Nucleos（t）ide类似物暴露患者的免疫逃逸突变可能导致耐药性

StephenW

Virginia Schad, PharmD
July 05, 2018
Immune-Escape Mutations in Nucleos(t)ide Analogue-Exposed Patients May Lead to Drug-Resistance


The researchers found at least 1 immune-associated escape mutation in 22.1% of patients. The researchers found at least 1 immune-associated escape mutation in 22.1% of patients.

Immune-escape mutations and stop-codons may develop in nucleos(t)ide analogue (NA)-exposed patients, potentially resulting in hepatitis B virus (HBV) transmission to vaccinated persons and stimulating drug-resistance emergence, according to a study published in BMC Infectious Diseases.1

Immune-escape mutations in hepatitis B surface antigens (HBsAgs)2,3 have been demonstrated to evade neutralizing antibodies, allow persistent HBV infection, and promote viral fitness.4,5 In addition, stop-codons are another type of mutation that can be detected in HBsAg, which can enhance HBV oncogenic properties.6

Researchers in Europe studied the prevalence and characteristics of these mutations in 828 chronically HBV-infected patients with detectable HBV-DNA and an available HBsAg sequence receiving treatment with at least 1 NA.1

The immune-associated escape mutations and the NA-induced immune-escape mutations sI195M, sI196S, and sE164D (resulting from drug-resistance mutations rtM204 V, rtM204I, and rtV173L) were examined.

Mutations were defined as an amino acid substitution with respect to the genotype A or D reference sequence.

The researchers found at least 1 immune-associated escape mutation in 22.1% of patients. Genotype D correlated with a higher selection of 1 or more immune-associated escape mutations, and this was significantly higher in drug-exposed patients with drug-resistant strains than with wild-type virus (29.5% vs 20.3%, respectively; P =.012).

A strong correlation was observed between sP120T and rtM204I/V, and their copresence determined an increased HBV-DNA. At least 1 NA-induced immune-escape mutation occurred in 28.6% of patients, and their selection correlated with genotype A.

Finally, stop-codons were present in 8.4% of patients at HBsAg-positions 172 and 182, which are known to enhance viral oncogenic properties.



"Immune-escape mutations and stop-codons develop in a large proportion of NA-exposed patients in Europe. These mutant isolates may potentially transmit in general population, including vaccinated individuals, and fuel drug-resistance emergence," concluded the authors.1

StephenW

Virginia Schad，PharmD
2018年7月5日
Nucleos（t）ide类似物暴露患者的免疫逃逸突变可能导致耐药性


研究人员在22.1％的患者中发现至少1例与免疫相关的逃避突变。研究人员在22.1％的患者中发现至少1例与免疫相关的逃避突变。

根据发表在一项研究中的一项研究，免疫逃逸突变和终止密码子可能在核（t）ide类似物（NA）暴露的患者中发展，可能导致乙型肝炎病毒（HBV）向接种疫苗的人传播并刺激耐药性出现。 BMC传染病

乙型肝炎表面抗原（HBsAgs）2,3中的免疫逃逸突变已被证明可以逃避中和抗体，允许持续的HBV感染，并促进病毒适应性.4,5此外，终止密码子是另一种类型的突变，可以是在HBsAg中检测到，可以增强HBV的致癌特性

欧洲研究人员研究了这些突变的患病率和特征，这些突变发生在828名HBV感染的HBV感染患者中，可检测到HBV-DNA，HBsAg序列可用至少1 NA.1治疗。

检测免疫相关逃逸突变和NA诱导的免疫逃逸突变sI195M，sI196S和sE164D（由药物抗性突变rtM204V，rtM204I和rtV173L产生）。

突变定义为相对于基因型A或D参考序列的氨基酸取代。

研究人员在22.1％的患者中发现至少1例与免疫相关的逃避突变。基因型D与1个或更多免疫相关的逃避突变的选择较高相关，并且在药物暴露的耐药菌株患者中显着高于野生型病毒（分别为29.5％和20.3％; P =。 012）。

在sP120T和rtM204I / V之间观察到强烈的相关性，并且它们共同确定了增加的HBV-DNA。 28.6％的患者至少发生1例NA诱导的免疫逃逸突变，其选择与基因型A相关。

最后，在HBsAg-位置172和182的8.4％患者中存在终止密码子，已知这些患者增强病毒致癌性质。



“免疫逃逸突变和终止密码子在欧洲大部分NA暴露患者中发生。这些突变分离株可能在一般人群中传播，包括接种疫苗的个体，以及燃料耐药性的出现，”作者总结道。