antiviral-naïve CHB patients were included to receive clevudine 30 mg (n=55) or entecavir 0.5 mg (n=73) once daily for a mean follow-up period of 18.4 months. RESULTS Thirty-three (60.0%) in the clevudine group and 40 (54.8%) in the entecavir group were HBeAg positive (P>0.05). At 6 months from the baseline, the mean decreases in HBV-DNA were 4.86 and 4.72 log(10) copies/ml in the clevudine and entecavir groups respectively (P>0.05). The proportion of patients with undetectable serum HBV-DNA (<300 copies/ml) at 6 months was 65.5 and 74.0% in the clevudine and entecavir groups respectively (P>0.05). The proportion of patients with normal alanine aminotransferase levels at 6 months was 74.5 and 84.9% in the clevudine and entecavir groups respectively. During the mean follow-up of 18.4 months, genotypic resistance was noted in three patients (5.5%) in the clevudine group and no cases in the entecavir group. Eight patients (14.6%) in the clevudine group experienced symptoms, signs and laboratory abnormalities relevant to clevudine-induced myopathy. CONCLUSIONS Clevudine and entecavir treatment effectively suppresses HBV replication in most antiviral-naïve patients with CHB. During a mean follow-up of 18.9 months, a small proportion (5.5%) of patients in the clevudine group developed genotypic resistance. However, a substantial proportion (14.6%) of patients in the clevudine group had an adverse effect of clevudine-induced myopathy.
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Affiliation(s)
- Hong Joo Kim
- Department of Internal Medicine, Division of Gastroenterology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
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