Service d'Ophtalmologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris-Sud, DHU Vision et Handicaps, 78, rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France; Service d'Immunologie des Infections Virales et des Maladies Auto-immunes (IMVA), 18, Route du Panorama, 92260 Fontenay-aux-Roses, France.
Service de Virologie, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, 47-83 Boulevard de l'Hôpital, 75013 Paris, France; Sorbonne Universités, UPMC Université Paris 6, CR7, CIMI, INSERM U1135, 91, Boulevard de l'Hôpital, 75013, Paris, France.
Antiviral Res. 2017 Oct;146:205-212. doi: 10.1016/j.antiviral.2017.09.013. Epub 2017 Sep 20.
Recurrent herpes simplex keratitis (HSK) is a leading infectious cause of blindness in industrialized countries. Antiviral prophylaxis (AVP) may fail to prevent recurrence of HSK due to viral resistance, inadequate dosing, or poor patient compliance. In this prospective multicenter study, we enrolled immunocompetent patients with recurrent HSK despite AVP. Ocular samples were tested by PCR for herpes simplex virus 1 (HSV-1). HSV-1 drug resistance was assessed with a genotypic assay based on UL23 and UL30 gene sequencing. After curative full dose valacyclovir (VACV) treatment was started, peak and trough acyclovir (ACV) plasma concentrations were measured, and patient compliance to AVP was assessed with a questionnaire. The study sample was comprised of 43 patients. Six (14%) patients were positive for HSV-1 using PCR, of whom 5 (83%) harbored genotypically ACV-resistant (ACV) virus, due to mutations in UL23 (n = 4) or UL30 (n = 1). Disease duration was statistically significantly longer in patients with viral resistance compared to other HSK patients [35.5 ± 23.4 years (range, 6.8-68.4 years) versus 11.1 ± 12.3 years (range, 0.8-56.3 year) respectively; Mann-Whitney p = 0.01)]. While patients were treated with full dose VACV, trough ACV plasma concentrations were below the threshold for ACV sensitivity in 9.5% of cases, and compliance was poor in 5.3% of cases. To summarize, HSV-1 resistance to ACV seems to be a significant cause of failure of prophylaxis in patients with HSK and is associated with longer disease duration. Most PCR-positive samples contained genotypically ACV virus and identification may aid in adapting treatment. Incomplete 24-h drug coverage may also explain some cases of failure of prophylaxis.
复发性单纯疱疹性角膜炎（HSK）是工业化国家致盲的主要传染性病因。由于病毒耐药、剂量不足或患者顺应性差，抗病毒预防（AVP）可能无法预防 HSK 的复发。在这项前瞻性多中心研究中，我们招募了尽管进行了 AVP 但仍反复发作 HSK 的免疫功能正常的患者。通过聚合酶链反应（PCR）对单纯疱疹病毒 1（HSV-1）进行眼部样本检测。通过基于 UL23 和 UL30 基因测序的基因分型检测评估 HSV-1 耐药性。开始进行有疗效的全剂量伐昔洛韦（VACV）治疗后，测量阿昔洛韦（ACV）的峰浓度和谷浓度，并通过问卷评估患者对 AVP 的顺应性。研究样本包括 43 名患者。6 名（14%）患者的 HSV-1 通过 PCR 呈阳性，其中 5 名（83%）患者携带基因上 ACV 耐药（ACV）病毒，原因是 UL23（n=4）或 UL30（n=1）突变。与其他 HSK 患者相比，病毒耐药患者的疾病持续时间明显更长[35.5±23.4 岁（范围，6.8-68.4 岁）与 11.1±12.3 岁（范围，0.8-56.3 岁）；Mann-Whitney p=0.01)]。在患者接受全剂量 VACV 治疗时，9.5%的情况下 ACV 谷浓度低于 ACV 敏感性阈值，5.3%的情况下顺应性差。总之，HSV-1 对 ACV 的耐药性似乎是 HSK 患者预防失败的一个重要原因，与疾病持续时间较长有关。大多数 PCR 阳性样本含有基因上的 ACV 病毒，鉴定可能有助于调整治疗。24 小时药物覆盖不完全也可能解释了一些预防失败的情况。
