Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance: implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing.
OBJECTIVE
The introduction of two new non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the past 5 years and the identification of novel NNRTI-associated mutations have made it necessary to reassess the extent of phenotypic NNRTI cross-resistance.


METHODS
We analysed a dataset containing 1975, 1967, 519 and 187 genotype-phenotype correlations for nevirapine, efavirenz, etravirine and rilpivirine, respectively. We used linear regression to estimate the effects of RT mutations on susceptibility to each of these NNRTIs.


RESULTS
Sixteen mutations at 10 positions were significantly associated with the greatest contribution to reduced phenotypic susceptibility (≥10-fold) to one or more NNRTIs, including: 14 mutations at six positions for nevirapine (K101P, K103N/S, V106A/M, Y181C/I/V, Y188C/L and G190A/E/Q/S); 10 mutations at six positions for efavirenz (L100I, K101P, K103N, V106M, Y188C/L and G190A/E/Q/S); 5 mutations at four positions for etravirine (K101P, Y181I/V, G190E and F227C); and 6 mutations at five positions for rilpivirine (L100I, K101P, Y181I/V, G190E and F227C). G190E, a mutation that causes high-level nevirapine and efavirenz resistance, also markedly reduced susceptibility to etravirine and rilpivirine. K101H, E138G, V179F and M230L mutations, associated with reduced susceptibility to etravirine and rilpivirine, were also associated with reduced susceptibility to nevirapine and/or efavirenz.


CONCLUSIONS
The identification of novel cross-resistance patterns among approved NNRTIs illustrates the need for a systematic approach for testing novel NNRTIs against clinical virus isolates with major NNRTI-resistance mutations and for testing older NNRTIs against virus isolates with mutations identified during the evaluation of a novel NNRTI.
Department of Medicine, Stanford University, Stanford, CA, USA.
George L
GL
Melikian
Soo-Yon
SY
Rhee
Vici
V
Varghese
Danielle
D
Porter
Kirsten
K
White
Jonathan
J
Taylor
William
W
Towner
Paolo
P
Troia
Jeffrey
J
Burack
Edwin
E
Dejesus
Gregory K
GK
Robbins
Kristin
K
Razzeca
Ron
R
Kagan
Tommy F
TF
Liu
W Jeffrey
WJ
Fessel
Dennis
D
Israelski
Robert W
RW
Shafer
D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D060005:Genotyping Techniques; D006678:HIV / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D015658:HIV Infections / Q000821:virology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D012194:RNA-Directed DNA Polymerase
HIV-1; drug resistance; etravirine; linear regression; rilpivirine