A SHORT-TERM CLINICAL-EVALUATION OF L-697,661, A NONNUCLEOSIDE INHIBITOR OF HIV-1 REVERSE-TRANSCRIPTASE

Background. The non-nucleoside reverse transcriptase inhibitors are no vel antiretroviral agents with selective activity in vitro against hum an immunodeficiency virus type 1 (HIV-1). They act through direct inhi bition of reverse transcriptase and are not incorporated into DNA. Met hods. We evaluated a pyridinone non-nucleoside reverse transcriptase i nhibitor, L-697,661, in separate six-week double-blind trials in patie nts with HIV-1 infection whose CD4 counts ranged from 200 to 500 cells per cubic millimeter (68 patients) or less than 200 cells per cubic m illimeter (67 patients). Eligible patients were randomly assigned to r eceive L-697,661 orally in one of three doses (25 mg twice a day, 100 mg three times a day, or 500 mg twice a day) or zidovudine (100 mg fiv e times a day). Clinical and laboratory assessments were performed wee kly. Viral isolates were obtained from a subgroup of patients before a nd after treatment and were evaluated for in vitro sensitivity to L-69 7,661. Results. Both L-697,661 and zidovudine were well tolerated. Tra nsient increases in CD4 counts were noted in the patients with fewer t han 200 CD4 cells per cubic millimeter who received the two higher dos es of L-697,661, but not in those who received the lowest dose or zido vudine. Patients who received L-697,661 had rapid, dose-related decrea ses in plasma p24 antigen levels. However, this response virtually dis appeared after six weeks in some patients receiving L-697,661, coincid ently with the emergence of resistant viruses. This change in suscepti bility was more frequent among patients receiving the higher doses of L-697,661 and was associated with amino acid substitutions at position s 103 and 181 in the HIV-1 reverse transcriptase gene. Conclusions. L- 697,661 is safe and well tolerated and has significant dose-related ac tivity against HIV-1. However, resistant strains of the virus emerge r apidly and may limit the effectiveness of non-nucleoside reverse trans criptase inhibitors as monotherapy for HIV-1 infection.