Low-level K65R mutation in HIV-1 reverse transcriptase of treatment-experienced patients exposed to abacavir or didanosine.
BACKGROUND
Prior abacavir (ABC) or didanosine (ddI) therapy can result in the L74V/I or K65R mutation in HIV-1 reverse transcriptase. Preexisting K65R may have an impact on the treatment response to tenofovir disoproxil fumarate (TDF).


METHODS
An allele-specific polymerase chain reaction (AS-PCR) assay was developed to detect K65R with a lower limit of quantitation of 0.5%.


RESULTS
Among baseline plasma samples from 63 treatment-naive patients, no K65R was detected by AS-PCR. Among baseline samples from 154 treatment-experienced patients, 8 had K65R and 44 had L74V/I by population sequencing. Low-level K65R was detected in an additional 11 patients by AS-PCR, 3 of whom subsequently developed full K65R. Baseline K65R correlated with absence of thymidine analog mutations (TAMs; P = 0.003) and use of ABC or ddI (P = 0.004). Patients with full or low-level K65R at baseline or with L74V/I showed a diminished TDF response. Multivariate analyses confirmed that multiple TAMs, K65R, and L74V/I were independent predictors of diminished TDF response.


CONCLUSIONS
Prior therapy with ABC or ddI can result in a population genotype that shows K65R or L74V/I but does not reveal low-level K65R present in some patients. Subsequent treatment intensification with TDF resulted in a poor virologic response and may result in expansion of the preexisting K65R mutant.
Gilead Sciences, Inc., Durham, NC, USA.
Evguenia S
ES
Svarovskaia
Nicolas A
NA
Margot
Andrew S
AS
Bae
Joshua M
JM
Waters
Derrick
D
Goodman
Lijie
L
Zhong
Katyna
K
Borroto-Esoda
Michael D
MD
Miller
D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000483:Alleles; D016049:Didanosine / Q000008:administration & dosage / Q000627:therapeutic use*; D015224:Dideoxynucleosides / Q000008:administration & dosage / Q000627:therapeutic use*; D004311:Double-Blind Method; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D009154:Mutation; D063065:Organophosphonates / Q000627:therapeutic use; D016133:Polymerase Chain Reaction / Q000379:methods; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D016896:Treatment Outcome; D000099227:Abacavir
D000225:Adenine; D016049:Didanosine; D015224:Dideoxynucleosides; D054303:HIV Reverse Transcriptase; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000099227:Abacavir; C514824:reverse transcriptase, Human immunodeficiency virus 1