Fardeau C, Langlois M, Mathys B, Rafales P, Nugier F, Godard V, Aymard M, Denis J
Unité de Recherches d'Ophtalmologie, INSERM U 86, Hôtel-Dieu, Paris, France.
Curr Eye Res. 1991;10 Suppl:151-8. doi: 10.3109/02713689109020372.
The acquisition of drug resistance in vivo was investigated by 7 serial passages (from P0 to P7) of herpes simplex virus (HSV-1) in rabbit cornea treated with either IUdR (idoxuridine), IDC (idoxycytidine), ACV (acyclovir), TFT (trifluridine), or Ara A (adenine arabinoside). Therapeutic failure was acquired gradually: at P3 for IUdR, at P4 for ACV and at P5 for TFT. At P7, viral thymidine kinase (TK) activity was reduced to 5.6% of the parental strain for IUdR, to 7.5% for ACV and to 4.6% for TFT treatment. No signs of clinical unresponsiveness occurred with IDC or Ara A. The in vitro determination of antiviral drug sensitivity performed by the dye-uptake assay on HSV isolates at each passage showed a correlation between the increase in the 50% effective dose (ED50) and the increase of ulcer area grade at each passage under antiviral drug (p less than 0.1). Both IUdR- and TFT-resistant HSV1 developed cross-resistances to TK dependent drugs. However ACV-resistant HSV1 did not show cross-resistance to other antiviral TK dependent drugs. The acquisition of the cross-resistances is discussed, and the practical implications in case of therapeutic failures are suggested.
通过在接受碘苷（IUdR）、碘氧胞苷（IDC）、阿昔洛韦（ACV）、三氟胸苷（TFT）或阿糖腺苷（Ara A）治疗的兔角膜中对单纯疱疹病毒（HSV - 1）进行7次连续传代（从P0到P7），研究了体内耐药性的获得情况。治疗失败是逐渐出现的：IUdR在传代3次时出现，ACV在传代4次时出现，TFT在传代5次时出现。在传代7次时，对于接受IUdR治疗的病毒，其胸苷激酶（TK）活性降至亲本毒株的5.6%；对于ACV治疗的病毒，降至7.5%；对于TFT治疗的病毒，降至4.6%。使用IDC或Ara A治疗未出现临床无反应的迹象。通过对每次传代的HSV分离株进行染料摄取试验来体外测定抗病毒药物敏感性，结果显示在抗病毒药物作用下，每次传代时50%有效剂量（ED50）的增加与溃疡面积等级的增加之间存在相关性（p小于0.1）。对IUdR和TFT耐药的HSV1均对TK依赖性药物产生交叉耐药性。然而，对ACV耐药的HSV1并未显示出对其他抗病毒TK依赖性药物的交叉耐药性。文中讨论了交叉耐药性的获得情况，并提出了治疗失败时的实际影响。
