Gilleece Y, Torti C, Mandalia S, Gazzard B G, Pillay D, Pozniak A L
Chelsea and Westminster Hospital, London, UK.
HIV Med. 2003 Oct;4(4):305-10. doi: 10.1046/j.1468-1293.2003.00163.x.
There is increasing in vitro and in vivo evidence that reduced zidovudine (ZDV) susceptibility is generated by the selective pressure conferred by other nucleoside reverse transcriptase inhibitors (NRTIs). However, the degree to which this occurs in clinical practice remains unclear. We assessed phenotypic and genotypic resistance in ZDV-naive patients with virological failure on stavudine (d4T)-containing regimens, with particular reference to potential cross-resistance between d4T and ZDV.
Patients were identified from a clinical database. Treatment history was confirmed by case note evaluation and discussion with patients. Genotypic and phenotypic analyses were undertaken by Virco (Virco BVBA, Mechelen, Belgium).
Sixty-seven drug-experienced, ZDV-naive patients who underwent a resistance test while failing a d4T-containing regimen were identified. Of these patients, 23% had received three or more NRTIs and 42% at least one non-nucleoside reverse transcriptase (RT) inhibitor; 22% had viruses with reduced d4T susceptibility (>1.8-fold resistance), and 25% had viruses with reduced ZDV susceptibility (>4-fold). The most frequently observed RT mutations were identified. A significant correlation was found between susceptibility to d4T and susceptibility to ZDV (r=0.36; P=0.003), and also between virtual resistance to d4T and that to ZDV (r=0.38; P=0.002).
A significant minority of d4T-treated, ZDV-naive patients were found to have viruses with reduced ZDV susceptibility, with a variable association with classical ZDV resistance mutations. These data suggest that cross-resistance between d4T and ZDV may involve novel constellations of mutations. Correlations between d4T and ZDV susceptibilities and resistances further support cross-resistance between NRTIs.
越来越多的体外和体内证据表明，其他核苷类逆转录酶抑制剂（NRTIs）产生的选择性压力会导致齐多夫定（ZDV）敏感性降低。然而，在临床实践中这种情况发生的程度仍不清楚。我们评估了初治的、接受含司他夫定（d4T）方案治疗且出现病毒学失败的患者的表型和基因型耐药性，特别关注d4T和ZDV之间的潜在交叉耐药性。
从临床数据库中识别患者。通过病例记录评估和与患者讨论来确认治疗史。由Virco（比利时梅赫伦的Virco BVBA公司）进行基因型和表型分析。
确定了67例有药物治疗史、初治的患者，他们在含d4T方案治疗失败时接受了耐药性检测。在这些患者中，23%接受过三种或更多种NRTIs治疗，42%至少接受过一种非核苷类逆转录酶（RT）抑制剂治疗；22%的患者病毒对d4T的敏感性降低（耐药性>1.8倍），25%的患者病毒对ZDV的敏感性降低（耐药性>4倍）。确定了最常观察到的RT突变。发现对d4T的敏感性与对ZDV的敏感性之间存在显著相关性（r = 0.36；P = 0.003），对d4T的虚拟耐药性与对ZDV的虚拟耐药性之间也存在显著相关性（r = 0.38；P = 0.002）。
发现一小部分接受d4T治疗的初治患者的病毒对ZDV的敏感性降低，并与经典的ZDV耐药突变存在可变关联。这些数据表明，d4T和ZDV之间的交叉耐药可能涉及新的突变组合。d4T和ZDV敏感性及耐药性之间的相关性进一步支持了NRTIs之间的交叉耐药。
