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

Margulies, Barry

Abstract

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.