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

描述（由申请人提供）：疱疹病毒是在世界各地的人群中发现的传染性病原体。该家族的一个典型成员，单纯疱疹病毒-1 (HSV-1)，引起复发性唇疱疹和发热水疱。作为疱疹病毒的一员，HSV-1以一种被称为潜伏期的静止状态在宿主体内生活。然而，潜伏的HSV-1可以随时重新出现，导致潜在的使人衰弱的疾病。目前对感染HSV-1的患者的长期治疗主要是基于每日多次口服核苷类似物，如阿昔洛韦（ACV）或伐昔洛韦（Valtrex）。然而，这些治疗方案并不理想；它们需要患者高度的依从性来维持药物的抑制水平，因为从胃肠道药物中吸收的药物量很低，被吸收的药物很快就会被肾脏清除。此外，患者依从性差可能导致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给药，可以持续很长时间，甚至几年。因此，ACV被结合到硅胶植入物中，在至少两个月的过程中，以一种可控的方式释放出抑制水平的药物，接近零级动力学。这种干预理论上可以持续3-5年。这些植入物在体外可预防HSV-1的原发性感染和体内的复发性感染，并且具有更广泛的适用性，因为一种类似的抗疱疹药喷昔洛韦（penciclovir）在体外可替代ACV。在这个拨款申请中提出的实验是为了更好地实现这些硅胶植入物在临床环境中的最终效用。首先，这些植入物的工程将通过改变几何形状、聚合物、药物和药物百分比负载来不断改进，以建立更好、更有效的药物释放动力学。其次，将在小鼠模型中探索预防HSV-1再激活复发的相对功效。更长时间的抑制，超过9个月，和改进的植入物设计的效用，将被检查。所有这些实验应该导致改进这些硅- acv植入物的实施。在遥远的将来，我们希望这种长期连续的ACV输送可以进行临床试验，在那里它们可以通过一次植入来预防hsv -1诱导的疾病。

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.