Holguín A, Dietrich U, Immelmann A, Soriano V
Service of Infectious Diseases, Instituto de Salud Carlos III, Madrid, Spain.
Antivir Ther. 1998;3(3):183-6.
Protocol BMS 020 was a double-blind, prospective clinical trial in which two different doses of stavudine (20 and 40 mg twice daily) were compared in human immunodeficiency virus (HIV)-infected patients with previous exposure to zidovudine for longer than 16 weeks. Genotypic and phenotypic resistance to both zidovudine and stavudine were examined after at least 2 years of stavudine monotherapy. None of 35 tested individuals harboured the codon 50 and/or 75 mutations previously described to be associated with stavudine resistance. However, more than 80% of the individuals carried mutations associated with zidovudine resistance, despite all these patients having stopped zidovudine at least 2 years earlier. Significant phenotypic resistance to stavudine was observed only in 2 of 5 tested individuals, although IC50 values were increased only 6.6- and 9.2-fold, respectively. These two patients had suffered a decline in their CD4 count, and one of them had high levels of plasma viraemia. The sequence analysis of the reverse transcriptase (RT) gene (aa 30 to 240) in these five patients revealed no changes that could be involved in stavudine resistance. In contrast, and despite having stopped treatment with zidovudine more than 2 years before, phenotypic resistance to zidovudine was observed in all five subjects, with IC50 values raised by more than 75-fold in all of them. Moreover, all harboured codon substitutions within the RT gene associated with zidovudine resistance, and these mutations remained in viral genomes examined after virus co-culture, suggesting that they provided some biological advantage to mutants, even in the absence of drug pressure. In conclusion, both genotypic and phenotypic resistance to stavudine seem to be a rare event in patients exposed to the drug, even after long periods of exposure.
方案BMS 020是一项双盲前瞻性临床试验，在曾接受齐多夫定治疗超过16周的人类免疫缺陷病毒（HIV）感染患者中比较两种不同剂量的司他夫定（每日两次，每次20毫克和40毫克）。在司他夫定单药治疗至少2年后，检测了对齐多夫定和司他夫定的基因型和表型耐药性。35名受试个体中没有一人携带先前描述的与司他夫定耐药相关的密码子50和/或75突变。然而，超过80%的个体携带与齐多夫定耐药相关的突变，尽管所有这些患者至少在2年前就已停用齐多夫定。仅在5名受试个体中的2名中观察到对司他夫定有显著的表型耐药性，尽管IC50值仅分别增加了6.6倍和9.2倍。这两名患者的CD4细胞计数有所下降，其中一名患者血浆病毒血症水平较高。对这五名患者逆转录酶（RT）基因（第30至240位氨基酸）的序列分析显示，没有发现可能与司他夫定耐药有关的变化。相反，尽管在2年多前就已停用齐多夫定治疗，但在所有五名受试者中均观察到对齐多夫定的表型耐药性，他们的IC50值均提高了75倍以上。此外，所有受试者的RT基因内都存在与齐多夫定耐药相关的密码子替换，并且这些突变在病毒共培养后检测的病毒基因组中仍然存在，这表明即使在没有药物压力的情况下，它们也为突变体提供了一些生物学优势。总之，即使在长期接触后，在接触过司他夫定的患者中，对司他夫定的基因型和表型耐药似乎都是罕见事件。
