Development of drug resistance in patients receiving combinations of zidovudine, didanosine and nevirapine.
OBJECTIVE
To evaluate the development of phenotypic and genotypic resistance to zidovudine, didanosine and nevirapine as a function of the virologic response to therapy in a group of drug-naive individuals receiving various combinations of these agents.


METHODS
All patients were enrolled in a double-blind controlled randomized trial (the INCAS study) and were selected for detailed resistance studies based on specimen availability and virologic response.


METHODS
Within the three study groups (zidovudine/nevirapine, zidovudine/didanosine or zidovudine/nevirapine/didanosine), 16, 19 and 24 patients, respectively, had evaluable baseline isolates and remained in the study > 24 weeks. Phenotypic resistance to all three drugs was evaluated using the VIRCO recombinant virus assay. Genotypic sequencing was done on selected specimens from patients receiving zidovudine/nevirapine/didanosine.


RESULTS
After 24 weeks, all available isolates taken from patients receiving nevirapine were resistant to this agent, while 18/21 (86%) patients receiving triple therapy carried such isolates at 30--60 weeks. At 24 weeks, zidovudine resistance developed in 4/40 isolates but was more frequent after 30--60 weeks, especially in patients on two drugs. The degree of zidovudine resistance (rise in concentration required for 50% inhibition) appeared lower in the triple therapy group compared with zidovudine/didanosine (P = 0.0004). All nevirapine-resistant isolates that were sequenced carried at least one mutation associated with resistance, most often K103N and/or Y181C.


CONCLUSIONS
The use of highly active drug therapies may be associated with a beneficial effect on the development of antiretroviral drug resistance. The characteristics of virologic suppression that must be maintained to avoid resistance are currently being studied in hypothesis-driven clinical trials.
Conway
B
B
Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
Wainberg
M A
MA
Hall
D
D
Harris
M
M
Reiss
P
P
Cooper
D
D
Vella
S
S
Curry
R
R
Robinson
P
P
Lange
J M
JM
Montaner
J S
JS
D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016049:Didanosine / Q000008:administration & dosage / Q000627:therapeutic use*; D004311:Double-Blind Method; D004352:Drug Resistance, Microbial / Q000235:genetics*; D004359:Drug Therapy, Combination; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009154:Mutation; D019829:Nevirapine / Q000008:administration & dosage / Q000627:therapeutic use*; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D015215:Zidovudine / Q000008:administration & dosage / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D019829:Nevirapine; D016049:Didanosine