Description of the condition
Herpes simplex viruses (HSVs) are ever-present human pathogens with the capability to cause asymptomatic infection or active disease at different end-organs. Two types are known: type 1 (HSV-1), which primarily affects the oropharynx, and type 2 (HSV-2), which primarily affects the genital area. Although HSV-1 typically causes ocular disease, both types can affect the eye (Neumman-Haefelin 1978). HSV has a broad spectrum of ocular manifestations. All structures of the ocular surface including lid margins, conjunctiva and cornea can be affected; but it is herpetic stromal keratitis (HSK) that is of utmost importance because of its deleterious effects on vision.
Primary infection manifests clinically in only 1% to 6% of occasions. It is recurrence of the disease from primary infection, either symptomatic or asymptomatic, that causes significant visual morbidity. Therefore, recurrence physiopathology has drawn the attention of virologists and scientists for a long time. It is well known that recrudescent disease results from HSV reactivation from latency in trigeminal ganglion neurons (Baringer 1973, Margolis 1992, Margolis 2007). However, it has been shown that the cornea can be a reservoir for HSV viral deoxyribonucleic acid (DNA) (Kaye 1991), that the virus can become latent or can persist in an infectious state within the cornea, and that anterograde spread from the trigeminal ganglion is not necessary for recurrent HSK (Polcicova 2005). Furthermore, superinfection with a different strain of HSV may occur (Remeijer 2002).
Latency allows for spontaneous and recurrent reactivation of disease, with clinical sequelae caused by the immunologic response associated with each episode. Stromal keratitis (inflammation of the stromal layer of the cornea), a common ocular manifestation of HSV infection, usually occurs at the ocular site with the highest recurrence risk and is strongly associated with previous HSV infectious episodes (HEDS 2001).
The epidemiology of HSV ocular involvement has been studied extensively (Liesegang 2001). The incidence of ocular HSV per 100,000 people per year has been estimated at 5.9 to 12 in Denmark (Mortensen 1979), compared with 20.7 in Rochester, Minnesota (Liesegang 1989), and 31.5 in France (Labetoulle 2005). The incidence of HSV epithelial keratitis is six times (120 per 100,000 people per year) higher in patients who have undergone corneal transplantation (for non-herpetic corneal disease) (Remeijer 1997). It is estimated that 10% to 12% of people with ocular HSV have bilateral disease (Liesegang 2001).
The main focus of this review will be herpetic stromal keratitis, which is the most important clinical manifestation in recurrent disease. An estimate of the recurrence rate of HSV keratitis is approximately 10% per year (Kaye 2006). Herpetic stromal disease accounts for 2% of initial presentations and 20% to 48% of cases of recurrent herpetic disease. Corneal scarring is seen in 18% to 28%, with a corresponding reduction in visual acuity to less than 20/100 in 3% to 12% of cases and to less than 20/40 in 10% to 25% (Liesegang 1989). Different stimuli have been associated with recurrent disease, such as fever, psychological stress, hormonal changes, and minor ocular trauma, among others (Binder 1977; Dawson 1977; HEDS 2001). Study results on the association between participant age, gender or race, and risk of recurrence have been conflicting; some investigators have reported no association, and others have described increased risk among male participants (Wilhelmus 1981) and members of the younger population (Wishart 1987).
Description of the intervention
Herpes simplex viruses (HSV-1 and HSV-2) belong to the α-herpesvirus family subgroup. Adequate oral treatments available for this viral family include acyclovir and its oral prodrug valacyclovir, penciclovir and its oral prodrug famciclovir, ganciclovir and its oral prodrug valganciclovir, and brivudine. As acyclic nucleoside analogues, these drugs require phosphorylation by the virus-encoded thymidine kinase to exert their antiviral activity; they do not inhibit the thymidine kinase－deficient HSV strains. When this occurs, other types of antivirals such as foscarnet can be used (De Clerq 2004). It has been shown that oral antivirals in a prophylactic schema are safe and efficient in avoiding recurrence of HSV labialis (Spruance 1993) and HSV genitalis (Gupta 2007).
Oral acyclovir has become the standard prophylactic therapy for recurrent HSV stromal keratitis. Some interventional case series (Colin 1993; Simon 1996) and randomized controlled clinical trials (RCTs) (HEDS 1998) have reported that prophylactic doses of acyclovir reduce the recurrence rate of HSV keratitis. Usually, the prophylactic dose of acyclovir is 800 mg a day in divided doses, 400 mg twice a day, or 200 mg four times daily, over varying periods of time (ranging from 1 month to 62 months). Oral valacyclovir, the acyclovir prodrug, is known to increase the bioavailability of acyclovir three to five times. The reported prophylactic dose of valacyclovir is 500 mg once a day, which provides a benefit regarding patient compliance and convenience when compared with multiple daily doses.
How the intervention might work
Although further knowledge of the pathogenesis of HSV stromal keratitis is needed, two main factors have been implicated: host immune response and viral replication. Antiviral therapy addresses viral replication by inhibiting viral DNA synthesis in virally infected cells.
Nucleoside analogues, such as acyclovir, have in vitro and in vivo inhibitory activity against HSV-1 and HSV-2, as well as against varicella-zoster virus (VZV). Acyclovir is highly selective against herpes simplex viruses in that it binds to enzymes encoded by these viruses, specifically thymidine kinase (TK) (De Clerq 2004). This viral enzyme, TK, converts acyclovir to acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted to diphosphate by cellular guanylate kinase and to triphosphate by various cellular enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA in three ways: (1) through competitive inhibition of viral DNA polymerase; (2) by incorporation into and termination of the growing viral DNA chain; and (3) via inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK (King 1988). In the treatment of epithelial HSV keratitis, purine nucleoside analogues have shown superiority over pyrimidine analogues, specifically, acyclovir and trifluridine were shown to be more effective in a systematic review of treatments for epithelial HSV keratitis (Wilhelmus 2010).
It has been reported that nucleoside analogues have no effect in latent HSV, but reactivation is necessary for completion of the HSV viral cycle; targeting reactivation prevents spread of the virus and disease recurrence. Studies reported that reactivation is an isolated event that is limited to a few neurons in sensory ganglia. The frequency with which an individual experiences reactivation ranges from 0 to 12 episodes per year and is positively correlated with the number of trigeminal ganglia latently infected (Sawtell 1998). Also, a high proportion of human subjects have asymptomatic shedding of HSV-1 DNA, and approximately 90% of human trigeminal ganglia contain HSV-1 DNA (Hill 2008). Suppression of asymptomatic shedding is one way that transmission of the virus might be blocked.
In vitro studies have shown that acyclovir preferentially affects cells that have been infected by HSV, and, unlike other antivirals, acyclovir has relatively little effect on normal, uninfected cells. Therefore, its toxicity is minimal. An important toxic effect of acyclovir is its potential to cause obstructive nephropathy. The drug is excreted primarily by the kidney; therefore, smaller doses may be required in patients with decreased kidney function (Lietman 1982). Valacyclovir has been reported to produce mild adverse effects. However, neurotoxicity has been reported among elderly and renally impaired patients (Asahi 2009).
It is important to note that a relatively high prevalence of acyclovir-resistant corneal HSV-1 has been reported in immunocompetent patients with HSV keratitis (Duan 2008).
Why it is important to do this review
This review is needed so the reader can better understand the potential benefits and harms of using oral antivirals for the prevention of recurrent HSV stromal keratitis.