Ep. Coakley et al., Phenotypic and genotypic resistance patterns of HIV-1 isolates derived from individuals treated with didanosine and stavudine, AIDS, 14(2), 2000, pp. F9-F15
Objective: To evaluate the phenotypic susceptibilities and genotypic resist
ance patterns to both didanosine and stavudine of baseline and follow-up HI
V-1 isolate pairs, derived from antiretroviral naive subjects treated with
this dual nucleoside combination.
Design and methods: Phenotypic drug susceptibility testing was performed in
peripheral blood mononuclear cells on 34 viral isolate pairs derived from
patients participating in the EMS AI-460 trial. Sequencing of the complete
reverse transcriptase of 36 study isolate pairs, baseline and follow-up, wa
s performed using standard dideoxy techniques.
Results: The mean fold change in susceptibilities to didanosine was 1.6 (P
= 0.278) and to stavudine 1.9 (P = 0.002, Wilcoxon's signed rank lest). Mut
ations classically associated with zidovudine resistance were observed to e
merge in 7 out of 36 isolates, T215Y/F (four), M41L + T215Y/F (two) and D67
N tone). Other mutations observed included the A62V, V751, F77L, F116Y, Q15
1M multinucleoside resistance complex (one), the Q151M mutation (two) and t
he rare V75T mutation (two). No mutations classically associated with didan
osine exposure and resistance were observed. No relationship was evident be
tween the emergence of zidovudine associated mutations and the level of phe
notypic resistance to either stavudine or didanosine or between the emergen
ce of zidovudine associated mutations and changes in plasma HIV RNA levels.
Conclusion: These comprehensive data demonstrate modest (( twofold) mean re
ductions in didanosine and stavudine susceptibilities at follow-up. The eme
rgence of zidovudine associated mutations in this retroviral-naive populati
on treated with combination didanosine and stavudine therapy is notable. Fu
rthermore, the emergence of these mutations and of the Q151M multinucleosid
e resistance complex raise concerns for potential nucleoside analog cross-r
esistance. The potential mechanisms driving the selection of the zidovudine
associated mutations in the setting of didanosine and stavudine therapy an
d the relevance of these findings to current three and four drug regimens m
erit further evaluation. (C) 2000 Lippincott Williams & Wilkins.