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J Antimicrob Chemother. 2019 Jan 18. doi: 10.1093/jac/dky561. [Epub ahead of print]

Detection of pretreatment minority HIV-1 reverse transcriptase inhibitor-resistant variants by ultra-deep sequencing has a limited impact on virological outcomes.

Su B1,2, Zheng X3, Liu Y1,2, Liu L1,2, Xin R4, Lu H4, Huang C4, Bai L4, Mammano F5, Zhang T1,2, Wu H1,2, Sun L1, Dai L1.

Author information

1
Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
2
Beijing Key Laboratory for HIV/AIDS Research, Beijing 100069, China.
3
EZKIT L.L.C., Honolulu, HI 96825, USA.
4
Institute for AIDS/STD Control and Prevention, Beijing Center for Disease Prevention and Control, Beijing 100013, China.
5
INSERM U941, Genetics and Ecology of Viruses, Hospital Saint Louis, Université Paris Diderot, Sorbonne Paris Cité, Paris 75475, France.

Abstract

Objectives:

Ultra-deep sequencing (UDS) is a powerful tool for exploring the impact on virological outcome of minority variants with low frequencies, some even <1% of the virus population. Here, we compared HIV-1 minority variants at baseline, through plasma RNA and PBMC DNA analyses, and the dominant variants at the virological failure (VF) point, to evaluate the impact of minority drug-resistant variants (MDRVs) on virological outcomes.

Methods:

Single-molecule real-time sequencing (SMRTS) was performed on baseline RNA and DNA. The Stanford HIV-1 drug resistance database was used for the identification and evaluation of drug resistance-associated mutations (DRAMs).

Results:

We classified 50 patients into virological success (VS) and VF groups. We found that the rates of reverse transcriptase inhibitor (RTI) DRAMs determined by SMRTS did not differ significantly within or between groups, whether based on RNA or DNA analyses. There was no significant difference in the level of resistance to specific drugs between groups, in either DNA or RNA analyses, except for the DNA-based analysis of lamivudine, for which there was a trend towards a higher prevalence of intermediate/high-level resistance in the VF group. The RNA MDRVs corresponded to DNA MDRVs, except for M100I and Y188H. Sequencing from DNA appeared to be more sensitive than from RNA to detect MDRVs.

Conclusions:

Detection of pretreatment minority HIV-1 RTI-resistant variants by UDS showed that MDRVs at baseline were not significantly associated with virological outcome. However, HIV-1 DNA sequencing by UDS was useful for detecting pretreatment drug resistance mutations in patients, potentially affecting virological responses, suggesting a potential clinical relevance for ultra-deep DNA sequencing.

PMID:
30668734
DOI:
10.1093/jac/dky561

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