Low-frequency K103N strengthens the impact of transmitted drug resistance on virologic responses to first-line efavirenz or nevirapine-based highly active antiretroviral therapy.
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.
Department of Virology, Royal Free Hampstead NHS Trust, London, UK. a.geretti@medsch.ucl.ac.uk
Anna Maria
AM
Geretti
Zoe V
ZV
Fox
Clare L
CL
Booth
Colette J
CJ
Smith
Andrew N
AN
Phillips
Margaret
M
Johnson
Jin-Fen
JF
Li
Walid
W
Heneine
Jeffrey A
JA
Johnson
D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use*; D003521:Cyclopropanes; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D019829:Nevirapine / Q000494:pharmacology / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017211:Treatment Failure; D019562:Viral Load
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D054303:HIV Reverse Transcriptase; C098320:efavirenz