中国湖南省初治抗逆转录病毒治疗患者中通过深度测序检测到的世界卫生组织传播耐药性突变的流行情况
Prevalence of WHO transmitted drug resistance mutations by deep sequencing in antiretroviral-naïve subjects in Hunan Province, China.
作者信息
Xiaobai Zou, Xi Chen, Tian Hongping, Williams Ann B, Wang Honghong, He Jianmei, Zhen Jun, Chiarella Jennifer, Blake Lisebeth A, Turenchalk Gregory, Kozal Michael J
机构信息
Hunan Provincial Center for Disease Control and Prevention, Changsha, Hunan Province, China.
Yale-China Association, New Haven, Connecticut, United States of America.
出版信息
PLoS One. 2014 Jun 4;9(6):e98740. doi: 10.1371/journal.pone.0098740. eCollection 2014.
BACKGROUND
There are few data on the prevalence of WHO transmitted drug resistance mutations (TDRs) that could affect treatment responses to first line antiretroviral therapy (ART) in Hunan Province, China.
OBJECTIVE
Determine the prevalence of WHO NRTI/NNRTI/PI TDRs in ART-naïve subjects in Hunan Province by deep sequencing.
METHODS
ART-naïve subjects diagnosed in Hunan between 2010-2011 were evaluated by deep sequencing for low-frequency HIV variants possessing WHO TDRs to 1% levels. Mutations were scored using the HIVdb.stanford.edu algorithm to infer drug susceptibility.
RESULTS
Deep sequencing was performed on samples from 90 ART-naïve subjects; 83.3% were AE subtype. All subjects had advanced disease (average CD4 count 134 cells/mm3). Overall 25.6%(23/90) of subjects had HIV with major WHO NRTI/NNRTI TDRs by deep sequencing at a variant frequency level ≥ 1%; 16.7%(15/90) had NRTI TDR and 12.2%(11/90) had a major NNRTI TDR. The majority of NRTI/NNRTI mutations were identified at variant levels <5%. Mutations were analyzed by HIVdb.stanford.edu and 7.8% of subjects had variants with high-level nevirapine resistance; 4.4% had high-level NRTI resistance. Deep sequencing identified 24(27.6%) subjects with variants possessing either a PI TDR or hivdb.stanford.edu PI mutation (algorithm value ≥ 15). 17(19.5%) had PI TDRs at levels >1%.
CONCLUSIONS
ART-naïve subjects from Hunan Province China infected predominantly with subtype AE frequently possessed HIV variants with WHO NRTI/NNRTI TDRs by deep sequencing that would affect the first line ART used in the region. Specific mutations conferring nevirapine high-level resistance were identified in 7.8% of subjects. The majority of TDRs detected were at variant levels <5% likely due to subjects having advanced chronic disease at the time of testing. PI TDRs were identified frequently, but were found in isolation and at low variant frequency. As PI/r use is infrequent in Hunan, the existence of PI mutations likely represent AE subtype natural polymorphism at low variant level frequency.
背景
关于可能影响中国湖南省一线抗逆转录病毒治疗（ART）疗效的世界卫生组织传播耐药性突变（TDR）流行情况的数据较少。
目的
通过深度测序确定湖南省未接受过ART治疗的受试者中世界卫生组织核苷类反转录酶抑制剂/非核苷类反转录酶抑制剂/蛋白酶抑制剂TDR的流行情况。
方法
对2010年至2011年在湖南省诊断的未接受过ART治疗的受试者进行深度测序，以评估具有世界卫生组织TDR的低频HIV变异体至1%水平。使用HIVdb.stanford.edu算法对突变进行评分以推断药物敏感性。
结果
对90名未接受过ART治疗的受试者的样本进行了深度测序；83.3%为AE亚型。所有受试者均患有晚期疾病（平均CD4细胞计数为134个/立方毫米）。总体而言，通过深度测序，在变异频率水平≥1%时，25.6%（23/90）的受试者的HIV具有主要的世界卫生组织核苷类反转录酶抑制剂/非核苷类反转录酶抑制剂TDR；16.7%（15/90）有核苷类反转录酶抑制剂TDR，12.2%（11/90）有主要的非核苷类反转录酶抑制剂TDR。大多数核苷类反转录酶抑制剂/非核苷类反转录酶抑制剂突变在变异水平<5%时被鉴定出来。通过HIVdb.stanford.edu对突变进行分析，7.8% 的受试者具有对奈韦拉平高水平耐药的变异体；4.4% 有高水平核苷类反转录酶抑制剂耐药。深度测序确定24名（27.6%）受试者的变异体具有蛋白酶抑制剂TDR或HIVdb.stanford.edu蛋白酶抑制剂突变（算法值≥15）。17名（19.5%）的蛋白酶抑制剂TDR水平>1%。
结论
中国湖南省主要感染AE亚型的未接受过ART治疗的受试者，通过深度测序经常具有携带世界卫生组织核苷类反转录酶抑制剂/非核苷类反转录酶抑制剂TDR的HIV变异体，这会影响该地区使用的一线ART。在7.8% 的受试者中鉴定出了赋予奈韦拉平高水平耐药的特定突变。检测到的大多数TDR的变异水平<5%，可能是由于受试者在检测时患有晚期慢性病。蛋白酶抑制剂TDR经常被鉴定出来，但发现是孤立存在且变异频率较低。由于湖南省很少使用蛋白酶抑制剂/利托那韦，蛋白酶抑制剂突变的存在可能代表AE亚型在低变异水平频率下的自然多态性。
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