Emergence of YMDD motif mutant of hepatitis B virus during short-term lamivudine therapy in South Korea

Paik, Yong Han; Chung, Hyo Young; Ryu, Wang Shick; Lee, Kwan Sik; Lee, Jisook; Kim, Jung Hee; Lee, Chun Kyun; Chon, Chae Yoon; Moon, Young Myoung; Han, Kwang Hyub

doi:10.1016/s0168-8278(01)00065-4

Cited by 33 publications

(34 citation statements)

References 31 publications

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“…They did not show VBT during treatment period. But we might have missed VBT in these patients because the test for HBV DNA had not been tested at the right time, or YMDD mutants may have existed even before LAM monotherapy [18] . The experimental results from both direct sequencing and InnoLipa DR2 line probe assay were consistent in all patients.…”

Section: Peer Reviewmentioning

confidence: 99%

Baseline HBV DNA level is the most important factor associated with virologic breakthrough in chronic hepatitis B treated with lamivudine

Chae

Hann

2007

WJG

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INTRODUCTIONA high incidence of virologic breakthrough (VBT) that results from viral resistance is a major disadvantage of lamivudine (LAM) treatment for patients with chronic hepatitis B (CHB). Data from a study of 592 patients who had undergone four years of LAM treatment indicated that resistance increased from 23% in year 1 to 71% in year 4 [1,2] . The clinical consequences of viral resistance can be severe, but early studies suggest that median HBV DNA and ALT levels continue to improve even as resistance develops [3] . LAM is known to have long-term therapeutic effects, with well-known resistance and side effects. LAM therapy for CHB patients with advanced fibrosis significantly reduced the incidence of hepatic decompensation and hepatocellular carcinoma (HCC) [4] . In addition, it is becoming increasingly clear that CHB management requires a long-term therapy, thus making the cost of treatment an important consideration. The need for long-term therapy and the consequent financial burden become significant in the economically disadvantaged regions of the world which also happen to be the hyperendemic areas for HBV. Furthermore, this cost issue presents a serious economic burden for CHB patients who immigrated to the US from the hyper-endemic regions. One study suggested that upfront LAM therapy may be highly cost-effective, assuming that patients who develop resistance begin a regimen of adefovir instead of continuing LAM treatment [5] . Our study sought to identify the factors associated with VBT in patients on LAM therapy and attempted to select a subgroup of patients who may respond well to LAM without developing VBT. MATERIALS AND METHODS PatientsWe reviewed the medical records of 208 CHB patients who were treated at the Liver Disease Prevention Center, Abstract AIM: To identify the factors associated with virologic breakthrough and to select a subgroup of patients who respond well to lamivudine without developing virologic breakthrough (VBT). METHODS:Of 79 patients who had received lamivudine therapy for 9-57 mo, 34 were HBeAg-positive and 45 were HBeAg-negative, 24 developed virologic breakthrough and 55 did not. Clinical and virologic factors were compared between the two groups. RESULTS:The median duration of therapy was 25 (9-57) mo. Virologic breakthrough was defined as a > 1 log HBV DNA increase following initial suppression. When several factors, including gender, duration of infection, baseline HBV DNA, and baseline ALT in HBeAg-positive chronic hepatitis patients were analyzed by logistic regression, the most important predictor of virologic breakthrough was the baseline HBV DNA (r 2 = 0.12, P < 0.05). When HBeAg-postitive chronic hepatitis patients were divided into two groups by a point of 6.6 log HBV DNA, the incidence of virologic breakthough between two groups was significantly different. CONCLUSION:Lamivudine may remain an effective first line therapy for those HBeAg-positive patients with a baseline HBV DNA < 6.6 log10 copies/mL.

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Section: Peer Reviewmentioning

confidence: 99%

Baseline HBV DNA level is the most important factor associated with virologic breakthrough in chronic hepatitis B treated with lamivudine

Chae

Hann

2007

WJG

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“…HBV isolates with mutations in the YMDD motif of the polymerase gene have been detected in patients who have received long-term lamivudine therapy (1,5,8,10,12). Mutants with either the YVDD or the YIDD mutation were detected in 14 to 47% of patients after 1 year of lamivudine therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Mutants with either the YVDD or the YIDD mutation were detected in 14 to 47% of patients after 1 year of lamivudine therapy. Moreover, the mutants with YMDD mutations were detected as early as a few weeks (12 weeks) after the start of lamivudine therapy in Korea (12). Rapid and accurate detection of lamivudine-resistant HBV provides us with important information about therapies (13,17).…”

Section: Discussionmentioning

confidence: 99%

“…However, prolonged lamivudine therapy has been associated with increased rates of emergence of lamivudine-resistant HBV. The cause of lamivudine-resistant HBV was revealed to be the amino acid substitutions from leucine to methionine at codon 180 of the B domain (rtL180M) and amino acid substitutions of the YMDD motif from methionine to valine or leucine at codon 204 of the C domain (rtM204V or rtM204I) of the reverse transcriptase (rt) region of the polymerase gene (1,2,8,9,11,12,18). The detection of lamivudine-resistant HBV is of clinical importance.…”

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confidence: 99%

“…The development of nucleotide analogs which inhibit HBV reverse transcriptase activity, such as lamivudine, famciclovir, and others, has provided an alternative to interferon for therapy for CHB. Lamivudine, (Ϫ)-␤-L-2Ј,3Ј-dideoxy-3Ј-thiacytidine, is a known inhibitor of RNA-dependent DNA polymerase of HBV and human immunodeficiency virus (2,12,18). Lamivudine treatment of patients with CHB has been shown to be effective in suppressing virus replication and to result in reduced inflammatory activity (1,2,8,9,17).…”

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Oligonucleotide Chip for Detection of Lamivudine-Resistant Hepatitis B Virus

Jang¹,

Cho²,

Heo³

et al. 2004

J Clin Microbiol

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Hepatitis B virus (HBV) is one of the major causes of liver disease worldwide. It is important to conduct antiviral therapy against chronic hepatitis B to minimize the amount of liver damage. Lamivudine has been known to be an effective antiviral agent for the treatment of HBV infection. However, the emergence of viral mutants resistant to lamivudine is the main concern during the treatment of HBV-infected patients. Therefore, the detection of lamivudine-resistant mutants is of clinical importance. We have developed an oligonucleotide chip for the detection of lamivudine-resistant HBV which is rapid and accurate. The oligonucleotide chip consists of quality control probes, negative control probes, and specific oligonucleotide probes for the detection of lamivudine-resistant HBV. The specific probes consist of five probes for the detection of wild-type rtL180, rtM204, and rtV207 sequences and seven probes for the detection of HBV mutations. We tested 123 serum samples from patients with chronic HBV infection who had received lamivudine therapy. Eighty samples contained mutants with YMDD mutations. Among these, 17 contained rtM204V (YVDD), 24 contained rtM204I3 (YIDD3), 3 contained rtM204I2 (YIDD2), and 36 contained mixed types. We compared the results obtained with our oligonucleotide chip with those obtained by PCR-restriction fragment length polymorphism (RFLP) analysis and sequencing. The rate of concordance between the assay with the oligonucleotide chip and PCR-RFLP analysis for detection of the YMDD motif was 96.7%. The rate of concordance between the results obtained with the oligonucleotide chip for the detection of rtL180 and rtV207 and the results obtained by sequencing was 100%. Thus, the oligonucleotide chip is a reliable and useful tool for the detection of antiviralresistant HBV.Hepatitis B virus (HBV) is one of the major causes of liver disease worldwide, and chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma. It is important to conduct antiviral therapy against CHB to minimize the amount of liver damage (15). The development of nucleotide analogs which inhibit HBV reverse transcriptase activity, such as lamivudine, famciclovir, and others, has provided an alternative to interferon for therapy for CHB. Lamivudine, (Ϫ)-␤-L-2Ј,3Ј-dideoxy-3Ј-thiacytidine, is a known inhibitor of RNA-dependent DNA polymerase of HBV and human immunodeficiency virus (2, 12, 18). Lamivudine treatment of patients with CHB has been shown to be effective in suppressing virus replication and to result in reduced inflammatory activity (1, 2, 8, 9, 17). However, prolonged lamivudine therapy has been associated with increased rates of emergence of lamivudine-resistant HBV. The cause of lamivudine-resistant HBV was revealed to be the amino acid substitutions from leucine to methionine at codon 180 of the B domain (rtL180M) and amino acid substitutions of the YMDD motif from methionine to valine or leucine at codon 204 of the C domain (rtM204V or rtM204I) of the reverse transcriptase (rt) region of th...

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Patterns of circulating hepatitis B virus serum nucleic acids during lamivudine therapy

Zhang

Hacker

Tokus

et al. 2003

Journal of Medical Virology

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We examined whether lamivudine treatment, in addition to the rapid decline of HBV serum DNA described in a large number of laboratories, causes changes in composition and amount of discernable circulating viral DNA and RNA. Nucleic acids were extracted from serial serum samples of a patient infected chronically and treated with lamivudine for 14 weeks. Three sequence segments of the HBV genome synthesized successively during replication, X, C, and X-preC, were analyzed by competitive PCR and RT/PCR. In addition, RNA was examined for differential polyadenylation. Before treatment, identical DNA copy numbers (10(9)/ml) were found in all three segments. C segment DNA displayed the expected rapid decline. X-preC, a target contiguous only on plus-strand DNA behaved similarly. In contrast, the X segment DNA copy numbers showed a less pronounced decrease remaining at higher values (10(7)/ml) than the C and X-preC segment (both about 2 x 10(5)/ml) at the end of therapy. X segment RNA displayed a persisting copy number of about 10(7)/ml, while C and X-preC RNA decreased to about 10(5) copies/ml. Polyadenylated HBV RNA, full-length and truncated, persisted initially at 10(5) but decreased to 10(4) to 10(3) copies/ml at the end of treatment. The major conclusions are the actual numbers of virus particles during lamivudine therapy can only be assessed via X segment DNA, since it is reverse transcribed first, and Lamivudine induced coexistence of DNA and RNA for the C and X segment at similar levels indicates drug-arrested intermediates of reverse transcribed HBV DNA minus-strand. Packaged RNA lacks a poly(A) tail whereas polyadenylated RNA is likely not packaged.

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Emergence of YMDD motif mutant of hepatitis B virus during short-term lamivudine therapy in South Korea

Cited by 33 publications

References 31 publications

Baseline HBV DNA level is the most important factor associated with virologic breakthrough in chronic hepatitis B treated with lamivudine

Baseline HBV DNA level is the most important factor associated with virologic breakthrough in chronic hepatitis B treated with lamivudine

Oligonucleotide Chip for Detection of Lamivudine-Resistant Hepatitis B Virus

Patterns of circulating hepatitis B virus serum nucleic acids during lamivudine therapy

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