Modulation of K65R selection by zidovudine inclusion: analysis of HIV resistance selection in subjects with virologic failure receiving once-daily abacavir/lamivudine/zidovudine and tenofovir DF (study COL40263).
COL40263 was a pilot 48-week, open-label, multicenter study evaluating the efficacy and safety of once-daily coformulated abacavir/lamivudine/zidovudine plus tenofovir in ART-naive, HIV-infected subjects. We examined the patterns of resistance that were selected on-therapy through 48 weeks in subjects with virologic nonresponse (VF). A total of 123 antiretroviral-naive HIV-1-infected subjects with plasma HIV-1 RNA > or = 30,000copies/ml were enrolled. For subjects with confirmed VF (HIV-1 RNA > or = 400 copies/ml at week 24 or later), HIV population genotypic and phenotypic analysis was performed. Of the 123 enrolled subjects, 14 (11%) had confirmed plasma HIV-1 RNA > or = 400 copies/ml through week 48. Of these subjects, 3/14 had evidence of drug resistance at baseline: 2/14 had HIV with K103N, Y188F/H/L/Y, and/or T215A and 1/14 had reduced zidovudine susceptibility. At the last time point analyzed, 4/14 subjects had wild-type HIV, while 10/14 subjects had HIV with either thymidine analogue mutations (TAMS) alone (3/10), TAMS + M184V (4/10), M184V only (1/10), or K65R/K (2/10). Matched phenotype was obtained for 13/14 subjects and 8/13 (62%) subjects had reduced susceptibility to one or more study drugs: 2/13 tenofovir, 3/13 abacavir, 4/13 zidovudine, and 7/13 lamivudine. The resistance pattern in COL40263 subjects with VF differs significantly from that reported for tenofovir-containing triple-nucleoside regimens. TAMs were detected in the majority (7/10) of samples from subjects with VF who selected any resistance mutation. These data suggest that TAMs selection is a preferred resistance route of this combination, with zidovudine modulating the resistance pathway against selection for K65R.
Ross
Lisa
L
GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. lisa.l.ross@gsk.com
Elion
Richard
R
Lanier
Randall
R
Dejesus
Edwin
E
Cohen
Calvin
C
Redfield
Robert R
RR
Gathe
Joseph C
JC
Hsu
Ricky K
RK
Yau
Linda
L
Paulsen
D
D
Ha
Belinda
B
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000328:Adult; D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D015224:Dideoxynucleosides / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage*; D010865:Pilot Projects; D012367:RNA, Viral / Q000097:blood / Q000187:drug effects / Q000235:genetics; D000068698:Tenofovir; D017211:Treatment Failure; D015215:Zidovudine / Q000008:administration & dosage*; D000099227:Abacavir
D000225:Adenine; D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D019259:Lamivudine; D063065:Organophosphonates; D012367:RNA, Viral; D000068698:Tenofovir; D015215:Zidovudine; D000099227:Abacavir