Saag M S, Emini E A, Laskin O L, Douglas J, Lapidus W I, Schleif W A, Whitley R J, Hildebrand C, Byrnes V W, Kappes J C
Department of Medicine, University of Alabama at Birmingham 35294-2050.
N Engl J Med. 1993 Oct 7;329(15):1065-72. doi: 10.1056/NEJM199310073291502.
The non-nucleoside reverse transcriptase inhibitors are novel antiretroviral agents with selective activity in vitro against human immunodeficiency virus type 1 (HIV-1). They act through direct inhibition of reverse transcriptase and are not incorporated into DNA.
We evaluated a pyridinone non-nucleoside reverse transcriptase inhibitor, L-697,661, in separate six-week double-blind trials in patients 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 millimeter (67 patients). Eligible patients were randomly assigned to receive 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 five times a day). Clinical and laboratory assessments were performed weekly. Viral isolates were obtained from a subgroup of patients before and after treatment and were evaluated for in vitro sensitivity to L-697,661.
Both L-697,661 and zidovudine were well tolerated. Transient increases in CD4 counts were noted in the patients with fewer than 200 CD4 cells per cubic millimeter who received the two higher doses of L-697,661, but not in those who received the lowest dose or zidovudine. Patients who received L-697,661 had rapid, dose-related decreases in plasma p24 antigen levels. However, this response virtually disappeared after six weeks in some patients receiving L-697,661, coincidently with the emergence of resistant viruses. This change in susceptibility was more frequent among patients receiving the higher doses of L-697,661 and was associated with amino acid substitutions at positions 103 and 181 in the HIV-1 reverse transcriptase gene.
L-697,661 is safe and well tolerated and has significant dose-related activity against HIV-1. However, resistant strains of the virus emerge rapidly and may limit the effectiveness of non-nucleoside reverse transcriptase inhibitors as monotherapy for HIV-1 infection.
非核苷类逆转录酶抑制剂是一类新型抗逆转录病毒药物，在体外对1型人类免疫缺陷病毒（HIV-1）具有选择性活性。它们通过直接抑制逆转录酶发挥作用，且不掺入DNA。
我们在两项为期六周的双盲试验中评估了一种吡啶酮类非核苷类逆转录酶抑制剂L-697,661，试验对象为HIV-1感染患者，其CD4细胞计数每立方毫米为200至500个（68例患者）或低于200个（67例患者）。符合条件的患者被随机分配接受三种剂量之一的口服L-697,661（25毫克，每日两次；100毫克，每日三次；或500毫克，每日两次）或齐多夫定（100毫克，每日五次）。每周进行临床和实验室评估。从一部分患者治疗前后获取病毒分离株，并评估其对L-697,661的体外敏感性。
L-697,661和齐多夫定都具有良好的耐受性。接受两种较高剂量L-697,661的每立方毫米CD4细胞低于200个的患者，其CD4细胞计数有短暂升高，但接受最低剂量或齐多夫定的患者则没有。接受L-697,661的患者血浆p24抗原水平迅速出现与剂量相关的下降。然而，在一些接受L-697,661的患者中，这种反应在六周后几乎消失，与此同时出现了耐药病毒。这种敏感性变化在接受较高剂量L-697,661的患者中更为常见，并且与HIV-1逆转录酶基因第103和181位的氨基酸替代有关。
L-697,661安全且耐受性良好，对HIV-1具有显著的剂量相关活性。然而，病毒耐药株迅速出现，可能会限制非核苷类逆转录酶抑制剂作为HIV-1感染单一疗法的有效性。
