Low-Frequency K103N Strengthens the Impact of Transmitted Drug Resistance on Virologic Responses to First-Line Efavirenz or Nevirapine-Based Highly Active Antiretroviral Therapy
Low-Frequency K103N Strengthens the Impact of Transmitted Drug Resistance on Virologic Responses to First-Line Efavirenz or Nevirapine-Based Highly Active Antiretroviral Therapy
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DOI：
10.1097/qai.0b013e3181ba11e8
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发表时间：
2009-12-15
影响因子：
3.6
通讯作者：
Johnson, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Geretti, Anna Maria;Fox, Zoe V.;Johnson, Jeffrey A.
Background: There are conflicting data on the impact of low-frequency transmitted drug-resistant mutants on responses to first-line highly active antiretroviral therapy (HAART).Methods: Patients started nevirapine or efavirenz with two or more nucleoside/nucleotide reverse transcriptase inhibitors in 1998-2007 without a prior resistance test at a median 1.0 (interquartile range, 0.0-3.4) year after diagnosis and with a median 218 (interquartile range, 131-296) CD4 cells/mm(3), and had at least 24 weeks of follow up. Pre-HAART plasma samples were tested retrospectively by bulk genotyping and sensitive real-time polymerase chain reaction targeting reverse transcriptase K65R, K103N, Y181C, M184V, and G190A (interpretative cutoff 0.3%-0.9%).Results: Among 93 patients, seven of 18 who experienced virologic failure and zero of 75 who maintained virologic suppression showed pre-HAART resistance, including three with high-frequency mutations detectable by bulk genotyping (two K103N, one G190A) and four with low-frequency K103N detectable only by polymerase chain reaction. Detection of either bulk (P = 0.006) or low-frequency (P = 0.001) resistance was significantly associated with the odds of virologic failure; combining the two markedly increased the strength of the association (P < 0.0001). At failure, the pre-HAART mutations were detected by bulk genotyping in five of seven patients alongside additional reverse transcriptase mutations.Conclusions: Low-frequency K103N mutants were as. prevalent as bulk-detectable variants before starting HAART Both high- and low-frequency mutants were significantly associated with virologic failure.
