YSDD: a novel mutation in HBV DNA polymerase confers clinical resistance to lamivudine

Bozdayı, A. Mithat; Uzunalımoǧlu, Özden; Turkyilmaz, A.R.; Aslan, Nuray; Sezgın, Orhan; Şahin, Tülin; Bozdayı, Gülendam; Çınar, Kubilay; Pai, S. Balakrishna; Pai, Rekha B.; Bozkaya, Hakan; Karayalçın, Selim; Yurdaydın, Cihan; Schinazi, Raymond F.

doi:10.1046/j.1365-2893.2003.00435.x

Cited by 53 publications

(53 citation statements)

References 37 publications

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“…Recently, lamivudine was approved for the treatment of chronic HBV infection in many regions of the world. Although convenient and well-tolerated, lamivudine's efficacy rate was similar to interferon and prolonged administration of lamivudine was associated with development of resistance [24][25][26][27][28][29][30] . New agents, such as adefovir dipivoxil, offered a promise either alone or in combination with lamivudine in the treatment of individuals who were 'treatment naïve' have developed lamivudine resistance [31][32][33] .…”

Section: Discussionmentioning

confidence: 99%

Oxymatrine therapy for chronic hepatitis B: A randomized double-blind and placebo-controlled multi-center trial

Lu¹,

Zeng²,

Mao³

et al. 2003

WJG

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AIM:To evaluate the efficacy and safety of capsule oxymatrine in the treatment of chronic hepatitis B. METHODS:A randomised double-blind and placebocontrolled multicenter trial was conducted. Injection of oxymatrine was used as positive-control drug. A total of 216 patients with chronic hepatitis B entered the study for 24 weeks, of them 108 received capsule oxymatrine, 36 received injection of oxymatrine, and 72 received placebo. After and before the treatment, clinical symptoms, liver function, serum hepatitis B virus markers, and adverse drug reaction were observed. RESULTS:Among the 216 patients, six were dropped off, and 11 inconsistent with the standard were excluded. Therefore, the efficacy and safety of oxymatrine in patients were analysed. In the capsule treated patients, 76.47 % became normal in ALT level, 38.61 % and 31.91 % became negative both in HBV DNA and in HBeAg. In the injection treated patients, 83.33 % became normal in ALT level, 43.33 % and 39.29 % became negative both in HBV DNA and in HBeAg. In the placebo treated patients, 40.00 % became normal in ALT level, 7.46 % and 6.45 % became negative both in HBV DNA and in HBeAg. The rates of complete response and partial response were 24.51 % and 57.84 % in the capsule treated patients, and 33.33 % and 50.00 % in the injection treated patients, and 2.99 % and 41.79 % in the placebo treated patients, respectively. There was no significance between the two groups of patients, but both were significantly higher than the placebo. The adverse drug reaction rates of the capsule, injection and placebo were 7.77 %, 6.67 % and 8.82 %, respectively. There was no statistically significant difference among them. CONCLUSION:Oxymatrine is an effective and safe agent for the treatment of chronic hepatitis B.

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Section: Discussionmentioning

confidence: 99%

Oxymatrine therapy for chronic hepatitis B: A randomized double-blind and placebo-controlled multi-center trial

Lu¹,

Zeng²,

Mao³

et al. 2003

WJG

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“…Purified viral DNA was analyzed by real-time PCR using HBV-specific primers and Taqman probe using an Applied Biosystems 7900 sequence detection system (7). An aliquot of the cells was also processed for ␤-galactosidase activity.…”

Section: Patient Historymentioning

confidence: 99%

“…Recently, mutations other than rtM204I/V have been reported for HBV (7,19,20,23). These changes, albeit observed at a lesser frequency, underscore the multiple strategies employed by the virus to circumvent inhibition of the viral replication machinery.…”

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confidence: 99%

Emergence of a Novel Mutation in the FLLA Region of Hepatitis B Virus during Lamivudine Therapy

Pai

Bozdayı

Pai

et al. 2005

Antimicrob Agents Chemother

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The emergence of resistance to lamivudine has been one of the major stumbling blocks to successful treatment and control of hepatitis B virus (HBV) infections. The major mechanism of resistance has been attributed to the alteration in the YMDD motif of the HBV polymerase due to an amino acid change of rtM204 to V/I and an accompanying rtL180M conversion. A novel mutation pattern in a patient having clinical breakthrough under lamivudine therapy was discovered. The mutant had a rtL180C/M204I genotype and was detected after 2 years of therapy with lamivudine. To characterize this novel variant, site-directed mutagenesis was performed using a vector construct containing the HBV genome. Transient transfection studies in human hepatoma cells with HBV carrying the new mutant demonstrated that the rtL180C/M204I mutant was resistant to lamivudine up to 10 M. The resistance profile was comparable to that of the previously reported rtL180 M/M204I-containing virus. These observations were further confirmed by generation of stable cultures transfected with the mutant virus.Hepatitis B virus (HBV) is a pathogen that afflicts over 350 million people with liver disease worldwide (27). The persistence of the infection can have devastating consequences for the infected person, as the natural progression of the disease culminates with cirrhosis of the liver and hepatocellular carcinoma. Until recently, only two treatment options, alpha interferon and lamivudine, were available for the management of HBV. Recently, adefovir dipivoxil and entecavir were approved by the U.S. Food and Drug Administration for treatment of HBV (23,24).While the therapeutic utility of lamivudine is clearly documented in the literature (4,5,12,16,17), the emergence of resistance to lamivudine has been the major hurdle to viral clearance since long-term lamivudine monotherapy results in clinical resistance to the drug (18). The mutations responsible for the clinical nonresponse have been characterized (1,3,4,18) and can persist resulting in a major hurdle to viral clearance. While a number of mutations have been reported, the cardinal change that confers resistance has been the conversion of the methionine residue in the YMDD motif to valine or isoleucine (rtM204V/I) followed by the rtL180 M change (for review of mutations see references 19 and 23).There are some similarities in the resistance pattern to lamivudine between human immunodeficiency virus (HIV) and HBV (10). For example, a number of HIV cases show initial replacement of methionine with valine or isoleucine at residue 184 of the polymerase (6, 25), which corresponds to the rtM204V/I in HBV polymerase (26).Recently, mutations other than rtM204I/V have been reported for HBV (7,19,20,23). These changes, albeit observed at a lesser frequency, underscore the multiple strategies employed by the virus to circumvent inhibition of the viral replication machinery. The present studies are a continuation of our efforts to identify mechanisms underlying clinical resistance to lamivudine. A novel genotype wi...

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“…The principal mutations associated with lamivudine resistance are located in domain C of the YMDD motif. They include rtM204V (YVDD sequence), rtM204I (YIDD) (1), and the more recently identified rtM204S (YSDD) (2,27). Lamivudine-resistant mutants with amino acid substitutions in the YMDD motif appear to replicate less efficiently than the wild-type virus in vitro.…”

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confidence: 99%

Dynamics of Hepatitis B Virus Resistance to Lamivudine

Pallier

Castéra

Soulier

et al. 2006

J Virol

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Lamivudine was the first approved inhibitor of hepatitis B virus (HBV) reverse transcriptase (RT). Lamivudine resistance develops in 53% to 76% of patients after 3 years of treatment. We extensively characterized the dynamics of HBV quasispecies variant populations in four HBV-infected patients who developed lamivudine resistance. Virological breakthrough was preceded by 2 to 4 months by the emergence of quasispecies variants bearing amino acid substitutions at RT position 204, i.e., within the YMDD catalytic motif (rtM204V/ I). Three patients had a gradual switch from a YMDD variant population at baseline to a 100% lamivudineresistant variant population, whereas the remaining patient had a fluctuating pattern of resistance variant dynamics. Careful analysis of amino acid substitutions located outside domain C of HBV RT, including those known to partially restore replication capacities in vitro, showed that the in vivo replication of HBV variants is driven by multiple forces, including intrinsic replicative advantages conferred by mutations accumulating outside domain C and the changing environment in which these variants replicate. Our findings also suggest that individual treatment optimization will require sensitive methods capable of detecting the emergence of viral resistance before the relevant variants acquire optimal replicative capacities. Hepatitis B virus (HBV) infection is a major public health problem, with approximately 350 million individuals chronically infected worldwide (19). Chronic HBV carriers are exposed to a risk of complications, such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma, of which HBV is currently the most frequent cause (13). Up to one million people die every year from complications of HBV infection (19).HBV infection is characterized by high levels of virus production and turnover (28, 39), whereas the HBV reverse transcriptase (RT), like the human immunodeficiency virus (HIV) RT, is an error-prone enzyme lacking 3Ј-5Ј-exonuclease proofreading capacity (3,14). As a result, HBV, like other viruses with error-prone polymerases, such as HIV, hepatitis C virus, and poliovirus, has a quasispecies distribution in infected individuals (14). This means that HBV circulates as a complex mixture of genetically distinct but closely related variants that are in equilibrium at a given time point of infection in a given replicative environment. The quasispecies distribution of HBV implies that any newly generated mutation conferring a selective advantage to the virus in a given replicative environment will allow the corresponding viral population to overtake the other variants, following a classical Darwinian evolutionary process (10).Treatment of chronic hepatitis B is aimed at driving viral replication to the lowest possible level, and thereby to halt the progression of liver disease and prevent the onset of complications. However, HBV infection cannot be fully eradicated, because of covalently closed circular proviral DNA persistence in host cells. The first HBV RT inhibit...

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YSDD: a novel mutation in HBV DNA polymerase confers clinical resistance to lamivudine

Cited by 53 publications

References 37 publications

Oxymatrine therapy for chronic hepatitis B: A randomized double-blind and placebo-controlled multi-center trial

Oxymatrine therapy for chronic hepatitis B: A randomized double-blind and placebo-controlled multi-center trial

Emergence of a Novel Mutation in the FLLA Region of Hepatitis B Virus during Lamivudine Therapy

Dynamics of Hepatitis B Virus Resistance to Lamivudine

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