Demeter L M, Meehan P M, Morse G, Fischl M A, Para M, Powderly W, Leedom J, Holden-Wiltse J, Greisberger C, Wood K, Timpone J, Wathen L K, Nevin T, Resnick L, Batts D H, Reichman R C
Infectious Diseases Unit, University of Rochester School of Medicine and Dentistry, New York, USA.
J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Oct 1;19(2):135-44. doi: 10.1097/00042560-199810010-00006.
The safety, tolerability, and antiviral activity of atevirdine (ATV), a nonnucleoside reverse transcriptase inhibitor, were studied in a phase I/II clinical trial (ACTG 187) of patients with CD4 counts < or =500/mm3. In all, 34 HIV-1-infected patients were randomized to receive ATV for 12 weeks in doses chosen to achieve one of three serum trough levels: 5 to 13 microM, 14 to 22 microM, or 23 to 31 microM. Rash was the most common adverse event, with a grade 3 or 4 rash occurring in 4 patients. No significant change from baseline in HIV-1 plasma RNA mean copy number was detected at week 4 (+0.09 log10 copies/ml; p = .30). However, some evidence indicated moderate antiviral activity at week 4, based on median changes in CD4 count (+23/mm3; p = .05), and viral peripheral blood mononuclear cell (PBMC) titer (-0.68 log10) copies/ml; p = .03). In addition, 2 of 4 patients with detectable baseline serum p24 antigen showed declines of >50%. HIV-1 resistance to ATV was detected in 41% of patients and was most commonly associated with RT mutations K103N and Y181C. In contrast, the Y181C mutation was not detected in ATV-resistant isolates obtained from patients enrolled in ACTG 199, a study of ATV given in combination with zidovudine. Under the conditions of this study, ATV failed to demonstrate significant antiretroviral activity. However, transient in vivo activity might have been obscured by rapid development of resistance coupled with inadequate sampling at early time points following initiation of ATV therapy.
在一项针对CD4细胞计数≤500/mm³患者的I/II期临床试验（ACTG 187）中，对非核苷类逆转录酶抑制剂阿替维啶（ATV）的安全性、耐受性及抗病毒活性进行了研究。共有34例HIV-1感染患者被随机分组，接受ATV治疗12周，所选剂量旨在达到三种血清谷浓度之一：5至13微摩尔/升、14至22微摩尔/升或23至31微摩尔/升。皮疹是最常见的不良事件，4例患者出现3级或4级皮疹。在第4周时，未检测到HIV-1血浆RNA平均拷贝数相对于基线有显著变化（+0.09 log₁₀拷贝/毫升；p = 0.30）。然而，一些证据表明在第4周时有中度抗病毒活性，这基于CD4细胞计数的中位数变化（+23/mm³；p = 0.05）以及病毒外周血单个核细胞（PBMC）滴度（-0.68 log₁₀）拷贝/毫升；p = 0.03）。此外，4例基线血清p24抗原可检测的患者中有2例下降超过50%。在41%的患者中检测到HIV-1对ATV耐药，最常见的是与逆转录酶（RT）突变K103N和Y181C相关。相比之下，在ACTG 199研究（该研究为ATV与齐多夫定联合用药）中入组患者的ATV耐药分离株中未检测到Y181C突变。在本研究条件下，ATV未能显示出显著的抗逆转录病毒活性。然而，体内短暂的活性可能因耐药性的快速产生以及ATV治疗开始后早期时间点采样不足而被掩盖。
