[AASLD 2012]干扰素+替诺福韦治疗慢性乙型肝炎患者的HBV准种株

肝胆速递

聚乙二醇干扰素+替诺福韦治疗慢性乙型肝炎患者的HBV准种株分析
CONTROL ID: 1425302
PRESENTATION TYPE: Poster Only
CURRENT CATEGORY: Hepatitis B
CURRENT DESCRIPTORS: I03. Virology and Diagnostics
TITLE: Quasispecies analysis of HBV strains isolated from chronic hepatitis B patients treated with Peg-interferon+Tenofovir therapy
AUTHORS (FIRST NAME, LAST NAME): Olivier Lada1, Qian Zhang1, Martine Lapalus1, Francoise Cluzeaud1, Michelle Martinot-Peignoux1, Cédric Laouénan2, Emilie Estrabaud1, Nathalie Boyer1, Tarik Asselah1, Patrick Marcellin1
Institutional Author(s):
INSTITUTIONS (ALL): 1. Hepatologie, Hopital Beaujon and INSERM U773 CRB3, , Clichy, France.
2. Modèles et Méthodes de l’évaluation thérapeutique des maladies chroniques, Inserm UMR 738, UFR de Médecine– Université de Paris Diderot – Paris 7 – Site Bichat, Paris, France.
ABSTRACT BODY: Background: In chronic Hepatitis B (CHB), loss of hepatitis B surface antigen (HBsAg) and seroconversion to anti-HBs is generally considered as the ultimate goal of antiviral therapy. New combination therapy of Pegylated interferon (PegIFN) with potent HBV Inhibitors such as tenofovir (TDF) is assessed in order to improve the rate of HBsAg loss. The aim of this study is to investigate the S-gene variability of patients treated with combination of PegIFN with TDF.

Methods: Patients received 180 μg of Peg-IFN/week plus 300 mg of TDF /day during 48 week. Patients were seen every 3 months. Sustained virologic response (SVR) was defined as HBV DNA< 2000UI/mL 48 weeks after end of therapy (EOT). Non response (NR) was defined as HBV DNA > 2000 UI/mL 48 weeks after EOT. HBs Ag-encoding gene from each patient's serum at baseline was PCR-amplified and cloned. At least 15 clones per patient were analysed.

Results: Twenty-six patients were included in this analysis. Baseline characteristics were: median age 44 years (range=27-67 years), 80.8% male, mean of HBV DNA 6.8 log UI/mL (range 3.6- 7.9 log UI/mL) and mean of serum ALT 102 IU/L (range 24-287 IU/L). Nine patients (34.6%) were HBeAg-negative. After the 48 weeks of follow-up, 6/26 patients (23%) achieved a SVR and 5/26 patients (19%) had a loss of HBsAg. Comparison of variability along the S protein indicated a marked difference between patients with SVR vs NR. When considering the full-length S coding region, the number of residues substitutions was 1.66 times more frequent in NR patients than SVR patients (p=0.048). The residue substitutions frequency of the “a” determinant located in the major hydrophilic region (MHR) was higher in NR vs SVR patients; 8.77 vs 10.53 mutated residues per 100 amino acids respectively. This determinant is one of the main targets of anti-HBs antibodies. The highest frequency of residue changes was observed in the C-terminal part of the S protein from NR compared to SVR patients with 25.01 vs 20.11 mutated residues per 100 amino acids respectively. This region overlaps the polymerase ORF and is likely affected by resistance mutations induced by treatment with nuclos(t)ide analogues. The most frequent substitutions observed in NR patients were located at position s129, s133, s145, which are known as immune escape variants.

Conclusion: In patients receiving PEG-IFN plus tenofovir, a SVR was observed in 23% and an HBsAg loss in 19%. NR patients showed more variability along the S protein. The Accumulation of residue substitutions in and around the “a” determinant at baseline should be a sensitive predictor of response to combination of PegIFN and TDF therapy in CHB patients.

肝胆速递

背景：在慢性乙型肝炎（CHB），B型肝炎表面抗原（HBsAg）和抗-HBs血清转换的损失通常被认为是抗病毒治疗的最终目标。新的组合疗法的聚乙二醇化干扰素（PegIFN）具有强大的HBV抑制剂如替诺福韦（TDF）进行评估，以改善的HBsAg损失率。本研究的目的是调查相结合的PegIFN与TDF治疗的患者S基因变异的。

方法：患者在48周的180微克的Peg-IFN/week加300毫克的TDF /天。患者看到每3个月。持续病毒学应答（SVR）被定义为HBV DNA <2000UI/mL 48周后，治疗结束（EOT）。无应答（NR）被定义为HBV DNA> 2000 UI / mL的48周后EOT。 HBs抗体从每个病人的血清在基线的Ag-编码基因的PCR扩增和克隆。每名患者至少有15个克隆进行了分析。

结果：26例患者被纳入这一分析。基线特征是：年龄中位数为44岁（范围为27-67岁），80.8％为男性，平均HBV DNA 6.8日志UI / mL（范围3.6-7.9日志UI /毫升），平均血清ALT 102 IU / L（范围24-287 IU / L）。 9例（34.6％）为HBeAg阴性。经过48周的后续行动，6/26例（23％）获得了SVR和5/26例（19％），HBsAg消失了。沿S蛋白的变异性比较表明，SVR与NR患者之间的显着差异。在考虑全长S编码区，替换残留物的数量为1.66倍更频繁的在NR病人比SVR的患者（P = 0.048）。的残余物替换频率“a”决定的主要亲水区（MHR）位于在NR与SVR组为高; 8.77与每100个氨基酸中分别10.53突变的残基。这决定因素是抗-HBs抗体的主要目标之一。残基变化的最高频率观察到的S蛋白在C-末端部分，从SVR 25.01对20.11突变的残基每100个氨基酸中分别的患者相比，NR。这个区域重叠聚合酶ORF，并有可能受到诱导治疗nuclos（T）类似物耐药突变。 NR患者中观察到的最频繁的替换位于位置S129，S133，S145，这是已知的作为免疫逃逸变种。

结论：在患者接受的PEG-IFN加替诺福韦，一个SVR观察到在23％和19％的HBsAg消失。 NR患者表现为沿S蛋白的变化。 “a”决定在基线和周围的残基取代的积累应该是一个敏感的预测PegIFN和TDF治疗慢性乙型肝炎患者的组合。

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