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Low-Frequency K103N Strengthens the Impact of Transmitted Drug Resistance on Virologic Responses to First-Line Efavirenz or Nevirapine-Based Highly Active Antiretroviral Therapy

Geretti, Anna Maria MD, MSc, PhD, FRCPath*†; Fox, Zoe V PhD; Booth, Clare L MSc*; Smith, Colette J PhD; Phillips, Andrew N PhD; Johnson, Margaret MD*†; Li, Jin-Fen; Heneine, Walid PhD; Johnson, Jeffrey A PhD

JAIDS Journal of Acquired Immune Deficiency Syndromes: December 2009 - Volume 52 - Issue 5 - p 569-573
doi: 10.1097/QAI.0b013e3181ba11e8
Clinical Science

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/mm3, 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.

From *Royal Free Hampstead NHS Trust and †University College Medical School, London, UK; and ‡Centers for Disease Control and Prevention, Atlanta, GA.

Received for publication March 3, 2009; accepted June 25, 2009.

Supported by the British HIV Association Research Award 2008.

The work was presented at the 7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm, Sweden.

Correspondence to: Anna Maria Geretti, MD, MSc, PhD, FRCPath, Department of Virology, Royal Free Hampstead NHS Trust & University College London Medical School, Pond Street, London NW3 2QG, UK (e-mail:

© 2009 Lippincott Williams & Wilkins, Inc.