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^R) 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^R 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病原因。由于病毒抗药性，剂量不足或患者依从性差，抗病毒药物预防（AVP）可能无法防止HSK复发。在这项前瞻性多中心研究中，尽管有AVP，我们仍招募了具有免疫功能的HSK复发患者。通过PCR测试眼样本中的单纯疱疹病毒1（HSV-1）。通过基于UL23和UL30基因测序的基因型分析评估了HSV-1耐药性。开始治疗性全剂量伐昔洛韦（VACV）治疗后，测量阿昔洛韦（ACV）峰值和谷值血浆浓度，并通过问卷调查评估患者对AVP的依从性。

研究样本包括43名患者。使用UL23（n = 4）或UL30（n = 1）的突变，六（14％）名患者使用PCR呈HSV-1阳性，其中五名（83％）携带基因型ACV耐药（ACV ^R）病毒。 。与其他HSK患者相比，病毒耐药患者的病程明显更长[35.5±23.4年（范围6.8–68.4年），而分别为11.1±12.3年（范围0.8-56.3年）；Mann-Whitney p  = 0.01）]。

当患者接受全剂量VACV治疗时，低谷ACV血浆浓度在9.5％的病例中低于ACV敏感性阈值，在5.3％的病例中依从性较差。

综上所述，HSV-1对ACV的耐药性似乎是HSK患者预防性治疗失败的重要原因，并且与疾病持续时间长有关。大多数PCR阳性样品均包含基因型ACV ^R病毒，鉴定可能有助于适应性治疗。不完整的24小时药物覆盖率也可以解释某些预防失败的情况。