Fischl M A, Uttamchandani R B, Resnick L, Agarwal R, Fletcher M A, Patrone-Reese J, Dearmas L, Chidekel J, McCann M, Myers M
Department of Medicine, University of Miami School of Medicine, Florida 33101.
J Acquir Immune Defic Syndr (1988). 1991;4(1):1-10.
To determine the safety, maximum tolerated dose, and preliminary efficacy of concomitant interferon-alpha and zidovudine therapy in AIDS-related Kaposi's sarcoma (KS), 56 patients with biopsy-proven KS and documented human immunodeficiency virus type 1 (HIV) infection were enrolled into a phase I study. Interferon-alpha was given intramuscularly at a dose of 9, 18, or 27 mu once a day and zidovudine was administered as 100 or 200 mg every 4 h for 8 weeks followed by a 48-week maintenance period. The major toxicities were anemia, neutropenia, and hepatotoxicity. Neutropenia was dose limiting with 1,200 mg of zidovudine/day and the lowest dose of interferon-alpha (9 mu/day). Hepatotoxicity was dose limiting with 27 mu of interferon and 600 mg of zidovudine/day. Cumulative dose-related anemia or neutropenia was not seen during long-term follow-up. The maximum tolerated doses for the combination were defined as 18 mu daily for interferon-alpha and 600 mg daily for zidovudine. Variable changes in CD4 lymphocytes occurred during the first 8 weeks of therapy. At higher doses of the combination, sustained increases in median CD4 lymphocyte numbers were noted (p less than 0.001). In HIV antigenemic patients, progressive antigen suppression was seen with increasing doses of the combination (p less than 0.005). The overall antitumor response rate was 47%. Tumor regression was associated with better survival benefits (p less than 0.001) and a pretreatment CD4 cell count greater than or equal to 200 cells/mm3 (p = 0.01). In conclusion, intermediate doses of interferon-alpha and lower doses of zidovudine appear to be relatively well tolerated and associated with disease improvement, including survival benefits.
为确定α-干扰素与齐多夫定联合治疗艾滋病相关卡波西肉瘤（KS）的安全性、最大耐受剂量及初步疗效，56例经活检证实患有KS且记录有1型人类免疫缺陷病毒（HIV）感染的患者被纳入一项I期研究。α-干扰素以9、18或27μg的剂量每日一次肌肉注射，齐多夫定以100或200mg每4小时给药一次，持续8周，随后为48周的维持期。主要毒性反应为贫血、中性粒细胞减少和肝毒性。中性粒细胞减少是剂量限制性毒性，发生于齐多夫定每日1200mg及最低剂量的α-干扰素（9μg/天）时。肝毒性是剂量限制性毒性，发生于α-干扰素27μg及齐多夫定每日600mg时。长期随访期间未见累积剂量相关的贫血或中性粒细胞减少。联合治疗的最大耐受剂量定义为α-干扰素每日18μg，齐多夫定每日600mg。治疗的前8周内CD4淋巴细胞发生了可变变化。在联合治疗的较高剂量时，观察到CD4淋巴细胞中位数持续增加（p<0.001）。在HIV抗原血症患者中，随着联合治疗剂量增加可见逐步的抗原抑制（p<0.005）。总体抗肿瘤反应率为47%。肿瘤退缩与更好的生存获益相关（p<0.001），且与治疗前CD4细胞计数大于或等于200个细胞/mm³相关（p = 0.01）。总之，中等剂量的α-干扰素和较低剂量的齐多夫定似乎耐受性相对良好，并与疾病改善相关，包括生存获益。
