Stránská Růzena, Schuurman Rob, Nienhuis Elske, Goedegebuure Irma W, Polman Merjo, Weel Jan F, Wertheim-Van Dillen Pauline M, Berkhout Ron J M, van Loon Anton M
Department of Virology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
J Clin Virol. 2005 Jan;32(1):7-18. doi: 10.1016/j.jcv.2004.04.002.
Widespread and frequent use of acyclovir (ACV) for treatment, suppressive therapy and prophylaxis of herpes simplex virus (HSV) infections and its over the counter availability may be associated with emergence of HSV resistance.
To determine the prevalence of ACV-resistant HSV isolates in different patient groups between 1999 and 2002 in the Netherlands.
A total of 542 isolates, 410 HSV-1 and 132 HSV-2, from 496 patients were screened for reduced susceptibility to ACV. A newly developed ELVIRA HSV screening assay was used that allowed a high throughput screening. The genotypic analysis of the HSV thymidine kinase gene was performed to identify resistance-associated mutations.
Thirteen isolates, 8 HSV-1 and 5 HSV-2, from 10 patients (2%) were found resistant to ACV. A single ACV-resistant strain was identified among isolates from 368 immunocompetent patients (0.27%; 95% confidence interval [CI], 0.007%-1.5%), whereas in nine isolates from 128 immunocompromised patients resistant HSV was identified (7%; 95% CI, 3.26%-12.93%). The highest frequency of ACV-resistant HSV was associated with bone marrow transplantation: four patients out of 28 (14.3%) shed resistant virus. In addition, resistant virus was obtained from two HIV-positive patients, one patient with a hematological malignancy and two patients on immunosuppressive drugs. Further testing showed that none of the isolates was resistant to foscarnet. Several new mutations were identified in the thymidine kinase gene of these resistant isolates, and their effect on ACV-resistance is discussed.
Our study shows that the prevalence of ACV resistance is low in immunocompetent patients (0.27%), whereas ACV-resistant HSV infections occur relatively frequently in immunocompromised patients (7%; P < 0.0001). This emphasizes the need for drug susceptibility monitoring of HSV infections in immunocompromised patients with persisting infections despite antiviral therapy.
阿昔洛韦（ACV）广泛且频繁地用于单纯疱疹病毒（HSV）感染的治疗、抑制性治疗和预防，并且可在柜台购买，这可能与HSV耐药性的出现有关。
确定1999年至2002年期间荷兰不同患者群体中对ACV耐药的HSV分离株的流行情况。
对来自496例患者的总共542株分离株（410株HSV-1和132株HSV-2）进行了ACV敏感性降低的筛查。使用了一种新开发的ELVIRA HSV筛查试验，该试验允许进行高通量筛查。对HSV胸苷激酶基因进行基因分型分析以鉴定与耐药相关的突变。
在来自10例患者（2%）的13株分离株中发现对ACV耐药，其中8株HSV-1和5株HSV-2。在368例免疫功能正常的患者的分离株中鉴定出1株对ACV耐药的菌株（0.27%；95%置信区间[CI]，0.007%-1.5%），而在128例免疫功能低下患者的9株分离株中鉴定出耐药的HSV（7%；95%CI，3.26%-12.93%）。对ACV耐药的HSV的最高频率与骨髓移植相关：28例患者中有4例（14.3%）排出耐药病毒。此外，从2例HIV阳性患者、1例血液系统恶性肿瘤患者和2例接受免疫抑制药物治疗的患者中获得了耐药病毒。进一步检测表明，所有分离株均对膦甲酸钠不耐药。在这些耐药分离株的胸苷激酶基因中鉴定出了几个新的突变，并讨论了它们对ACV耐药性的影响。
我们的研究表明，免疫功能正常的患者中ACV耐药的流行率较低（0.27%），而免疫功能低下的患者中ACV耐药的HSV感染相对频繁发生（7%；P<0.0001）。这强调了对尽管接受抗病毒治疗但仍持续感染的免疫功能低下患者的HSV感染进行药物敏感性监测的必要性。
