Combination therapy with zidovudine prevents selection of human immunodeficiency virus type 1 variants expressing high-level resistance to L-697,661, a nonnucleoside reverse transcriptase inhibitor.
L-697,661 is a human immunodeficiency virus type 1 (HIV-1)-specific nonnucleoside reverse transcriptase (RT) inhibitor. Its tolerability and activity in combination with zidovudine were evaluated in a 48-week double-blind study. One hundred nineteen zidovudine-naive HIV-1-infected patients with CD4 cell counts of 200-500/mm3 received either combination therapy, L-697,661 alone, or zidovudine alone. Activity was assessed by CD4 cell count changes. Selection for L-697,661-resistant virus was monitored by susceptibility testing of RT expressed by circulating viral RNA. Therapy was generally well tolerated. All groups receiving zidovudine exhibited transient increases in CD4 cell counts, while the L-697,661 monotherapy group showed a significant decline and yielded RT > 100-fold resistant to L-697,661 and associated with substitutions at RT residue 181. The RT from patients receiving combination therapy was maximally 15-fold less susceptible to L-697,661. Hence, cotreatment with zidovudine prevents selection of HIV-1 variants that are highly resistant to L-697,661 in patients naive to both compounds.
Staszewski
S
S
Merck Research Laboratories, West Point, Pennsylvania, USA.
Massari
F E
FE
Kober
A
A
Göhler
R
R
Durr
S
S
Anderson
K W
KW
Schneider
C L
CL
Waterbury
J A
JA
Bakshi
K K
KK
Taylor
V I
VI
D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001483:Base Sequence; D001583:Benzoxazoles / Q000008:administration & dosage* / Q000009:adverse effects; D018791:CD4 Lymphocyte Count; D004311:Double-Blind Method; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors; D017422:Sequence Analysis, DNA; D015215:Zidovudine / Q000008:administration & dosage* / Q000009:adverse effects
D000998:Antiviral Agents; D001583:Benzoxazoles; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; C076516:L-697661; D015215:Zidovudine; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase