再谈乙型肝炎病毒反转录酶区/表面抗原区基因变异的临床发生特点及意义

Re-discussion on features of clinical occurrence and implications of hepatitis B virus mutations in reverse transcriptase/surface antigen genes

在我国,拉米夫定(LAM)、阿德福韦酯(ADV)和恩替卡韦(ETV)长期广泛用于临床抗乙型肝炎病毒(HBV)治疗,导致恩替卡韦耐药患者累积增加,耐药变异形式复杂多样,其挽救治疗也成了临床关注的重点问题。HBV聚合酶/反转录酶(RT)区/表面抗原(HBsAg)S区基因重叠,核苷(酸)类似物引起的耐药变异可同时造成S区基因变异,其中rt A181T变异可同时引起sW172终止突变,形成截短型HBsAg,影响疾病进展;rt A181T有时还可引起sW172非终止变异,其临床发生特点和意义尚不明确;HBsAg阴转是慢性乙型肝炎功能性治愈的重要标志,但临床上有少数患者可同时检出血清HBsAg和HBs Ab阳性,其意义与机制尚未完全明确。我们的研究发现,发生在HBsAg主要亲水区(MHR)的免疫逃逸相关变异多见于隐匿性HBV感染患者和HBsAg/HBs Ab双阳性的HBV感染患者,其中如发生新增N-糖基化变异,则进展为肝细胞癌的风险显著增加;从患者分离的免疫逃逸变异株可显著降低HBsAg的抗原性和反应性。上述研究有助于深入认识HBV RT/S基因变异发生的临床特点、机制和意义,帮助临床合理制定抗病毒治疗方案,预测疾病进展风险。

Currently in China, lamivudine（LAM）, adefovir（ADV） and entecavir（ETV） have been widely used for a long time for anti-hepatitis B virus（HBV） treatment, leading to escalated ETV-resistant patients with complex mutational patterns. The rescue therapy for ET V resistance is a key issue concerned in clinic. Owing to overlapping of HBV polymerase/reversetranscriptase（RT） and the surface antigen（S） genetic region, certain mutations in the RT region will simultaneously cause S gene mutation. Among these, rt A181 T mutation may cause sW172 stop mutation and form truncated HBsAg which may influence disease progression. However, rt A181 T may cause sW172 non-stop mutation which the features of clinical occurrence and implications have not been fully understood. HBsAg turn to negative is a key marker for functional cure of chronic hepatitis B（CHB）. However, a few of patients could be detected with double positivity of serum HBsAg and anti-HBs, the mechanism and clinical implications of this phenomenon have not been fully understood. Our study revealed that immune escape-related mutations in major hydrophilic region（MHR） of HBsAg were more frequently detected in patients with occult HBV infection and with double positivity of HBsAg and anti-HBs. Among them, if the patient harbored additional N-glycosylation mutation, he/she might take significantly higher risk to develop hepatocellular carcinoma. The patient-derived HBV strains with immune escape-related mutations have significantly decreased antigenicity and reactivity to anti-HBs. These findings are helpful for better understanding the features, mechanism and implications of HBV RT/S gene mutation occurred in clinic, and for optimizing anti-HBV schedule, as well as predicting disease progression risk.