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 inhibito ry activity against the reverse transcriptase of human immunodeficienc y 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 dou ble-blinded, placebo- and zidovudine-controlled trial using plasma vir emia as a marker of antiviral activity and real-time phenotypic evalua tion of viral isolates for the emergence of resistance. Participants r eceived 12 weeks of either placebo, 25 mg twice a day, 100 mg three ti mes a day, or 500 mg twice a day of L-697,661, or zidovudine, 100 mg r ive 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 a nd, 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 p aralleled emergence of viral isolates showing resistance to L-697,661. We conclude that although L-697,661 has potent antiretroviral activit y in vivo, its utility may be compromised by rapid emergence of L-697, 661-resistant virus. Plasma viremia is a highly sensitive technique af fording considerable utility in the early testing of such agents.