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. 2014 Jun 4;9(6):e98740.
doi: 10.1371/journal.pone.0098740. eCollection 2014.

Prevalence of WHO transmitted drug resistance mutations by deep sequencing in antiretroviral-naïve subjects in Hunan Province, China

Zou Xiaobai  1 , Chen Xi  1 , Hongping Tian  2 , Ann B Williams  3 , Honghong Wang  4 , Jianmei He  1 , Jun Zhen  1 , Jennifer Chiarella  5 , Lisebeth A Blake  6 , Gregory Turenchalk  6 , Michael J Kozal  5
Affiliations

Prevalence of WHO transmitted drug resistance mutations by deep sequencing in antiretroviral-naïve subjects in Hunan Province, China

Zou Xiaobai et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: Yale University receives grant support from Merck, Pfizer, ViiV, Vertex, Gilead, Abbott, Glaxo Smith Kline, Hologic Inc., and Bristol-Myers Squibb for studies that Dr. Kozal serves as the principal investigator. Dr. Kozal is a federal employee and does not receive grant support directly – the grant is held by Yale University. Dr. Kozal receives royalties from a patent owned by Stanford University for some HIV genotyping tests. The COI reported by Dr Kozal does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. Lisabeth Blake and Gregory Turenchalk are employees of Roche-454 Life Sciences and their participation does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

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