Herpesvirus infections cause serious acute and recurrent diseases in a significant proportion of the population worldwide and may increase susceptibility to HIV [4, 20, 24–26]. As a widespread and serious infectious agent for cats, FHV-1 serves as an excellent model for human herpesviruses and their infections . FHV-1 infections are prevalent in the domestic feline population worldwide with up to 97% of cats being seropositive , 80% becoming latently infected , and up to half of some normal populations shedding virus at any time [28, 29]. Infected cats are affected by a variety of cytolytic and immunopathologic ocular and dermatologic syndromes , including herpetic stromal keratitis , and thereby representing an excellent spontaneous model of human herpetic disease. Typically, alphaherpesviral infections in humans are treated using orally or topically administered drugs such as ACV, the first commercially available antiherpetic nucleoside analogue [9, 30, 31]. However, ACV has relatively poor in vitro antiviral efficacy versus FHV-1 , and is poorly bioavailable  and unacceptably toxic  in cats. By contrast, PCV is highly efficacious against FHV-1 in vitro [10–12, 32], and its oral prodrug famciclovir appears to be safe and efficacious when administered to cats [13, 21]. Therefore, while PCV is a suitable drug for treatment of FHV-1-infected cats, current pharmacokinetic data suggest that thrice daily therapy is required [14, 21, 33]. This is impractical in many clinical situations and associated with considerable expense. Therefore, a long-term, steady-state drug delivery system that could be placed in the subconjunctival space and provide constant FHV-1 suppression would be preferred in cats and might provide an alternative to daily oral maintenance therapy with ACV, famciclovir, or valacyclovir in HSV-infected humans. Such subconjunctival steady-state release systems also are likely to maintain consistent drug levels above the minimum inhibitory concentration and thereby prevent development of drug-resistant viral strains while also improving patient compliance. Similar ocular devices such as the non-biodegradable, ganciclovir-containing intravitreal implant Vitrasert [34, 35] are used in humans and bode well for the potential deployment of our subconjunctival silicone-PCV implants in cats. In the present study maximum PCV release during the initial burst phase was 190 μg/day for about 10 days. Assuming a typical adult cat of 3-5 kg body weight, this would result in a systemic dose of 38-65 μg/kg/day, which is more than 1000-fold less than doses that are currently safely administered . Regardless, determination of the in vivo safety and efficacy of these devices placed subconjunctivally in FHV-1infected cats will be an important next step.
Based on the steady-state levels of PCV delivered by these implants in vitro, we expect that a single implant can continuously release drug for 3-17 years. This expectation is centered on the total starting drug quantity encased in a single implant, the initial burst of drug release (Figure 1), the steady-state daily release level in vitro (Figures 1 and 2), and an approximation of expected drug delivery at that rate for about 60% of the drug load; the 60% approximation is derived from calculations for delivery of small molecules from non-biodegradable materials according to Fick and Higuchi [36, 37]. Although our previous work with ACV release from the same silicone compound did not suggest a temperature-dependent release rate within the temperature range tested , it is important to note that drug release experiments in the present study were conducted at 25°C, whereas in vitro efficacy and cytotoxicity studies were conducted at 37°C. Likewise in vivo use of the implants would be at temperatures above 25°C. Therefore, we project that, given the typical lifespan of domestic cats, a single subconjunctival implant (in essence a single dose), via a single surgical intervention, has the potential to treat a cat for its entire lifetime. Over that lifetime PCV would be expected to reduce the frequency and severity of FHV-1 reactivations and to minimize transmission among cats in multicat settings.