title: Prevalence of WHO transmitted drug resistance mutations by deep sequencing in antiretroviral-naïve subjects in Hunan Province, China.
abstract: 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.
authors.affiliation: Hunan Provincial Center for Disease Control and Prevention, Changsha, Hunan Province, China.
authors.forename: Zou
authors.initials: Z
authors.lastname: Xiaobai
authors.affiliation: Hunan Provincial Center for Disease Control and Prevention, Changsha, Hunan Province, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Xi
authors.affiliation: Yale-China Association, New Haven, Connecticut, United States of America.
authors.forename: Hongping
authors.initials: H
authors.lastname: Tian
authors.affiliation: UCLA School of Nursing, Los Angeles, California, United States of America.
authors.forename: Ann B
authors.initials: AB
authors.lastname: Williams
authors.affiliation: Central South University, Hunan Province, China.
authors.forename: Honghong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Hunan Provincial Center for Disease Control and Prevention, Changsha, Hunan Province, China.
authors.forename: Jianmei
authors.initials: J
authors.lastname: He
authors.affiliation: Hunan Provincial Center for Disease Control and Prevention, Changsha, Hunan Province, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhen
authors.affiliation: Yale School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chiarella
authors.affiliation: 454 Life Science, Branford, Connecticut, United States of America.
authors.forename: Lisebeth A
authors.initials: LA
authors.lastname: Blake
authors.affiliation: 454 Life Science, Branford, Connecticut, United States of America.
authors.forename: Gregory
authors.initials: G
authors.lastname: Turenchalk
authors.affiliation: Yale School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kozal
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000494:pharmacology; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000453:epidemiology* / Q000276:immunology / Q000635:transmission / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D019562:Viral Load; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents