HIV Drug Resistance Mutations Detection by Next-Generation Sequencing during Antiretroviral Therapy Interruption in China.

Hui Xing,Chunhua Liu,Chao Zhou,Lei Liu,Shu Liang,Yi Feng,Lingjie Liao,Zhongbao Zuo,Chang Song,Yiming Shao,Yuhua Ruan,Shujia Liang,Min Chen,Miaomiao Li

doi:10.3390/pathogens10030264

Abstract

Patients with antiretroviral therapy interruption have a high risk of virological failure when re-initiating antiretroviral therapy (ART), especially those with HIV drug resistance. Next-generation sequencing may provide close scrutiny on their minority drug resistance variant. A cross-sectional study was conducted in patients with ART interruption in five regions in China in 2016. Through Sanger and next-generation sequencing in parallel, HIV drug resistance was genotyped on their plasma samples. Rates of HIV drug resistance were compared by the McNemar tests. In total, 174 patients were included in this study, with a median 12 (interquartile range (IQR), 6–24) months of ART interruption. Most (86.2%) of them had received efavirenz (EFV)/nevirapine (NVP)-based first-line therapy for a median 16 (IQR, 7–26) months before ART interruption. Sixty-one (35.1%) patients had CRF07_BC HIV-1 strains, 58 (33.3%) CRF08_BC and 35 (20.1%) CRF01_AE. Thirty-four (19.5%) of the 174 patients were detected to harbor HIV drug-resistant variants on Sanger sequencing. Thirty-six (20.7%), 37 (21.3%), 42 (24.1%), 79 (45.4%) and 139 (79.9) patients were identified to have HIV drug resistance by next-generation sequencing at 20% (v.s. Sanger, p = 0.317), 10% (v.s. Sanger, p = 0.180), 5% (v.s. Sanger, p = 0.011), 2% (v.s. Sanger, p < 0.001) and 1% (v.s. Sanger, p < 0.001) of detection thresholds, respectively. K65R was the most common minority mutation, of 95.1% (58/61) and 93.1% (54/58) in CRF07_BC and CRF08_BC, respectively, when compared with 5.7% (2/35) in CRF01_AE (p < 0.001). In 49 patients that followed-up a median 10 months later, HIV drug resistance mutations at >20% frequency such as K103N, M184VI and P225H still existed, but with decreased frequencies. The prevalence of HIV drug resistance in ART interruption was higher than 15% in the survey. Next-generation sequencing was able to detect more minority drug resistance variants than Sanger. There was a sharp increase in minority drug resistance variants when the detection threshold was below 5%.

Highlights

The scale-up of antiretroviral therapy (ART) has reduced HIV-related deaths and prevented new HIV infections [1]
60 (34.5%) patients were followed up a median 10 months later, with 49 still in ART interruption and 11 re-initiating ART
A cross-sectional survey was conducted among 174 patients with ART interruption in five areas more heavily affected by HIV/AIDS in China

Summary

Introduction

The scale-up of antiretroviral therapy (ART) has reduced HIV-related deaths and prevented new HIV infections [1]. While the number of patients with ART increases, so does the number of patients with treatment interruption. The emergence of HIV drug resistance (HIVDR) results from the low fidelity of HIV reverse transcriptase, the rapid replication of the virus and the selective pressure of antiretroviral drugs [10]. It will compromise the efficacy of ART, lead to virological failure and hamper the progress of HIV/AIDS treatment and prevention [11]. New HIVDR variants may be selected by residual drugs with longer half-lives in combined antiretroviral regimens [14]

Methods

Results

Conclusion