本文選題：乙肝病毒 + 拉米夫定��； 參考：《河北醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的:分析石家莊地區(qū)454例各種經(jīng)核苷(酸)類似物治療的慢性乙型肝炎病例體內(nèi)乙肝病毒耐藥突變的基因位點(diǎn)類型及變異狀況,觀察使用拉米夫定(LAM)及LAM聯(lián)合阿德福韋酯(ADV)進(jìn)行治療的乙肝患者中P區(qū)基因出現(xiàn)突變患者換藥后療效,為提高慢性乙型肝治療效果提供科學(xué)依據(jù)方法:1實(shí)驗(yàn)研究對(duì)象慢性乙型肝炎患者來(lái)源于2011年10月-2016年3月石家莊市第五醫(yī)院就診的患者,診斷標(biāo)準(zhǔn)依據(jù)中華醫(yī)學(xué)會(huì)肝病學(xué)分會(huì)與中華醫(yī)學(xué)會(huì)感染病學(xué)分會(huì)聯(lián)合制定的《慢性乙型肝炎防治指南(2010年版)進(jìn)行,篩選均進(jìn)行核苷類似物的治療患者。2研究對(duì)象分組對(duì)篩選出的研究對(duì)象均進(jìn)行乙肝耐藥基因測(cè)序、ALT、AST、HBV-DNA定量及乙肝五項(xiàng)的檢測(cè)。將其中初始用藥為L(zhǎng)AM治療的慢性乙肝患者101例分為三組:第一組為發(fā)生LAM耐藥后換用LAM聯(lián)合ADV進(jìn)行治療者,共71例;第二組為發(fā)生LAM耐藥后換用恩替卡韋(ETV)聯(lián)合ADV進(jìn)行治療者,共17例;第三組為發(fā)生LAM耐藥后換用ETV進(jìn)行治療者,共13例。另外將初始用藥為L(zhǎng)AM聯(lián)合ADV治療的34例慢性乙肝患者分為兩組:第一組為發(fā)生耐藥后換用ETV進(jìn)行治療者,共19例;第二組發(fā)生耐藥后換用ETV聯(lián)合ADV進(jìn)行治療,共15例。3血液和基因檢測(cè)各組患者均于換藥進(jìn)行治療后的3個(gè)月、6個(gè)月及12個(gè)月進(jìn)行ALT、AST及HBV-DNA定量的檢測(cè)。其中乙肝病毒耐藥基因采用基因測(cè)序技術(shù)進(jìn)行檢測(cè),ALT、AST采用7600型全自動(dòng)生化分析儀進(jìn)行檢測(cè),HBV DNA采用熒光定量PCR技術(shù)檢測(cè),乙肝五項(xiàng)采用ELISA方法進(jìn)行檢測(cè)。4數(shù)據(jù)分析應(yīng)用SPSS21.0軟件進(jìn)行統(tǒng)計(jì)分析。計(jì)量資料進(jìn)行正態(tài)性檢驗(yàn),正態(tài)分布資料的比較采用t檢驗(yàn);非正態(tài)分布資料采用中位數(shù)描述,采用秩和檢驗(yàn)。HBV DNA取對(duì)數(shù)計(jì)算;以P0.05為差異有統(tǒng)計(jì)學(xué)意義。結(jié)果:1 HBV-P區(qū)突變基因位點(diǎn)分型及突變率情況在對(duì)石家莊地區(qū)454例乙肝患者所感染的乙肝病毒的P區(qū)的14個(gè)位點(diǎn)的堿基序列進(jìn)行分析,其中437例檢出有為96.3%。所檢測(cè)的14個(gè)位點(diǎn)突變率分別為M204I/V/S 64.3%(292/454)、L180M 38.8%(176/454)、A181V/T/S 22.7%(103/454)、V173L位點(diǎn)9.9%(45/454),N236T位點(diǎn)9.3%(42/454),V207I/L/G位點(diǎn)8.8%(40/454),S213T位點(diǎn)7.0%(32/454),V214A位點(diǎn)5.3%(24/454),M250V/L位點(diǎn)4.4%(20/454),S202G/I位點(diǎn)4.4%(20/454),N/H238T/D位點(diǎn)4.0%(18/454),T184A/G/I/S位點(diǎn)3.5%(16/454),P237H位點(diǎn)2.6%(12/454),Q215S位點(diǎn)1.5%(7/454)。2 LAM耐藥的乙肝患者不同挽救方案的HBV DNA載量變化情況LAM耐藥的三組乙肝患者換藥后第3個(gè)月、第6個(gè)月、第12個(gè)月的HBV DNA載量分別與換藥前相比,均呈顯著下降,P0.05,差異均具有統(tǒng)計(jì)學(xué)意義。三組ALT值分別與換藥前的ALT值均顯著下降,P0.05,差異均具有統(tǒng)計(jì)學(xué)意義。換用LAM聯(lián)合ADV方案的AST值分別與換藥前相比均呈顯著下降,P0.05,差異均具有統(tǒng)計(jì)學(xué)意義,換用ETV及ETV聯(lián)合ADV方案的AST值與換藥前相比差異不顯著,P0.05,無(wú)統(tǒng)計(jì)學(xué)意義。3 LAM聯(lián)合ADV耐藥的乙肝患者不同挽救方案臨床療效結(jié)果LAM聯(lián)合ADV耐藥的兩組乙肝患者換藥后第3個(gè)月、第6個(gè)月、第12個(gè)月的HBV DNA載量分別與換藥前相比,均呈顯著下降,P0.05,差異均具有統(tǒng)計(jì)學(xué)意義。換用ETV方案的ALT、AST分別與換藥前相比呈下降趨勢(shì),但是與換藥前相比差異不顯著,P0.05,差異無(wú)統(tǒng)計(jì)學(xué)意義;換用ETV聯(lián)合ADV方案ALT、AST值與換藥前相比顯著下降,P0.05,差異有統(tǒng)計(jì)學(xué)意義。結(jié)論:1石家莊地區(qū)病例HBV P區(qū)主要的突變位點(diǎn)中M204I/V/S、L180M和A181V/T/S的突變檢出率最高,分別為64.3%、38.8%和22.7%。耐藥突變主要對(duì)應(yīng)LAM和ADV耐藥。2初始使用LAM治療的乙肝患者出現(xiàn)耐藥后,換用LAM聯(lián)合ADV方案治療優(yōu)于換用ETV和ETV分別聯(lián)合ADV方案,具有能有效抑制病毒復(fù)制,促使肝功能復(fù)常,節(jié)約成本等優(yōu)點(diǎn)。3初始使用LAM聯(lián)合ADV治療的乙肝患者出現(xiàn)耐藥后,換用ETV聯(lián)合ADV治療方案進(jìn)行治療,綜合療效明顯優(yōu)于ETV單藥治療。
[Abstract]:Objective: to analyze 454 cases of Shijiazhuang area after nucleoside (acid) gene locus mutation type and mutation status of analogues in the treatment of chronic hepatitis B patients in hepatitis B virus resistance, observation of lamivudine (LAM) and LAM combined with adefovir dipivoxil (ADV) gene P of hepatitis B patients in the treatment of patients with mutated dressing, to provide a scientific basis for the method to improve the effect of treatment of chronic hepatitis B liver: 1 Experimental Study of patients with chronic hepatitis B from October 2011 -2016 March in Shijiazhuang fifth hospital patients, diagnostic criteria of the Chinese Medical Association of Hepatology and Chinese Medical Association branch jointly developed the disease prevention and treatment of chronic hepatitis B infection "Guide (2010 Edition) by screening were nucleoside analogue therapy in patients with.2 group of study objects on the object of study were screened for hepatitis B drug resistance gene sequencing ALT, AST, HBV-DNA, and quantitative detection of hepatitis B five. The initial medication for the LAM treatment for chronic hepatitis B patients, 101 cases were divided into three groups: the first group occurred after LAM resistance for treatment with LAM combined with ADV, a total of 71 cases; second groups occurred after LAM resistance change with entecavir (ETV) combined with ADV treatment, a total of 17 cases; third groups occurred after LAM resistance for treatment with ETV, a total of 13 cases. In addition to the initial medication for 34 cases of chronic hepatitis B patients with LAM combined with ADV treatment were divided into two groups: the first group after treatment for drug resistance by ETV. A total of 19 cases; second groups were treated with the change of resistance after ETV combined with ADV, a total of 15 cases of detection of.3 gene and blood patients 3 months after treatment were dressing, ALT 6 and 12 months, the detection of AST and HBV-DNA. The quantitative hepatitis B virus resistance gene by gene sequencing technology detection of ALT AST, with 7600 automatic biochemical analyzer to detect HBV and DNA by fluorescence quantitative PCR detection of hepatitis B five was detected by ELISA method using SPSS21.0.4 data analysis software for statistical analysis. The measurement data was tested for normality, normal distribution data compared with t test; non normal distribution data using the median description using the Wilcoxon rank sum test and.HBV DNA logarithmic calculation based on P0.05; the difference was statistically significant. Results: the nucleotide sequence of 14 loci of 1 HBV-P gene mutation type and mutation rate in the infection of 454 cases of hepatitis B patients with hepatitis B virus P in Shijiazhuang area were analyzed, including 437 cases the detection for 96.3%. detection of 14 mutation rates were 64.3% M204I/V/S (292/454), L180M 38.8% (176/454), A181V/T/S 22.7% (103/454), V173L (45/454), N236T site 9.9% site 9.3% (42/454), V20 7I/L/G site 8.8% (40/454), S213T (32/454), V214A site 7% site 5.3% (24/454), M250V/L (20/454), S202G/I site 4.4% site 4.4% (20/454), N/H238T/D (18/454), T184A/G/I/S site 4% site 3.5% (16/454), P237H (12/454), Q215S site 2.6% site 1.5% (7/454) three groups hepatitis B patients. Hepatitis B patients with.2 resistant LAM HBV DNA different salvage regimens load changes LAM resistance after third months, sixth months, twelfth months HBV DNA load were compared with before dressing, decreased significantly, P0.05, the difference was statistically significant. The three groups respectively with ALT value before dressing ALT values were significantly decreased, P0.05, the difference was statistically significant. Change were decreased significantly, compared with before dressing P0.05 LAM combined with the ADV value of the AST program, the differences were statistically significant, for the ETV and ETV combined with ADV for AST compared with no significant difference before dressing, P0.05, the two groups of patients with hepatitis B was different in patients with hepatitis B was not statistically significant.3 LAM combined with ADV resistant clinical results LAM salvage regimens combined with ADV resistance after third months, sixth months, twelfth months HBV DNA load were compared with before dressing, P0.05 decreased significantly, and the differences were statistically significant for the ETV scheme. ALT, AST respectively and compared before dressing decreased, but the difference was not significant compared with before dressing, P0.05, the difference was not statistically significant; for the ETV combined with ADV for ALT, AST compared with before dressing decreased significantly, P0.05, the difference was statistically significant. Conclusion: 1 cases in Shijiazhuang area HBV P the main mutation sites of M204I/V/S, L180M and A181V/T/S mutation detection rate were 64.3%, 38.8% and 22.7%. mutations mainly correspond to LAM and ADV resistant.2 initial treatment with LAM in patients with hepatitis B is resistant, replaced by LA M combined with ADV regimen in the treatment is better than for the ETV and ETV respectively combined with ADV scheme, which can effectively inhibit virus replication, promote liver function recovery in patients with hepatitis B, saved and cost advantages of.3 initial use of LAM combined with ADV in the treatment of the emergence of drug resistance after treatment with ETV combined with ADV for treatment, the comprehensive curative effect is obviously superior to ETV monotherapy the treatment.

【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R512.62

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