Long-Term Herpes Simplex Virus-1 Suppression by Continuous Acyclovir Delivery

描述（由申请方提供）：疱疹病毒是在全球范围内人群中发现的传染性病原体。这个家族的典型成员，单纯疱疹病毒-1（HSV-1），导致复发性唇疱疹和发热水泡。作为疱疹病毒的一员，HSV-1以称为潜伏期的静止状态终生驻留在宿主体内。然而，潜伏的HSV-1可能随时重新出现，导致潜在的使人衰弱的疾病。目前用于感染HSV-1的患者的长期管理的疗法主要是基于核苷类似物的每日多次口服给药，例如阿昔洛韦（ACV）或伐昔洛韦（Valtrex（R））。然而，这些治疗方案并不理想;它们需要高度的患者依从性以维持药物的抑制水平，因为少量的药物从胃肠道药物中吸收，并且被吸收的药物被肾脏快速清除。此外，患者依从性差可导致HSV-1活跃复制期，这可能导致ACV耐药突变体的出现。对这些患者来说，一个更好的选择是单次服用ACV，可以持续长期，甚至数年。因此，ACV已被组合到硅胶植入物中，该硅胶植入物以受控方式释放抑制水平的药物，具有近零级动力学，持续至少两个月。这种干预理论上可以持续3-5年。这些植入物在体外预防HSV-1的原发性感染和在体内预防复发性感染，并且具有更广泛的适用性，具有类似的抗疱疹药阿昔洛韦代替ACV的体外疗效。 本资助申请中提出的实验旨在更好地实施这些硅胶植入物，以便最终在临床环境中使用。首先，这些植入物的工程将通过改变几何形状、聚合物、药物和药物载量百分比来不断改进，以建立更好和更有效的药物释放动力学。其次，将在鼠模型中探索预防HSV-1再活化复发发作的相对功效。将检查超过9个月的长期抑制和改进的植入物设计的实用性。 所有这些实验应导致这些硅酮-ACV植入物的改进实施。在遥远的将来，我们希望这种长期连续的ACV输送可以导致临床试验，在那里它们可以通过单次植入预防HSV-1诱导的疾病多年。 公共卫生相关性：HSV-1是引起唇疱疹、发热性水泡和特别是免疫功能低下患者的潜在危及生命的并发症的病原体，通常存在于60-80%的美国人口中。对硅酮-阿昔洛韦控释装置的长期、单次植入治疗的研究可能会防止病毒的再活化，减轻患者对这些药物每日多次口服剂量的需要，并防止病毒耐药株的潜在出现。本文提出的额外研究需要继续对这些植入物进行生物学、化学和药理学表征，并期待最终开发这种策略，以对HSV-1诱导的疾病产生重大影响。

DESCRIPTION (provided by applicant): Herpesviruses are infectious agents found worldwide throughout the human population. A paradigmatic member of this family, herpes simplex virus-1 (HSV-1), causes recurrent cold sores and fever blisters. As a member of the herpesviruses, HSV-1 resides within the host for life in a quiescent state called latency. However, latent HSV-1 can reappear at any time, causing potentially debilitating disease. Current therapies for long-term management in patients who are infected with HSV-1 are primarily based on daily multiple oral dosing of nucleoside analogues, such as acyclovir (ACV) or valacyclovir (Valtrex(R)). These therapeutic regimens, though, are not ideal; they require a high degree of patient compliance to maintain suppressive levels of the drug because low quantities of drug are absorbed from the gastrointestinal drug, and the drug that is absorbed is rapidly cleared by the kidneys. Furthermore, poor patient compliance can lead to periods of active HSV-1 replication that may result in the appearance of ACV-resistant mutants. A better option for these patients would be a single administration of ACV that could last for the long-term, even years. ACV has therefore been combined into a silicone implant that releases suppressive levels of the drug in a controlled manner, with near zero-order kinetics, over the course of at least two months. This intervention can theoretically last for 3-5 years. These implants prevent primary infection of HSV-1 in vitro and recurrent infection in vivo, and have broader applicability with proven in vitro efficacy of a similar antiherpetic, penciclovir, in place of ACV. The experiments proposed in this grant application are geared towards better implementation of these silicone implants for eventual utility in a clinical setting. First, engineering of these implants will continuously be improved by altering geometry, polymer, drug, and drug percent load to establish better and more effective drug release kinetics. Second, relative efficacy in preventing recurrent episodes of HSV-1 reactivation will be explored in the murine model. Both longer term suppression, over nine months, and the utility of improved implants design, will be examined. All of these experiments should lead to improved implementation of these silicone-ACV implants. In the distant future, we would expect that such long-term continuous ACV delivery could lead to clinical trials, where they may prevent HSV-1-induced disease for years with a single implantation. PUBLIC HEALTH RELEVANCE: HSV-1, the etiologic agent of cold sores, fever blisters, and potentially life-threatening complications in especially immunocompromised patients, is normally present in 60-80% of the American population. Research in long-term, single implantation therapies with silicone-acyclovir controlled release devices may prevent reactivations of the virus, relieving patients of the need for multiple oral daily doses of these drugs and preventing the potential appearance of drug-resistant strains of the virus. Additional research, proposed herein, is required for continued biological, chemical, and pharmacological characterization of these implants, looking towards ultimate development of this strategy to make a significant impact on HSV-1-induced disease.