Comparison of Multiplex Restriction Fragment Mass Polymorphism and Sequencing Analyses for Detecting Entecavir Resistance in Chronic Hepatitis B

Han, Kyung Ho; Hong, Sun; Choi, Seo Hee; Shin, Seong Kee; Cho, Sung Won; Ahn, Sang Hoon; Hahn, Ji Sook; Kim, Soo Ok

doi:10.3851/imp1702

Cited by 37 publications

(48 citation statements)

References 30 publications

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“…HBV DNA level was measured at baseline and at weeks 12, 24, 36, and 52, using a real-time PCR assay (Abbott Laboratories, Chicago, IL) with a linear dynamic detection range of 15 to 1 ϫ 10 9 IU/ml. Restriction fragment mass polymorphism (RFMP) assays of the HBV genome were performed to detect ADV resistance mutations at baseline and at week 52 and ETV resistance mutations at week 52, as described previously (12). Because over 98% of South Korean patients with CHB have HBV genotype C (1), HBV genotype was not determined.…”

Section: Methodsmentioning

confidence: 99%

Randomized Trial of Entecavir plus Adefovir in Patients with Lamivudine-Resistant Chronic Hepatitis B Who Show Suboptimal Response to Lamivudine plus Adefovir

Lim

Lee

et al. 2012

Antimicrob Agents Chemother

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A substantial proportion of patients with lamivudine-resistant hepatitis B virus (HBV) show suboptimal virologic response during rescue combination treatment with lamivudine plus adefovir. In this randomized active-control trial, 90 patients with serum HBV DNA levels of >2,000 IU/ml after at least 24 weeks of treatment with lamivudine-plus-adefovir therapy for lamivudineresistant HBV were randomized to combination treatment with entecavir plus adefovir (ETV؉ADV, n ‫؍‬ 45) or continuation of lamivudine plus adefovir (LAM؉ADV, n ‫؍‬ 45) for 52 weeks. At baseline, patients' mean serum HBV DNA level was 4.60 log 10 IU/ml (standard deviation [SD], 1.03). All 90 patients completed 52 weeks of treatment. At week 52, the proportion of patients with serum HBV DNA levels of <60 IU/ml, the primary endpoint, was significantly higher in the ETV؉ADV group than in the LAM؉ADV group (n ‫؍‬ 13, 29%, versus n ‫؍‬ 2, 4%, respectively; P ‫؍‬ 0.004). The mean reduction in serum HBV DNA levels from baseline was significantly greater in the ETV؉ADV group than in the LAM؉ADV group (؊2.2 log 10 IU/ml versus ؊0.6 log 10 IU/ml, respectively; P < 0.001). At week 52, additional mutations causing resistance to adefovir or entecavir were analyzed in all patients with detectable HBV DNA by restriction fragment mass polymorphism assays and detected in none of the ETV؉ADV group but in 15% of patients in the LAM؉ADV group (P ‫؍‬ 0.018). Safety and adverse event profiles were similar in the two groups. In conclusion, entecavir-plus-adefovir combination therapy provides superior virologic response and favorable resistance profiles, compared with the continuing lamivudine-plus-adefovir combination, in patients with lamivudine-resistant HBV who fail to respond to lamivudine-plus-adefovir combination therapy.

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Section: Methodsmentioning

confidence: 99%

Randomized Trial of Entecavir plus Adefovir in Patients with Lamivudine-Resistant Chronic Hepatitis B Who Show Suboptimal Response to Lamivudine plus Adefovir

Lim

Lee

et al. 2012

Antimicrob Agents Chemother

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“…The HBV DNA level was measured at baseline and at each study visit using a real-time PCR assay (Abbott Laboratories, Chicago, IL) with a linear dynamic detection range of 15 to 1 ϫ 10 9 IU/ml. The HBV genome was assayed for ADV and ETV resistance mutations by restriction fragment mass polymorphism (RFMP) analysis at baseline and at weeks 52 and 104, as described previously (21,22). HBeAg and anti-HBe were assessed at baseline and at weeks 52 and 104, using a commercially available enzyme immunoassay (Abbott Laboratories).…”

Section: Methodsmentioning

confidence: 99%

Randomized Trial of the Virologic Response during up to Two Years of Entecavir-Adefovir Combination Therapy in Multiple-Drug-Refractory Chronic Hepatitis B Virus Patients

Lim

Lee

et al. 2013

Antimicrob Agents Chemother

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A 1-year trial with entecavir plus adefovir resulted in a rate of virological response (VR) higher than that seen with lamivudine plus adefovir in multiple-drug-refractory chronic hepatitis B (CHB) patients. This extension study enrolled 89 of 90 patients who completed a 52-week randomized trial comparing treatment with entecavir plus adefovir (EA) to treatment with lamivudine plus adefovir (LA). At the baseline of the original study, all patients had lamivudine-resistant hepatitis B virus (HBV) and serum HBV DNA > 2,000 IU/ml despite prior lamivudine plus adefovir therapy. Of the 89 enrolled patients, 45 initially randomized to receive entecavir plus adefovir and the other 44 randomized to receive lamivudine plus adefovir received entecavir plus adefovir for an additional 52 weeks (EA-EA and LA-EA, respectively). The proportions of patients with a VR (serum HBV DNA < 60 IU/ ml) gradually increased in both groups and were comparable at week 104 (42.2% in the EA-EA group and 34.1% in the LA-EA group; P ‫؍‬ 0.51). The mean reductions in serum HBV DNA from baseline in the two groups were similar (؊2.8 log 10 IU/ml and ؊2.8 log 10 IU/ml, respectively; P ‫؍‬ 0.87). At week 104, the number of patients who retained the preexisting HBV mutants resistant to adefovir or entecavir had decreased from 8 to 2 in the EA-EA group and from 15 to 6 in the LA-EA group (P ‫؍‬ 0.27). Both study groups had favorable safety profiles. In conclusion, up to 104 weeks of entecavir plus adefovir treatment was associated with a progressive VR, a decrease of levels of preexisting drug-resistant mutants, and no selection for additional resistance mutants of HBV in multiple-drug-refractory CHB patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01023217.) A pproximately 400 million people worldwide are chronically infected with hepatitis B virus (HBV) (1, 2). The goal of HBV treatment is to prevent the development of cirrhosis, liver failure, and hepatocellular carcinoma (HCC). A high serum HBV DNA level in patients with chronic hepatitis B (CHB) is an independent risk factor for disease progression to cirrhosis and HCC (3, 4). Reducing HBV DNA to very low or undetectable levels with nucleos(t)ide analogue (NUC) therapy is associated with reduced risks of disease progression (5-8).With the availability of potent NUCs, such as entecavir (ETV) and tenofovir disoproxil fumarate (TDF), suppression of serum HBV DNA to levels undetectable by PCR assays is achievable in most NUC treatment-naive patients without selecting for drugresistant HBV mutants (9, 10). Until recently, however, many patients worldwide began antiviral treatment with the less potent NUCs, such as lamivudine (LAM) or adefovir (ADV), which also have a low genetic barrier to resistance.Add-on combination therapy with LAM and ADV has been the most common rescue therapy in patients with LAM-resistant HBV. However, in such patients, the continued use of LAM does not provide additional antiviral suppression (11). Consequently, a substantial proporti...

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“…Although emergence of drug-resistant strains is closely related to the duration of the antiviral treatment, such variants have also been shown to exist in treatment-naive CHB patients. Therefore, faithful analysis of all mutations associated with antiviral resistance is essential for optimal management of CHB (37). Currently, the identification of resistant HBV strains in hepatitis B patients is usually performed by direct sequencing and reverse hybridization (INNOLiPA) (9).…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry as an Alternative Approach to Monitoring Drug Resistance of Hepatitis B Virus

et al. 2014

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Comparison of Multiplex Restriction Fragment Mass Polymorphism and Sequencing Analyses for Detecting Entecavir Resistance in Chronic Hepatitis B

Abstract: The multiplex RFMP assay is an accurate and sensitive means to detect entecavir and lamivudine resistance mutations, simultaneously. The method is expected to enable early and efficient diagnosis of multiple drug resistance mutations for optimal management of CHB.

Cited by 37 publications

References 30 publications

Randomized Trial of Entecavir plus Adefovir in Patients with Lamivudine-Resistant Chronic Hepatitis B Who Show Suboptimal Response to Lamivudine plus Adefovir

Randomized Trial of Entecavir plus Adefovir in Patients with Lamivudine-Resistant Chronic Hepatitis B Who Show Suboptimal Response to Lamivudine plus Adefovir

Randomized Trial of the Virologic Response during up to Two Years of Entecavir-Adefovir Combination Therapy in Multiple-Drug-Refractory Chronic Hepatitis B Virus Patients

High-Throughput Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry as an Alternative Approach to Monitoring Drug Resistance of Hepatitis B Virus

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