Plasma viremia as a sensitive indicator of the antiretroviral activity of L-697,661.
L-697,661 is a non-nucleoside analogue with potent, selective inhibitory activity against the reverse transcriptase of human immunodeficiency virus type 1 (HIV-1). The present study evaluated the potential role of this compound in the treatment of HIV-1-infected patients in a double-blinded, placebo- and zidovudine-controlled trial using plasma viremia as a marker of antiviral activity and real-time phenotypic evaluation of viral isolates for the emergence of resistance. Participants received 12 weeks of either placebo, 25 mg twice a day, 100 mg three times a day, or 500 mg twice a day of L-697,661, or zidovudine, 100 mg five times a day. Mean logarithmic reciprocal titers of plasma virus in patients taking either L-697,661 or zidovudine decreased by week 4 of therapy; for L-697,661 recipients these changes were dose-dependent and, at the highest dose tested, were comparable in magnitude to those seen with zidovudine. Viral suppression induced by L-697,661 persisted through 8 weeks of treatment but decreased by week 12. This rebound paralleled emergence of viral isolates showing resistance to L-697,661. We conclude that although L-697,661 has potent antiretroviral activity in vivo, its utility may be compromised by rapid emergence of L-697,661-resistant virus. Plasma viremia is a highly sensitive technique affording considerable utility in the early testing of such agents.
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
R T
RT
Davey
R L
RL
Dewar
G F
GF
Reed
M B
MB
Vasudevachari
M A
MA
Polis
J A
JA
Kovacs
J
J
Falloon
R E
RE
Walker
H
H
Masur
S E
SE
Haneiwich
D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D000328:Adult; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001583:Benzoxazoles / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D015704:CD4 Antigens / Q000097:blood; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016655:HIV Core Protein p24 / Q000097:blood; D006679:HIV Seropositivity / Q000097:blood / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000097:blood / Q000209:etiology; D011728:Pyridones / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors; D014766:Viremia / Q000097:blood* / Q000188:drug therapy*; D015215:Zidovudine / Q000493:pharmacokinetics / Q000627:therapeutic use; D001613:beta 2-Microglobulin / Q000032:analysis
D000998:Antiviral Agents; D001583:Benzoxazoles; D015415:Biomarkers; D015704:CD4 Antigens; D016655:HIV Core Protein p24; D011728:Pyridones; D001613:beta 2-Microglobulin; C076516:L-697661; D015215:Zidovudine