Following initial infection, herpesviruses retreat into a permanent latent state with periodic reactivation resulting in an enhanced likelihood of transmission and clinical disease. The nucleoside analogue acyclovir reduces clinical symptoms of the three human alpha herpesviruses, HSV-1, HSV-2, and VZV. Long-term administration of acyclovir (ACV) can reduce the frequency and severity of reactivation, but its low bioavailability and short half-life require a daily drug regimen. Our lab is working to develop a subcutaneous delivery system to provide long-lasting, sustained release of ACV. Previously, we demonstrated that an implantable silicone (MED-4050) device, impregnated with ACV protected against HSV-1 both in vitro and in vivo. Here, we extend our in vitro observations to include protection against both HSV-2 and VZV. We also demonstrate protection against HSV-2 in vitro using MED-4750, a silicone polymer designed for long-term use in humans. When release of ACV from MED-4750 is quantitated on a daily basis, an initial burst of 5 days is observed, followed by a long period of slow release with near-zero-order kinetics, with an average daily release of 1.3923 ± 0.5908？μg ACV over days 20–60. Development of a slow-release implant has the potential to significantly impact the treatment of human alpha herpesvirus infections. 1. Introduction Herpesviruses are among the most prevalent human pathogens, and most individuals are infected with multiple species by the time they reach adulthood. Following primary infection of the human host, herpesviruses retreat into a latent infectious state that persists for the host’s lifetime. Periodic activation of the latent infection is associated with an enhanced risk of transmission and may be symptomatic, resulting in characteristic lesions, or asymptomatic [1–5]. The human alpha herpesvirus subfamily includes three members: herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), and varicella zoster virus (VZV). All three establish a primary infection in epithelial cells followed by latent infection of neurons. Among residents of the United States of ages 14–49, seroprevalence of HSV-1 is estimated at 57.7% and HSV-2 at 16.2%, while VZV infection was nearly universal prior to introduction of a childhood vaccine in 1995 [6–9]. Herpesviruses can be reactivated by a variety of physical or emotional stressors. Clinical reactivation of alpha herpesviruses is estimated to occur in roughly 10–30% of infected human hosts, although subclinical shedding occurs with greater frequency [8, 10–12]. Herpesvirus outbreaks
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