Schmit J C, Van Laethem K, Ruiz L, Hermans P, Sprecher S, Sönnerborg A, Leal M, Harrer T, Clotet B, Arendt V, Lissen E, Witvrouw M, Desmyter J, De Clercq E, Vandamme A M
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
AIDS. 1998 Oct 22;12(15):2007-15. doi: 10.1097/00002030-199815000-00012.
To study the prevalence of multiple dideoxynucleoside (ddN)-resistant (MddNR) HIV-1 in European patients under treatment with multiple ddN analogues, and to characterize MddNR strains genotypically and phenotypically.
Blood samples from patients after > or = 6 months of treatment with multiple ddN were screened for the MddNR mutation Q151M. After confirmation of MddNR in 15 patients from five European countries, genotypic resistance was evaluated by DNA sequencing of the reverse transcriptase (RT) gene. Phenotypic resistance was measured by the recombinant virus assay. Results were compared with the clinical evolution of the patients.
The prevalence of MddNR strains in European patients treated with multiple ddN analogues was 3.5%. Viruses typically contained amino acid substitutions V75F, F77L, F116Y and Q151M in the RT gene. A new mutation, S68G, was frequently associated with MddNR. Phenotypically, viruses displayed high-level resistance to zidovudine (ZDV), didanosine (ddl), zalcitabine (ddC), stavudine (d4T) and partial resistance to lamivudine (3TC) once multiple mutations were present. Under in-vivo treatment pressure, some MddNR strains additionally developed resistance to protease inhibitors or non-nucleoside RT inhibitors (NNRTI). Clinically, most patients had advanced HIV disease with low CD4 cell counts, high viral loads and a rapid progression, but two patients harbouring MddNR virus responded well to dual protease inhibitor associations.
MddNR resistant HIV-1 can be found in European patients. MddNR is characterized by a specific set of drug resistance mutations, cross-resistance to most ddN analogues and a fast clinical progression. MddNR can be associated with protease inhibitor or NNRTI resistance.
研究在接受多种双脱氧核苷（ddN）类似物治疗的欧洲患者中多重双脱氧核苷耐药（MddNR）HIV-1的流行情况，并从基因型和表型上对MddNR毒株进行特征分析。
对接受多种ddN治疗≥6个月的患者的血样进行MddNR突变Q151M筛查。在确认来自五个欧洲国家的15例患者存在MddNR后，通过逆转录酶（RT）基因的DNA测序评估基因型耐药性。通过重组病毒试验测定表型耐药性。将结果与患者的临床病程进行比较。
接受多种ddN类似物治疗的欧洲患者中MddNR毒株的流行率为3.5%。病毒在RT基因中通常含有氨基酸替代V75F、F77L、F116Y和Q151M。一种新的突变S68G经常与MddNR相关。在表型上，一旦存在多个突变，病毒对齐多夫定（ZDV）、去羟肌苷（ddI）、扎西他滨（ddC）、司他夫定（d4T）表现出高水平耐药，对拉米夫定（3TC）表现出部分耐药。在体内治疗压力下，一些MddNR毒株还对蛋白酶抑制剂或非核苷类逆转录酶抑制剂（NNRTI）产生耐药。临床上，大多数患者患有晚期HIV疾病，CD4细胞计数低、病毒载量高且病情进展迅速，但两名携带MddNR病毒的患者对双重蛋白酶抑制剂联合治疗反应良好。
在欧洲患者中可发现MddNR耐药的HIV-1。MddNR的特征是一组特定的耐药突变、对大多数ddN类似物的交叉耐药以及快速的临床进展。MddNR可能与蛋白酶抑制剂或NNRTI耐药相关。
