Effects of the G190A substitution of HIV reverse transcriptase on phenotypic susceptibility of patient isolates to delavirdine.
BACKGROUND
Cross resistance is common among the non-nucleoside reverse transcriptase inhibitors (NNRTIs). G190A appears in 5-15% of the patients treated with nevirapine or efavirenz who develop clinical resistance.


OBJECTIVE
In this study we investigated the effect of G190A and other NNRTI substitutions on the phenotypic susceptibility to this class of drugs.


METHODS
We identified 15 individuals, who after treatment with NNRTIs (nevirapine or efavirenz; median exposure of 20 months), developed isolated G190A, G190A in combination with K103N, or K103N alone. Phenotypic and genotypic analyses of stored plasma specimens were performed before and after the mutations occurred to assess NNRTI susceptibility.


RESULTS
All isolates that developed only G190A substitution became less susceptible to nevirapine (median: 125-fold) and efavirenz (median: 10-fold) but were 2.5-fold more sensitive to delavirdine (Wilcoxon P = 0.06). In the group with only K103N substitution, acquisition of resistance to all NNRTIs was observed. In the group with the double substitutions, G190A and K103N, delavirdine susceptibility decreased 13-fold, while resistance to nevirapine and efavirenz decreased by 239- and 154-folds, respectively (Kruskal-Wallis H P = 0.009).


CONCLUSIONS
The data suggest that the presence of a G190A substitution attenuates the phenotypic resistance associated with a K103N substitution, although resistance is still present. The in vivo significance of the increased phenotypic susceptibility to delavirdine is not known but could be evaluated in a clinical trial.
Uhlmann
Erik J
EJ
Department of Pathology, Box 8118, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Tebas
Pablo
P
Storch
Gregory A
GA
Powderly
William G
WG
Lie
Yolanda S
YS
Whitcomb
Jeannette M
JM
Hellmann
Nicholas S
NS
Arens
Max Q
MQ
D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020008:Delavirdine / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D005838:Genotype; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D020008:Delavirdine; D054303:HIV Reverse Transcriptase