Detection of YMDD Motif Mutants by Oligonucleotide Chips in Lamivudine-Untreated Patients with Chronic Hepatitis B Virus Infection

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Abstract

Lamivudine, a nucleoside analogue, has been used widely as an effective antiviral agent for the treatment of patients with chronic hepatitis B virus (HBV) infection. However, the YMDD motif mutation of HBV polymerase resistant to lamivudine occurs very frequently after long term therapy. We developed an oligonucleotide chip for the detection of YMDD motif mutants resistant to lamivudine and investigated the prevalence of the mutants in patients with chronic HBV infection who had not been treated by lamivudine before. Forty patients who had not been treated with lamivudine were included in this study. Serum samples were tested by the oligonucleotide chips designed for detection of wild-type YMDD motif, M552V and M552I. Samples were confirmed by restriction fragment length polymorphism (RFLP) and direct sequencing. M552I mutants were detected by the oligonucleotide chips in 7.5% (3/40) of chronic HBV infected patients (2 chronic hepatitis and 1 cirrhosis). The results were in accordance with those of RFLP. YMDD motif mutants occur as natural genome variabilities in patients with chronic HBV infection who had not been treated with lamivudine before. Oligonucleotide chip technology is a reliable and useful diagnostic tool for the detection of mutants resistant to antiviral therapy in chronic HBV infection.

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Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy.

R Guan, S Edmundson, Albert W. N. Leung … (2001)

A study in Chinese patients with chronic hepatitis B showed that treatment with lamivudine for 1 year significantly improves liver histology and enhances hepatitis B e antigen (HBeAg) seroconversion compared with placebo. Fifty-eight patients from this 1-year study have received long-term treatment with lamivudine 100 mg; the outcome of 3 years of lamivudine is reported here. Before treatment, all patients had detectable HBeAg. HBeAg seroconversion (HBeAg-negative, anti-HBe-positive), hepatitis B virus (HBV)-DNA suppression, alanine transaminase (ALT) normalization, emergence of YMDD variant HBV, liver histology, and long-term safety were assessed. After 3 years of continuous treatment with lamivudine 100 mg daily, 40% (23 of 58) of patients achieved HBeAg seroconversion. In patients with baseline serum ALT >2 x upper limit of normal (ULN), the rate of HBeAg seroconversion was 65% (17 of 26). Median serum HBV-DNA concentrations were below the level of detection, and median ALT concentrations were within the normal range throughout 3 years of treatment. YMDD variant HBV emerged in 33 of 58 (57%) patients during the 3 years, of whom 9 (27%) achieved HBeAg seroconversion (6 after emergence of YMDD variant HBV). ALT levels and histologic scores after emergence of YMDD variant HBV did not show major deterioration. Lamivudine was well tolerated during 3 years of therapy. In conclusion, these data in Chinese patients with chronic hepatitis B show enhanced seroconversion rates with extended lamivudine treatment. Up to two thirds of patients with moderately elevated pretreatment ALT achieved HBeAg seroconversion after 3 years of therapy.

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Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy.

Kenneth R. Chien, Francis Yeh, B Chu … (1999)

Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication, but its long-term use may be associated with HBV tyrosine-methionine-aspartate-aspartate (YMDD) motif mutation. To examine the clinical features and course after emergence of YMDD mutants, 55 patients who received lamivudine therapy over 104 weeks at our unit were assayed for YMDD mutation(s). Thirty-two of them were found to have the YMDD mutation. They continued lamivudine therapy and were followed up weekly or biweekly if clinically indicated. Thirty (93.7%) of them showed elevation of alanine transaminase (ALT), and 13 (40.6%) experienced acute exacerbation at 4 to 94 weeks (median, 24 weeks) after emergence of the YMDD mutant. The incidence of exacerbation is much higher than 4.3% in patients without the YMDD mutation (P =.003). Compared with patients without exacerbation, patients with exacerbation had a significantly higher serum HBV-DNA level after emergence of the YMDD mutant (P <.005). Before exacerbation, serum HBV-DNA level was rising to its peak, followed by the peaking of ALT (247-2,010 U/L) 1 to 4 weeks later. Three patients developed hepatic decompensation, but then in association with hepatitis B e antigen (HBeAg) seroconversion, recovered. Of the 12 evaluable patients, 8 (75%) showed HBeAg seroconversion, and 3 showed mutant clearance within 1 to 5 months after exacerbation. In contrast, none of the patients without exacerbation showed HBeAg seroconversion (P <.001). These results indicate that acute exacerbations may occur after emergence of the YMDD mutation. The incidence, clinicopathological features, and subsequent course, and possibly the underlying immune mechanisms, are similar to those of wild-type HBV chronic infection. Because severe hepatitis may occur, patients should be followed carefully once the YMDD mutant emerges.

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Long-term therapy of chronic hepatitis B with lamivudine.

Marc G Ghany, J Hoofnagle, H. Park … (2000)

Lamivudine therapy induces improvements in chronic hepatitis B in a high proportion of patients, but prolonged therapy is limited by the development of viral resistance. We analyzed clinical responses and virologic resistance in 27 patients treated continuously with lamivudine for 2 to 4 years. Serum transaminases, hepatitis B virus (HBV) DNA by both branched DNA (bDNA) signal amplification and quantitative polymerase chain reaction were monitored at 4- to 8-week intervals. Virologic resistance to lamivudine was confirmed by the presence of mutations in the YMDD motif of the polymerase gene by restriction fragment-length polymorphism analysis. Serum HBV-DNA levels decreased rapidly in all treated patients, falling by 4 to 5 logs within 1 year. Transaminase levels also decreased and were normal in 70% of patients at 1 year, at which point liver histology had improved in 81% of patients. Viral resistance began to emerge after 8 months of therapy, eventually developing in 14 patients, including 76% of hepatitis B e antigen (HBeAg)-positive patients but only 10% of HBeAg-negative patients. Lamivudine withdrawal led to reappearance of wild-type HBV species, but retreatment led to more rapid reappearance of the mutant virus. Clinical, serum biochemical, and histologic improvements were maintained in the 13 patients who did not develop resistance. Thus, long-term therapy with lamivudine resulted in maintained improvements in virologic, biochemical, and histologic features of disease in most patients with HBeAg-negative chronic hepatitis B and in the subgroup of HBeAg-positive patients with high serum transaminase levels. A high rate of resistance limited efficacy, particularly in patients who remained HBeAg positive on therapy.

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Author and article information

Journal

Journal ID (nlm-ta): J Korean Med Sci

Journal ID (publisher-id): JKMS

Title: Journal of Korean Medical Science

Publisher: The Korean Academy of Medical Sciences

ISSN (Print): 1011-8934

ISSN (Electronic): 1598-6357

Publication date (Print): August 2004

Publication date (Electronic): 20 May 2009

Volume: 19

Issue: 4

Pages: 541-546

Affiliations

Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea.

[* ]Department of Laboratory Medicine, Pusan National University College of Medicine, Busan, Korea.

[† ]Department of Microbiology, Pusan National University College of Natural Science, Busan, Korea.

[‡ ]Department of Biochemistry, Pusan National University College of Medicine, Busan, Korea.

Author notes

Address for correspondence: Mong Cho, M.D. Department of Internal Medicine, Pusan National University College of Medicine, 1-10 Ami-dong, Seo-gu, Busan 602-739, Korea. Tel: +82.51-240-7215, Fax: +82.51-244-8180, mcho@ 123456pusan.ac.kr

Article

DOI: 10.3346/jkms.2004.19.4.541

PMC ID: 2816888

PubMed ID: 15308845

SO-VID: 0ab094eb-4cf5-4901-a8fe-b30869311cde

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 11 November 2003

Date accepted : 01 April 2004

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Detection of YMDD Motif Mutants by Oligonucleotide Chips in Lamivudine-Untreated Patients with Chronic Hepatitis B Virus Infection

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Most cited references 10

Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy.

Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy.

Long-term therapy of chronic hepatitis B with lamivudine.

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