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RISS 인기검색어
- 검색키워드
- 저자 : ( Kathryn M Kitrinos ) (검색결과 2 건)
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( Yang Liu ),( Michael D Miller ),( Kathryn M Kitrinos ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1
Background/Aim: Hepatitis B virus (HBV) genotypes can influence clinical outcomes as well as antiviral therapy responses. The adefovir resistance-associated mutations (ADV-R) rtN236T and/or rtA181V demonstrate reduced tenofovir (TFV) susceptibility in vitro. However, several clinical studies suggest patients with ADV-R respond well to tenofovir treatment. This study evaluated the TFV susceptibility of HBV genotype B, C, and D clinical isolates with ADV-R. Methods: Full length HBV genomes were amplified from patients with genotypes B, C, and D. Each isolate had rtA181T, rtA181V, rtN236T and rtA181V+rtN236T mutations introduced by site-directed mutagenesis. All isolates (including a wild-type control) were transfected into HepG2 cells. TFV and ADV susceptibility were assessed using quantitative PCR of intracellular HBV DNA. Results: Clinical HBV isolates containing rtA181T, rtA181V, or rtN236T as single mutants remained sensitive to TFV across genotypes B, C, and D. Viruses containing the double mutant rtA181V+rtN236T in genotype B and D exhibited reduced susceptibility to TFV with EC50 fold changes (FC) of 3.8 and 2.5, respectively, while genotype C viruses containing rtA181V + rtN236T either remained sensitive (FC=1.3) or exhibited re duced susceptibility to TFV (FC=2.9). All rtA181V+rtN236T isolates conferred reduced susceptibility to ADV (FC values 2.3-4.2). Conclusions: Genotype B, C, and D clinical isolates with single ADV resistance mutations remained fully sensitive to TFV, while the double mutant rtA181V+rtN236T exhibited either no change or low-level reduced susceptibility to TFV across genotypes. These results are consistent with the clinical efficacy observed with tenofovir disoproxil fumarate (TDF) treatment across all genotypes in vivo and the limited impact of ADV-R mutations on TDF therapy.
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( Edward Gane ),( Amoreena C Corsa ),( Yang Liu ),( Ben C Mitchell2 ),( John F Flaherty ),( Michael D Miller ),( Kathryn M Kitrinos ),( Scott Fung ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1
Background/Aim: To evaluate amino acid changes within HBV pol/RT after 96 weeks of treatment with TDF or FTC/ TDF and determine their potential association with TDF resistance. Methods: In Study GS-US-174-0121, 280 patients receiving lamivudine (LAM) with detectable LAM-resistance mutations in HBV pol/RT (LAM-R: rtM204V/I±rtL180M) were randomized 1:1 to receive blinded treatment with TDF or FTC/TDF for 96 weeks. Virologic breakthrough (VB) was defined as confirmed HBV DNA >1 log10 increase from nadir or HBV DNA ≥400 copies/mL (69 IU/mL) after <400 copies/mL. Resistance genotyping by HBV pol/RT sequencing was attempted for all patients at baseline and if viremic (HBV DNA ≥400 copies/ mL) at Week 96/study discontinuation. Results: Overall, 18 patients (9 TDF, 9 FTC/TDF) were viremic viremic at Week 96/last visit. The mean baseline HBV DNA was significantly higher for viremic patients (8.04 log10 copies/mL) compared to patients who did not qualify for genotyping (6.39 log10 copies/mL). In the TDF arm, 3 patients had conserved site changes/reversions (1 with VB), 1 had unique polymorphic site changes, 2 had no change, and 3 were unable to be genotyped. In the FTC/TDF arm, 2 patients had conserved site changes/reversions, 1 had unique polymorphic site changes, 4 had no change, and 2 were unable to be genotyped. No phenotypic resistance to TDF was observed. Four of eight (50%) patients had LAM-R reversions (rtV/I204M±rtM180L) on TDF while 1/8 (12.5%) patients on FTC/TDF had LAM-R reversions. Thirteen patients (4.6%) with prior entecavir (ETV) exposure and 25 patients (8.9%) with baseline ETV-R were enrolled; neither had an impact on viral kinetics. Conclusions: No TDF resistance has been detected through 96 weeks of treatment with either TDF or FTC/TDF in LAM-R patients. The presence of ETV-R or ETV exposure did not impact viral kinetics through 96 weeks. Resistance surveillance in this population will continue through Year 5.
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