本文選題：HBeAg陰性慢性乙型肝炎　切入點(diǎn)：丙氨酸氨基轉(zhuǎn)移酶　出處：《蘭州大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：背景:乙型肝炎病毒(Hepatitis B Virus,HBV)是導(dǎo)致肝硬化(Liver Cirrhosis,LC)和肝癌(Hepatocellular Carcinoma,HCC)的最主要因素,慢性乙型肝炎(Chronic Hepatitis B,CHB)仍然帶來了重大的健康和經(jīng)濟(jì)負(fù)擔(dān),特別是在亞太地區(qū)國家。越來越多的臨床與基礎(chǔ)研究表明,HBe Ag(Hepatitis B e Antigen)陰性CHB在HBV感染的慢性病毒性肝炎患者中所占的比例逐年升高。目前臨床上主要依據(jù)丙氨酸氨基轉(zhuǎn)移酶(Alanine Aminotransferase,ALT)高于2倍正常值上限(Upper Limit of Normal Value,ULN)啟動抗病毒治療,而越來越多的資料表明,ALT正�；蜉p度升高的HBe Ag陰性患者肝組織存在中重度炎癥或纖維化病變者不在少數(shù)。聚乙二醇干擾素α是一類兼有免疫調(diào)節(jié)與抗病毒效應(yīng)的抗病毒藥物,現(xiàn)有的研究資料均提示聚乙二醇干擾素α對HBe Ag陽性或HBe Ag陰性CHB患者均有較強(qiáng)的抗病毒效應(yīng),但很少有研究針對ALT正�；蜉p度異常且病理證實(shí)存在中重度病變的HBe Ag陰性CHB患者進(jìn)行聚乙二醇干擾素α的治療及隨訪觀察,評估其對這部分患者的療效及療效預(yù)測問題。目的:分析聚乙二醇干擾素α對ALT正�；蜉p度升高且METAVIR評分≥G2S2的HBe Ag陰性CHB患者的療效及療效預(yù)測因素。方法:對ALT正�；蜉p度升高且METAVIR評分≥G2S2的HBe Ag陰性CHB患者進(jìn)行連續(xù)48周的聚乙二醇干擾素α治療,收集治療前、治療12周、24周、36周、48周相關(guān)的生化學(xué)、病毒學(xué)、血清學(xué)、肝臟硬度值(Liver Stiffness Measurement,LSM)等資料進(jìn)行回顧性分析。結(jié)果:(1)根據(jù)納入排除標(biāo)準(zhǔn),共有42例ALT正常或輕度升高HBe Ag陰性CHB患者進(jìn)入本次研究,平均年齡為37.62±10.12歲,男性24例,女性18例,14例患者治療前血清HBV DNA低于檢測下限肝組織HBV DNA存在復(fù)制,28例患者治療前血清中HBV DNA存在復(fù)制。(2)治療過程中,ALT水平呈波動性升高,至48周時上升至最高水平,與基線ALT水平相比,差異具有統(tǒng)計學(xué)意義(P0.05);血清HBV DNA水平逐漸下降,基線血清HBV DNA水平與各隨訪點(diǎn)血清HBV DNA水平相比,差異具有統(tǒng)計學(xué)意義(P0.05);HBs Ag(Hepatitis B s Antigen)滴度逐漸下降,基線HBs Ag滴度與各隨訪點(diǎn)HBs Ag滴度及各隨訪點(diǎn)之間差異均具有統(tǒng)計學(xué)意義(P0.05);LSM波動性下降,基線LSM與12周、36周LSM差異具有統(tǒng)計學(xué)意義。(3)14例治療前血清HBV NDA低于檢測下限的患者,治療48周結(jié)束時,HBs Ag水平由基線時的(2.74±1.03)log10IU/m L下降至(1.79±1.69)log10IU/m L,有4例患者HBs Ag滴度達(dá)到100IU/ml,占28.57%(4/14),其中1例患者發(fā)生了HBs Ag的清除,完全應(yīng)答(Complete Response,CR)率為7.14%(1/14)。(4)14例治療前血清HBV DNA低于檢測下限的患者,治療過程中,血清ALT水平至12周、24周稍有下降,后逐漸升高,下降及升高水平無統(tǒng)計學(xué)意義(P0.05);血清HBs Ag滴度逐漸下降,24周后下降水平具有統(tǒng)計學(xué)意義(P0.05);LSM波動性升高,升高水平無統(tǒng)計學(xué)意義(P0.05)。(5)28例治療前血清中HBV DNA復(fù)制的患者,治療48周結(jié)束時,22例患者血清HBV DNA低于檢測下限,病毒學(xué)應(yīng)答(Virological Response,VR)率為78.60%(22/28),原發(fā)無應(yīng)答與部分應(yīng)答率為17.90%(5/28);6例患者HBs Ag滴度達(dá)到100IU/ml,占21.43%(6/28),其中1例患者發(fā)生了HBs Ag的清除,完全應(yīng)答率為3.57%(1/28)。(6)28例治療前血清HBV DNA復(fù)制的患者,治療過程中,病毒學(xué)應(yīng)答組ALT水平在12周升高,后逐漸下降,升高及下降水平無統(tǒng)計學(xué)意義(P0.05);血清HBV DNA水平逐漸下降,基線與12周、24周、36周、48周之間差異具有統(tǒng)計學(xué)意義(P0.05);HBs Ag滴度逐漸下降,基線與36周、基線與48周、12周與48周、24周與36周、24周與48周、36周與48周之間差異具有統(tǒng)計學(xué)意義(P0.05);LSM波動性下降,基線與12周、24周、36周之間差異具有統(tǒng)計學(xué)意義(P0.05)。病毒學(xué)應(yīng)答組與無應(yīng)答組在年齡、性別分布、家族史有無、白細(xì)胞計數(shù)、血小板計數(shù)、基線ALT水平、基線HBV DNA水平、基線HBs Ag滴度、基線LSM及治療各隨訪點(diǎn)ALT水平、HBV DNA水平、HBs Ag滴度、LSM均無統(tǒng)計學(xué)差異(P0.05)。(7)多因素二分類logistics回歸分析顯示沒有能預(yù)測治療48周時病毒學(xué)應(yīng)答的因素(P0.05)。結(jié)論:(1)聚乙二醇干擾素α對ALT正常或輕度升高M(jìn)ETAVIR評分≥G2S2的HBe Ag陰性CHB患者治療48周結(jié)束時具有較高的抗病毒效應(yīng),病毒學(xué)應(yīng)答率為78.60%,與ALT≥2ULN的HBe Ag陰性CHB患者療效相似;(2)聚乙二醇干擾素α對ALT正�；蜉p度升高M(jìn)ETAVIR評分≥G2S2且基線HBV DNA陰性的HBe Ag陰性CHB患者可以顯著降低HBs Ag滴度,尤其是在治療24周以后。
[Abstract]:Background: hepatitis B virus (Hepatitis B Virus HBV (Liver Cirrhosis) is leading to cirrhosis, and hepatocellular carcinoma (LC) Hepatocellular Carcinoma, HCC) the most important factor in chronic hepatitis B (Chronic, Hepatitis, B, CHB) still pose a major health and economic burden, especially in countries in the Asia Pacific Region. The basic and clinical more and more studies show that HBe Ag (Hepatitis B e Antigen) CHB negative for HBV infection in patients with chronic viral hepatitis in the proportion increased year by year. At present the main clinical basis of alanine aminotransferase (Alanine, Aminotransferase, ALT) 2 times higher than the upper limit of normal (Upper Limit of Normal Value, ULN) to start antiviral therapy, and more and more data show that the presence of moderate to severe inflammation or fibrosis ALT normal or mildly elevated HBe Ag negative patients with liver tissue were few. Interferon alpha is a Both types of immune regulation of antiviral drugs and antiviral effect, the available data suggest that pegylated interferon alpha on HBe Ag or HBe CHB positive Ag negative patients had strong antiviral effects, but few studies have focused on the treatment and follow-up of ALT normal or mildly abnormal and pathological lesions confirmed the presence of severe HBe Ag negative CHB patients pegylated interferon alpha, the assessment for these patients to predict efficacy and problems. Objective: to analyze the pegylated interferon alpha on ALT normal or slightly elevated and predict the effect of METAVIR score was G2S2 HBe Ag negative CHB patients and effect factors. Methods: ALT normal or slightly elevated and METAVIR score was G2S2 HBe Ag negative CHB patients were 48 consecutive weeks of therapy with pegylated interferon alpha, collected before treatment, treatment for 12 weeks, 24 weeks, 36 weeks, 48 weeks of related biochemistry, virology, Serum, liver stiffness values (Liver Stiffness Measurement, LSM), were retrospectively analyzed. Results: (1) according to the inclusion and exclusion criteria, a total of 42 cases of ALT normal or slightly elevated HBe Ag negative CHB patients in this study, the average age was 37.62 + 10.12 years old, male 24 cases, female 18 cases, 14 patients before treatment serum HBV DNA in liver tissue below the detection limit HBV DNA replication, 28 patients were treated with HBV DNA in serum before replication. (2) in the course of treatment, the level of ALT increased volatility, to 48 weeks rose to the highest level, compared with the baseline level of ALT, the difference was statistically significant (P0.05); the serum HBV DNA level decreased compared to baseline serum HBV DNA level and the follow-up serum HBV DNA level, the difference was statistically significant (P0.05); HBs Ag (Hepatitis B s Antigen) was gradually decreased, baseline HBs titer of Ag and HBs Ag were all follow-up points And the differences between each follow-up point were statistically significant (P0.05); LSM volatility decreased baseline LSM and 12 weeks, 36 weeks were statistically significant difference in LSM. (3) of 14 patients before treatment serum HBV NDA below the detection limit of the end of 48 weeks of treatment, the level of Ag by HBs at baseline (2.74 + 1.03) log10IU/m L down to (1.79 + 1.69) log10IU/m L, 4 cases of patients with HBs Ag titer reached 100IU/ml, accounting for 28.57% (4/14), of which 1 cases occurred in patients with clear HBs Ag, complete response (Complete Response CR) rate was 7.14% (1/14). (4) of 14 patients with refractory before treatment the serum HBV DNA was below the detection limit, the course of treatment, the serum level of ALT to 12 weeks, 24 weeks after a slight decline, gradually increased, decreased and increased the level of no statistical significance (P0.05); serum HBs Ag titer decreased gradually after 24 weeks decreased with statistical significance (P0.05); LSM volatility elevated, elevated levels of no statistical significance 涔，

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