Emerging drugs for the treatment of herpetic keratitis

Abstract

Introduction:

Herpes simplex keratitis stands as a prominent factor contributing to infectious blindness among developed nations. On a global scale, over 60% of the population tests positive for herpes simplex virus type-1 (HSV-1). Despite these statistics, there is currently no vaccine available for the virus. Moreover, the conventional nucleoside drugs prescribed to patients are proving ineffective in addressing issues related to drug resistance, recurrence, latency, and the escalating risk of vision loss. Hence, it is imperative to continually explore all potential avenues to restrict the virus. This review article centers on the present treatment methods for HSV-1 keratitis (HSK), highlighting the ongoing clinical trials. It delves into the emerging drugs, their mode-of-action and future therapeutics.

Areas covered:

The review focuses on the significance of a variety of small molecules targeting HSV-1 lifecycle at multiple steps. Peer-reviewed articles and abstracts were searched in MEDLINE, PubMed, Embase, and clinical trial websites.

Expert opinion:

The exploration of small molecules that target specific pathways within the herpes lifecycle holds the potential for substantial impact on the antiviral pharmaceutical market. Simultaneously, the pursuit of disease-specific biomarkers has the capacity to usher in a transformative era in diagnostics within the field.

1. Background

The HSV includes two closely related serotypes, HSV-1 (see Figure 1) and HSV-2, both capable of causing severe diseases in humans. HSV-1 is predominantly transmitted via oral contact and secretions, giving rise to oral-facial herpes, with the potential for transmission to the genital tract and subsequent development of genital herpes [1,2]. About 3,583.5 million people, out of the worldwide population of 5,632.6 million aged 0–49 years, were estimated to have oral infection with HSV type 1, leading to a prevalence of 63.6% [1]. The incidence of oral HSV-1 was highest in the WHO Southeast Asia Region, followed by the Western Pacific Region. Genital HSV type 1 infection affected an estimated 192.0 million individuals aged 15–49 worldwide, corresponding to a prevalence of 5.2%. The Americas region had the highest count of individuals with genital HSV type 1, with the European region following closely behind. Although seroprevalence differs with highest in Greenland (98%) followed by Italy (81–93%) and Germany (87%) [3]. HSV-2, in contrast, is almost exclusively transmitted through sexual routes, leading to genital infections [1,4]. The prevalence of HSV type 2 in the global population, encompassing 3,735.6 million individuals aged 15–49 years, was estimated to be 13.2%. Noteworthy, the African region exhibited the highest prevalence, followed by the region of the Americas [5].

Figure 1.

Structure of HSV-1.

HSV-1, upon oral transmission, establishes latency within the trigeminal ganglion and is correlated with manifestations encompassing orolabial, ocular, and neurological domains. HSV-1 stands out as the overwhelmingly causative pathogen for eye infections [4,6,7]. Ocular infection presents a common challenge in primary care and remains a substantial healthcare issue. According to the guidelines provided by the American Academy of Ophthalmology (AAO), HSV-1 keratitis (HSK) stands out as the predominant contributor to infectious blindness on a global scale [8]. HSK is defined as an inflammatory corneal condition triggered by an infection with the HSV [9]. The worldwide occurrence of herpetic keratitis is approximately 1.5 million cases annually, resulting in 40,000 new cases characterized by significant visual impairment due to corneal scarring and opacification [10,11].

HSK presents diverse manifestations, and careful examination reveals distinct involvement of individual corneal layers (epithelium, stroma, and endothelium). Data also suggests that HSK, impacting various layers of the cornea, involves functionally disparate processes of pathogenesis [12]. In HSV-linked dendritic epithelial keratitis, the source lies in the direct infection of corneal epithelial cells, while HSV stromal keratitis is primarily linked to immune mechanisms. The careful choice of therapeutic intervention for a patient with HSV keratitis is critically dependent on accurately delineating the nature of the keratitis. For HSV dendritic epithelial keratitis, antiviral therapy is essential, while HSV stromal keratitis typically requires a combination of antiviral and topical corticosteroid therapy.

The primary treatment approach for herpes epithelial keratitis, as recommended by the American Academy of Ophthalmology (AAO), involves the use of topical formulations containing antiviral agents [8]. Certainly, administration of nucleoside analogs such as acyclovir (ACV) and in particular ganciclovir, and trifluorothymidine or trifluridine (TFT) stand out as the preferred options for ocular treatment due to their effective results. However, the current antiviral agents have several drawbacks. The efficacy of these antiviral formulations faces challenges due to factors like drug resistance, and the absence of a controlled drug release profile [13]. The use of oral antiviral drugs presents an alternative treatment option; however, administering these drugs at high doses can lead to undesirable systemic toxicities in patients with other complications. Therefore, there is a need to harness pharmaceutical technology to create a more efficient, sustained release, efficient against resistant strains and affordable antiviral formulations. This is essential to impede disease progression and further explore their potential roles in preventing HSK Following the initial corneal episode, recurrences of HSK may manifest in up to 63% of patients [14], with 51% of them encountering more than 2 relapses over a 15-year follow-up period [15]. Repeated relapses can ultimately lead to visual dysfunction, characterized by optical irregularities, corneal opacification, and/or neovascularization [16]. After 10 years of disease progression, 10% of affected eyes may exhibit vision below 20/100. Furthermore, recurrent HSK induces persistent alterations in the ocular surface and trigeminal nerve, eventually resulting in conditions such as dry eye and neurotrophic keratopathy [17]. Approximately one HSK patient out of ten develop blindness after 20 years of disease evolution [18]. In summary, HSK stands as a primary reason for infection-linked blindness in industrialized countries and significantly diminishes the quality of life for a majority of patients [19]. Despite being highly prevalent, HSK continues to pose challenges in both diagnosis and treatment [20,21]. This review article aims to explore the potential and limitations of existing treatments, drugs, and therapies currently under development for the treatment of HSK [22].

2. Medical need

The initial treatment option for addressing herpetic epithelial keratitis involves selecting between: Ganciclovir or TFT that are the two FDA-approved topical antiviral agents. Ganciclovir treatment is favored in cases where the ulcer is unresponsive to TFT, when prolonged therapy is necessary (as TFT treatment is restricted to 21 days), for individuals who are unable to administer eye drops every two hours during waking hours, or for children aged 2–6. TFT treatment is the preferred choice for patients who use contact lenses, individuals with ulcers resistant to ganciclovir, and those who prioritize a more economical option [8]. Epithelial keratitis should ideally be resolved within 2 to a maximum of 3 weeks when treated with topical antivirals administered five times daily. However, the primary challenge for clinicians lies in addressing recurrent HSK, given that the sole recommended prophylactic strategy is the comprehensive treatment of antiviral prophylaxis (AVP) [23]. The outcomes of the HEDS, conducted in the United States, demonstrated that the administration of 400 mg of ACV twice daily led to a 2-fold decrease in the recurrence of occurrences [23]. Considering its bioequivalence, a daily dose of 500 mg valacyclovir (VACV), which is an oral prodrug of ACV, can serve as a substitute for ACV in this particular context [24]. Nevertheless, following the recommended regimen, neither ACV nor VACV achieves a complete blockage of all clinical recurrences, nor do they preclude shedding of virus through tears between relapses [25]. Of greater concern, as noted in various other chronic viral diseases, the prolonged use of AVP is linked to the potential development of antiviral drug resistance, particularly ACV-resistant (ACVR) HSV-1 isolates [26–28]. Since VACV is converted into ACV, both drugs share similar modes of action. These antiviral agents exert their action by targeting the viral DNA polymerase (DNA pol) subsequent to the essential initial phosphorylation process. This pivotal step, crucial for their effectiveness, is exclusively achievable through the viral thymidine kinase (TK). Hence, resistance to ACV may arise from the selection of strains carrying mutations in either TK or DNA polymerase, adversely affecting the antiviral effectiveness of both ACV and VACV [29]. In 95% cases, resistance to ACV is linked to a mutation in the TK gene, as this enzyme is non-essential for viral replication, unlike viral DNA polymerase, which rarely contributes to resistance. Strains resistant to ACV typically show cross-resistance to other TK-dependent drugs like penciclovir and famciclovir. Foscarnet or cidofovir can manage resistant infections, but they’re more toxic than ACV. While these drugs inhibit viral DNA polymerase and are effective against most ACV-resistant HSV strains, mutations in DNA polymerase resulting in ACV resistance may lead to cross-resistance to these alternative [30]Foscarnet, an FDA-approved medication, serves as an alternative treatment for HSV infections in AIDS and immunocompromised individuals who cannot tolerate ganciclovir. Its mode of action involves the direct inhibition of viral DNA polymerase, a key enzyme essential for viral DNA replication [31,32]*****. Complications associated with HSK also vary depending on multiple factors, including differences in the general susceptibility of the host, alterations or stress in the immune system, and variations in the local susceptibility of host tissue. The substantial variations among individuals necessitate a more comprehensive treatment approach rather than only prescribing nucleoside analogs. In the uncommon occurrence of antiviral resistance resulting from DNA pol mutation, there is currently no approved cure for HSK. In this scenario, the use of interferon eye drops may be contemplated to boost the resident immune response and counteract viral replication [33]. Similarly, in occasions of strains with mutations in both thymidine kinase (TK) or DNA polymerase (DNA pol), there is presently no permitted alternative for enduring antiviral prophylaxis (AVP). Researchers have proposed the possibility of utilizing long-term topical ganciclovir (GCV) for cytomegalovirus uveitis/endotheliitis [34], but its tolerance and effectiveness in the context of HSK remain unestablished. Currently, there are no vaccines approved by any drug administering agency like FDA, National Institute for Health and Clinical Excellence (NICE) (www.evidence.nhs.uk) and the European Medicines Agency (EMA) (www.ema.europa.eu/ema/) for precluding herpes simplex infection or relapse. Furthermore, there have been restricted clinical trials assessing the efficacy of vaccines in preventing ocular HSV infections, whereas various research reports have concentrated on the effectiveness of vaccines in preventing genital herpes infections.

3. Existing treatment

It is fundamental that the accurate classification of any illness is crucial for appropriate therapeutic intervention. The goal of a disease classification system for a complex disorder should be to clearly define distinct disease forms in a manner that simplifies classification for healthcare providers and directly guides evidence-based treatment algorithms. Otherwise, it becomes problematic when imprecise or confusing terminology is employed to characterize or classify the different forms [35]. The appropriate selection of therapeutic intervention for a patient with HSK is crucially reliant on the accurate characterization of the keratitis. Although some terms employed to categorize HSK might lack precision and comprehensive description. Terms such as ‘immune stromal,’ ‘necrotizing,’ and ‘disciform’ are commonly utilized in the published literature and among ophthalmologists to characterize HSV keratitis, but they present challenges due to potential imprecision and lack of comprehensive description [36,37]. The utilization of the term ‘immune stromal’ keratitis suggests that other forms of HSV stromal keratitis do not engage the immune system. Whereas all types of stromal keratitis involve some degree of immune disposition. Likewise, a cornea presumed to have HSV necrotizing keratitis may not consistently display genuine necrosis. Referring to endothelial keratitis as ‘Herpes simplex virus disciform keratitis’ overlooks instances where the involvement extends to the entire corneal endothelium, specifically in cases of diffuse engagement. To further complicate the situation, the diagnosis of HSK is predominantly reliant on the clinical appearance of the cornea. HSV infection of the corneal epithelium can be confirmed through viral culture, antigen detection test, PCR (viral proteins or biomarkers) [38], antigen test, antibody test, Goldmann – Witmer coefficient (GWC) test [39], and specified IgG in lacrimal fluid [40]. However, PCR testing is widely used and straightforward, it can be expensive for some people in low income countries. Currently, there are no quick, office-based diagnostic tests available for HSV keratitis involving the corneal stroma and endothelium.

Thus, a straightforward classification system for HSV keratitis, founded on the anatomical localization of the primary site of corneal involvement, directly fulfills the requirement for consistent and easily applicable descriptors of the disorder. The unique characteristics of the HSK manifestations can be distinctly identified through a thorough examination involving the assessment of the individual corneal layers, encompassing the epithelium, stroma, and endothelium (see Table 1). Data also indicates that HSV keratitis impacting various corneal layers involves functionally distinct mechanisms of pathogenesis. For instance, HSV dendritic epithelial keratitis stems from the direct infection of corneal epithelial cells, whereas HSV stromal keratitis is principally linked to immune mechanisms. Treatment for HSV dendritic epithelial keratitis involves antiviral therapy, while HSV stromal keratitis typically requires a combination of antiviral and topical corticosteroid therapy. For instance, both HSV dendritic and HSV geographic keratitis are classified as HSV epithelial keratitis because they both indicate epithelial infection by HSV and respond to the same antiviral therapies. The involvement of the stroma by HSV can be discerned from the epithelial and endothelial forms using slit-lamp biomicroscope. The application of fluorescein dye helps distinguish stromal keratitis with epithelial ulceration from cases without ulceration. This uncomplicated test guides the practitioner in balancing antiviral and topical corticosteroid therapy. The existence of stromal and epithelial edema with inflammation at the corneal endothelium level, indicated by keratitis precipitates in the absence of substantial anterior uveitis, is categorized as endothelial keratitis. It responds promptly to the appropriate combination of antiviral and topical corticosteroid therapy.

Table 1.

Classification system for HSV-1 keratitis.

rS.No.	Corneal Layer	Nomenclature	Alternate Terms
1.	Epithelium	HSV epithelial keratitis	Dendritic epithelial ulcer
			Geographic epithelial ulcer
2.	Stroma	HSV stromal keratitis without ulceration	Non-necrotizing keratitis, Interstitial keratitis, Immune stromal keratitis
		HSV stromal keratitis with ulceration	Necrotizing keratitis
3.	Endothelium	HSV endothelial keratitis	Disciform keratitis

3.1. Treatment approvals against HSV epithelial keratitis

The ideal approach for treating HSV epithelial keratitis involves antiviral agents without the addition of topical corticosteroids in the initial management phase. In the United States, two topical antiviral agents, TFT and ganciclovir, and three systemic antiviral agents, ACV [41], famciclovir [42], and VACV [43] are available and commonly employed for the treatment of HSV epithelial keratitis. The subsequent treatment guidelines provide recommendations for the antiviral agents accessible in the United States, incorporating topical ACV, despite its lack of FDA approval as a topical ophthalmic agent, but widespread usage outside the U.S. (see Table 2). Although not approved by U.S. topical ACV is preferred over any other nucleoside analog in many countries. Between one and 28 studies were available to compare the relative effectiveness of antiviral agents, interferon, and corneal debridement in the treatment of HSV epithelial keratitis. The authors showed that no significant differences in healing emerged among trifluridine, acyclovir, brivudine, and foscarnet. Ganciclovir is equivalent or less effective than acyclovir [33].

Table 2.

Summary of treatment recommendations for HSK [7].

S.No.	HSK manifestation	Drug	Regimen
1.	Epithelial Keratitis	Acyclovir/	400 mg 3–5 times daily for 7–10 days
	(Dendritic)	Valacyclovir/	500 mg twice daily for 7–10 days
		Famciclovir/	250 mg twice daily for 7–10 days
		Trifluridine ophthalmic solution/	1%–1 drop into eye for 9 times daily for 7 days.
		Ganciclovir ophthalmic solution	0.15% 1 drop into eye for 5 times daily until healed
2.	Epithelial Keratitis	Acyclovir/	800 mg 5 times daily for 14–21 days
	(Geographic)	Valacyclovir/	1 g 3 times daily for 14–21 days
		Famciclovir/	500 mg twice daily for 14–21 days
		Trifluridine ophthalmic solution/	1%–1 drop into eye for 9 times daily for 7 days.
		Ganciclovir ophthalmic solution	0.15% 1 drop into eye for 5 times daily until healed
3.	Stromal keratitis	Prednisolone plus	1% :6–8% times daily tapered over 10 weeks.
	(Without epithelial ulceration)	Acyclovir/	400 mg 3–5 times daily for 7–10 days
		Valacyclovir/	500 mg twice daily for 7–10 days
		Famciclovir	250 mg twice daily for 7–10 days
4.	Stromal keratitis	Prednisolone plus	1% twice daily
	(With epithelial ulceration)	Acyclovir/	800 mg 3–5 times daily for 7–10 days
		Valacyclovir/	1 g 3 times daily for 7–10 days
		Famciclovir	500 mg twice daily for 7–10 days
5.	Endothelial keratitis	Prednisolone plus	1% :6–8% times daily
		Acyclovir/	400 mg 3–5 times daily
		Valacyclovir/	500 mg twice daily
		Famciclovir	250 mg twice daily

3.1.1. Topical antiviral agent

Topical TFT solution and ganciclovir gel are both deemed safe and efficacious, holding approval for treating HSV epithelial keratitis. Although no clinical trials have directly compared topical ganciclovir gel to TFT solution, various trials have compared each of them individually to topical ACV ointment. Three randomized clinical trials with a double-blind design, comparing TFT ointment to ACV ointment, have consistently found that the efficacy of these antiviral agents is comparable. Both TFT and ACV ointments demonstrate high effectiveness in treating HSV epithelial keratitis. Likewise, three unmasked randomized clinical trials have determined that there is no significant difference in efficacy between ganciclovir gel and ACV ointment for the treatment of HSV epithelial keratitis. Therefore, by regarding ACV ointment as a proxy, it can be inferred that topical ganciclovir [44] and TFT exhibit roughly equivalent efficacy in treating HSV epithelial keratitis. Although both topical antiviral agents seem effective as treatment options, selecting one over the other may offer advantages in specific cases.

3.1.2. Oral antiviral agents

While oral antiviral agents seem to be safe and effective in treating HSV epithelial keratitis, it’s worth noting that they are not specifically FDA approved for this condition. Three oral antiviral agents (ACV, VACV, and famciclovir) exhibit standard safety and recognized efficacy for HSV infections [45–47]. Studies indicate that the efficacy of oral ACV at a dosage of 400 mg five times daily is comparable to that of topical ACV ointment administered five times daily in the treatment of HSV epithelial keratitis. Nevertheless, caution should be exercised when using oral antiviral agents, especially in elderly patients (>65 years old) and those with renal impairment. This is due to the potential nephrotoxicity associated with all three oral antiviral agents.

3.1.3. Debridement

While the clinical use of debridement in the context of HSV epithelial keratitis has a long history, the available literature strongly suggests that debridement alone is insufficient as a treatment for HSV epithelial keratitis [48]. One of the research findings indicated that debridement alone was statistically less effective in terms of the number of healed HSV ulcers compared to either using an antiviral alone or combining an antiviral with debridement. Further, no study provides evidence to support the addition of debridement to use of an antiviral agent.

3.1.4. Interferon

Even though topical formulations of interferon α2B show antiviral activity against HSV epithelial keratitis, the clinical application of topical interferon is still considered experimental [49]. Additionally, its usage is restricted by the availability of adequately concentrated interferon in the U.S. market, and it lacks FDA, NICE or EMA approval.

3.2. Approved treatment for HSV stromal keratitis

The recommended treatment for HSV stromal keratitis involves the use of a topical corticosteroid in combination with an oral antiviral agent for a minimum of ten weeks [50]. The adjustment of the balance between antiviral and corticosteroid therapy should be based on the presence or absence of epithelial ulceration.

There are multiple topical corticosteroid options available in the market such as Fluorometholone 0.1% ophthalmic solution, Rimexolone 1% ophthalmic suspension, Prednisolone Sodium Phosphate 1% ophthalmic solution, Prednisolone Acetate 1% ophthalmic suspension or Difluprednate 0.05% ophthalmic emulsion. In the case of HSV stromal keratitis, oral antiviral agents are favored over the two available topical antiviral agents in the United States, namely TFT solution and ganciclovir ophthalmic gel. Prolonged use of topical TFT solution leads to toxic keratoconjunctivitis, allergic conjunctivitis, and punctal stenosis [51,52]. The extended use of topical ganciclovir ophthalmic gel lacks sufficient study, and neither topical TFT nor ganciclovir demonstrates satisfactory penetration of the corneal stroma [44]. The study led by the HEDS group showed that patients undergoing treatment with a ten-week taper of topical prednisolone along with TFT solution experienced a quicker resolution and were less likely to fail treatment as compared to those treated with TFT solution alone. Therefore, the recommended approach for treating HSV stromal keratitis involves the use of oral antiviral agents along with a topical corticosteroid.

Additionally, a clinical trial indicated that patients treated with topical cyclosporine emulsion, with concentrations ranging from 0.05% to 0.4%, did not show an elevation in intraocular pressure. This suggests that topical cyclosporine could be beneficial as an adjunct in the treatment of HSV stromal keratitis, with the potential to minimize the use of steroids. Additionally, a treatment duration exceeding ten weeks is advised based on the findings of two double-blind, placebo-controlled randomized clinical trials conducted by the HEDS group. These trials revealed remarkably high rates of treatment failure at six weeks after a ten-week prednisolone taper (50% [53] and 75% [54]), suggesting that the initial ten-week treatment in earlier clinical studies might have been insufficient. In general, oral antiviral agents are preferred over topical antiviral agents due to their favorable safety profile and superior penetration into the cornea. The optimal treatment for HSV keratitis with epithelial ulceration has not been sufficiently examined in randomized clinical trials. However, existing evidence indicates a potential role for therapeutic doses of oral antiviral agents combined with the cautious application of topical corticosteroids.

3.3. Approved treatments for HSV endothelial infections

Endothelial keratitis caused by the HSV is relatively rare and typically manifests independently of other forms of HSV keratitis [55,56]. The recommended treatment for HSV endothelial keratitis involves the use of a topical corticosteroid in combination with an oral antiviral agent. Limited studies are available to provide guidance for treatment recommendations regarding HSV endothelial keratitis. A group compared the combination of topical ACV 3% ointment and topical beta-methasone (at 0.1% or 0.01%) with ACV ointment alone. The conclusions drawn from these randomized double-blind trials were consistent: in cases of HSV endothelial keratitis, the use of a topical corticosteroid agent in combination with a topical antiviral agent resulted in a faster response and significantly fewer treatment failures compared to using a topical antiviral agent alone [55,57–59]. Additionally, a study indicated that the group receiving oral ACV exhibited a significantly faster resolution of lacrimation and greater improvement in visual acuity. An oral antiviral agent is recommended to ensure sufficient corneal penetration, as the two available topical antiviral agents in the U.S., TFT and ganciclovir, do not achieve satisfactory corneal penetration in the treatment of HSV endothelial keratitis.

3.4. Therapy for complex cases

Managing HSV keratitis in children and individuals with atopic conditions may pose relative challenges and could necessitate relatively higher doses of oral antivirals. The simultaneous occurrence of HSV epithelial keratitis with stromal or endothelial keratitis is rare and may, on occasion, necessitate the concurrent use of both antiviral and corticosteroid therapy. However, as a general guideline, it is advisable to refrain from or minimize the use of topical corticosteroids in the context of HSV epithelial keratitis.

Typically, patients with renal insufficiency may necessitate reduced doses of oral antivirals and longer intervals between administrations. The dosing of oral antivirals in patients with renal insufficiency should be coordinated in consultation with a nephrologist.

4. Scientific rationale

The primary treatment for HSK involves the use of antiviral medications like ACV and its analogs. In addition, corticosteroids may be prescribed in conjunction with antivirals based on the diagnosis. Below we discuss the scientific rationale supporting their usage against ocular herpes.

4.1. Nucleoside analogs

Which have been in clinical use for nearly five decades, have emerged as fundamental components of treatment for individuals dealing with viral infections.

The approval of several additional drugs in the last decade highlights the enduring robust potential of this drug family [60]. Nucleoside and nucleotide analogs are artificially created, chemically modified compounds designed to emulate their natural physiological counterparts. Their purpose is to leverage cellular metabolism and be incorporated into DNA and RNA, thereby hindering cellular division and impeding viral replication. Apart from being integrated into nucleic acids, nucleoside and nucleotide analogs have the capability to interact with and impede crucial enzymes. These enzymes comprise human and viral polymerases, encompassing DNA-dependent DNA polymerases, RNA-dependent DNA polymerases, and RNA-dependent RNA polymerases. Moreover, their impact extends to kinases, ribonucleotide reductase, DNA methyltransferases, purine and pyrimidine nucleoside phosphorylase, as well as thymidylate synthase. The groundbreaking contributions of Gertrude B. Elion and George H. Hitchings paved the way for the development of agents like the nucleobase 6-mercaptopurine and the antiviral nucleoside analog ACV [61,62]. The continued pioneering efforts of Erik De Clercq and Antonín Holý played a crucial role in the development of numerous nucleoside and nucleotide analogs that are presently in clinical use [63,64]. Nucleoside and nucleotide analogs utilized in therapy currently enter cells via specific nucleoside transporters [65,66]. There is an increasing body of evidence suggesting that organic anion or cation transporters, as well as peptide transporters, play a role in the cellular uptake of specific antiviral analogs [67]. Within the cells, these drugs undergo subsequent phosphorylation by a nucleoside kinase and a nucleoside monophosphate kinase [68]. The final phosphorylation step is then catalyzed by either nucleoside diphosphate kinase, creatine kinase, or 3-phosphoglycerate kinase. This process results in the accumulation of di- and triphosphorylated nucleoside analogs within virus-infected cells. In cells infected by certain DNA viruses, like those infected by herpesvirus, the initial and second phosphorylation steps of thymidine are additionally executed by a thymidine kinase that is encoded by the virus itself [69].

Thymidine kinases from herpesviruses exhibit a broader substrate specificity compared to their mammalian counterparts. This distinction in substrate specificity serves as the foundation for the selectivity of nucleoside and nucleotide analogs as anti-herpes molecules. The active forms of these drugs are mono-, di-, and triphosphorylated nucleoside analog. They function by inhibiting intracellular enzymes, including viral or human polymerases and ribonucleotide reductase. Additionally, they act by being incorporated into newly synthesized DNA and RNA. The integration of nucleoside or nucleotide analogs into DNA can lead to various outcomes, including the termination of chain elongation, the accumulation of mutations in viral progeny, or the induction of apoptosis [60].

4.2. Corticosteroids

Corticosteroids play a crucial and life-saving role in therapy, especially when anti-inflammatory or immunosuppressive effects are required [70]. Therefore, they are commonly used in combination with antivirals for patients experiencing stromal keratitis. Corticosteroids impact multiple steps in the inflammatory pathway, enhancing their effectiveness and utility. The ability of HSV-1 to periodically reactivate from latency results in virus transmission and recurrent disease [71]. The incidence of reactivation from latency is increased by chronic or acute stress. Stress increases the levels of corticosteroids, which bind and activate the glucocorticoid receptor (GR).

To elicit an impact, the steroid molecule permeates cell membranes and attaches to glucocorticoid receptors, leading to a conformational alteration in the receptor. The complex of the receptor with glucocorticoid can translocate to the cell nucleus, where it undergoes dimerization and binds to glucocorticoid response elements. Genes associated with glucocorticoid response elements can either suppress or stimulate transcription, leading to ribonucleic acid and protein synthesis. These effects are referred to as transrepression or trans-activation respectively. Ultimately, these agents hinder transcription factors that govern the synthesis of pro-inflammatory mediators, affecting macrophages, eosinophils, lymphocytes, mast cells, and dendritic cells [72]. Another vital effect is the inhibition of phospholipase A2, which is accountable for the production of diverse inflammatory mediators. Corticosteroids suppress the genes that are accountable for the expression of cyclooxygenase-2, inducible nitric oxide synthase, and pro-inflammatory cytokines, such as tumor necrosis factor alpha and various interleukins [73]. On the contrary, corticosteroids trigger the upregulation of lipocortin and annexin A1, a protein that diminishes prostaglandin and leukotriene synthesis. Additionally, it inhibits cyclooxygenase-2 activity and reduces neutrophil migration to inflammatory sites. As corticosteroid action takes place intracellularly, the effects endure even in the absence of detectable levels in the plasma.

5. Competitive environment: a review of drugs in phase II and III development

There are multiple drugs under clinical trial for treating HSK (see Table 3) which are discussed in detail as follows.

Table 3.

Competitive environment of emerging drugs for herpetic keratitis treatment in phases I, II, III, and IV trials.

S. No.	Compound	Company/Location	Therapeutic Class	Stage of development	Mechanism of action	Indication	NCT no.
1	Pranoprofen	Peking Union Medical College	NSAIDs Drug	Unknown	It hinders the activity of both COX-1 and COX-2 enzymes, preventing the conversion of arachidonic acid into eicosanoids and thereby diminishing the synthesis of prostaglandins.	There are reports indicating that eye drops containing NSAIDs such as pranoprofen and bromfenac can inhibit the reactivation of HSV-1 and decrease inflammatory responses both in vitro and in vivo.	NCT03013959
2	Prednisolone Phosphate and Acyclovir	National Eye Institute (NEI)	Drug	Phase 3	To investigate the effectiveness of combining oral antiviral agents with the treatment of topical corticosteroids and topical antivirals.	HSV stromal keratitis and iridocyclitis.	NCT00000138
3	Acyclovir	National Eye Institute (NEI)	Drug	Phase 3	Acyclovir triphosphate competitively hinders the activity of viral DNA polymerase by functioning as an analogue to deoxyguanosine triphosphate (dGTP).	To investigate the impact of external factors, such as UV light or corneal trauma, as well as behavioral factors in triggering recurrent episodes of ocular HSV.	NCT00000139
4	Cyclosporine A 0.05% eye drops	Farwaniya Hospital	Drug	Phase 4	Cyclosporine A, as a calcineurin inhibitor, modulates the immune system by impeding T cell infiltration, activation, and the subsequent release of inflammatory cytokines.	To assess the additional impact of using topical cyclosporine A 0.05% eye drops in conjunction with prednisolone eye drops, as compared to the use of prednisolone acetate 1% eye drops alone, in the treatment of herpetic stromal keratitis.	NCT05720715
5	Oral acyclovir and valacyclovir	NYU Langone Health	Drug	Phase 4	Valacyclovir undergoes conversion to acyclovir, which, in turn, is transformed into its triphosphate form known as acyclovir triphosphate (ACV-TP). ACV-TP competitively inhibits the viral DNA polymerase, integrates into the growing viral DNA chain causing termination, and inactivates the viral DNA polymerase.	A randomized trial evaluating the use of topical corticosteroids in combination with oral antivirals for preventing the recurrence of HSV keratitis.	NCT03626376
6	Nexagon	University of California, San Francisco	Drug	Phase 2	Nexagon is an unaltered antisense oligonucleotide with the potential to restore ocular homeostasis. It achieves this by downregulating the transcription of the pathogenetically elevated connexin43 (Cx43) protein, typically associated with direct cell-to-cell communication through gap junctions, thereby preventing unregulated inflammation associated with primary congenital glaucoma (PCED).	To assess the effectiveness and safety of Nexagon in individuals experiencing PED following corneal epithelial debridement associated with diabetic vitrectomy surgery, HSV keratitis, HZV keratitis, corneal burns, post-PRK, or post-corneal transplant surgery.	NCT01165450
7	Pritelivir	AiCuris Anti-infective Cures AG	Drug	Phase 3	It is a helicase-primase complex inhibitor that prevents de novo synthesis of viral DNA.	It is a comparative trial to evaluate the effectiveness and safety in immunocompromised subjects with acyclovir resistant or acyclovir susceptible mucocutaneous HSV infection	NCT03073967
8	Amenamevir (ASP2151)	Maruho Co., Ltd.	Drug	Phase 3	It is a helicase-primase complex inhibitor that prevents de novo synthesis of viral DNA.	It is a study to evaluate the efficacy and safety of ASP2151 in patients with herpes simplex (labial/facial herpes or recurrent genital herpes)	NCT01959295

5.1. Pranoprofen

Profens are non-steroidal anti-inflammatory drugs (NSAIDs) belonging to the arylalkanoic acid class. They are applied topically to the eyes, notably for the treatment of chronic allergic conjunctivitis and as an anti-inflammatory and analgesic agent following strabismus surgery. This category encompasses a diverse range of drugs, including but not limited to ibuprofen, ketoprofen, naproxen, fenoprofen, flurbiprofen, carprofen, suprofen, benoxaprofen, pranoprofen, and tiaprofenic acid. Pranoprofen (PPF) is extensively utilized in clinical ophthalmology among numerous ophthalmic drugs. The application of topical Pranoprofen (PPF) at 0.1% concentration is a common practice in treating postoperative inflammation and postoperative pain. This is attributed to its properties that include reducing inflammation, alleviating pain, and stabilizing cell membranes [74]. Further, it is also a nonspecific inhibitor of VEGF, COX-1 and COX-2 enzymes [75]. Several COX inhibitors such as indomethacin, acetyl salicylic acid, celecoxib, etodolac, and bromfenac sodium have shown efficacy in suppressing HSV-1 reactivation, both in vitro and in vivo [76]. Preclinical and clinical trials have evaluated the potency of PPF in protection against HSK [77]. Further, it didn’t exhibit any risk of corneal tissue melting, glaucoma and cataract (NCT03013959).

5.2. Prednisolone phosphate and acyclovir

Herpetic stromal keratitis (HSK) is a consequence of a robust inflammatory response initiated by the viral infection of the corneal stroma. While there are antiviral agents available for treating herpes simplex epithelial keratitis, a considerable proportion of patients continue to encounter inflammation in the iris and connective tissue of cornea. In the absence of treatment, the prolonged inflammatory response can give rise to the formation of lesions, and scarring, and ultimately result in blindness [78]. The utilization of topical corticosteroids is a subject of controversy due to their known adverse effects, notably elevated intraocular pressure, and the development of cataracts. However, the conflicting research outcomes regarding the topical application of corticosteroids have also generated a sense of uncertainty. The HEDS-1 tests ended this ambiguity by evaluating the efficacy of an oral antiviral agent alongside topical corticosteroids. The HEDS-I trials were designed to evaluate the effectiveness of treating HSV stromal keratitis and iridocyclitis using a combination of topical corticosteroids and oral ACV. Those individuals exhibiting active HSV stromal keratitis, without recent use of a topical corticosteroid within the last 10 days, were subjected to randomization for treatment involving topical prednisolone phosphate drops and oral ACV capsules. (NCT00000138). The investigators observed fewer treatment failures and faster resolution of stromal keratitis [53].

5.3. Cyclosporine A

Non-necrotizing HSK is characterized by stromal inflammation, making it the hallmark of the condition. As a standard approach, the treatment of HSK engages a combination of antiviral medication with local immunosuppressants to reduce local symptoms, inflammation, and scar formation. However, the failure of reducing inflammation in some patients put forward the alternative approach of targeting T cells. Cyclosporine-A, being an immunosuppressive drug, gained attention due to its competence to hamper the propagation of T helper lymphocyte cells, and production of interleukin-2 [79]. Clinical trials evaluated the efficacy of combining topical cyclosporine A 0.05% eye drops with prednisolone eye drops, comparing it to the use of topical prednisolone acetate 1% eye drops alone in treating herpetic stromal keratitis. Both the groups received a therapeutic dose of systemic ACV at 400 mg five times daily, which was later tapered to a twice-daily prophylactic dose after one month of treatment. The study has progressed to phase 4 of clinical trials and continues to assess the effectiveness of the combinatorial treatment (NCT05720715).

5.4. Nexagon

Nexagon is a novel therapeutic agent demonstrated to be effective in treating skin lesions. It selectively inhibits connexin43 expression, that is a major gap junction protein. Animal studies and preliminary human studies have indicated its safety and efficacy in treating persistent corneal epithelial defects (PED) [80]. Its effectiveness was assessed in a phase 2 trial involving individuals with PED resulting from various conditions, including epithelial debridement in cornea during diabetic vitrectomy surgery, HSV keratitis, HZV keratitis, corneal burns, post-PRK, or post-corneal transplant surgery. The treatment demonstrated efficacy in promoting vascular recovery and reducing inflammation.

5.5. Pritelivir

Pritelivir, also recognized as AIC316 and BAY 57–1293, represents a novel pharmaceutical compound undergoing extensive research for combatting HSV infections. Developed by AiCuris, a German pharmaceutical firm, this drug is derived from thiazolylamides. It demonstrates remarkable antiviral efficacy against both HSV-1 and HSV-2 strains, showcasing potential effectiveness even against drug-resistant variants of the virus [81]. Pritelivir demonstrates a distinct mechanism of action, primarily functioning by inhibiting the helicase-primase complex, a pivotal enzyme crucial for viral DNA replication. This sets it apart from traditional antiviral medications such as acyclovir or valacyclovir, which target viral DNA polymerase. Such a unique mechanism of action positions pritelivir as potentially effective against HSV strains that have evolved resistance to current antiviral treatments. Surprisingly, it also exhibited excellent antiviral activity in immunodeficient (athymic-nude) animal models suggesting its potential implication in immunocompromised patients. It has successfully completed phase II trials and has entered phase III part of clinical trials (NCT03073967).

5.6. Amenamivir

Amenamevir (ASP2151) is an oxadiazolephenyl derivative and second of the helicase-primase inhibitors in development that exhibits potent activity against both HSV and VZV [82]. Its oral bioavailability, efficacy against drug resistant HSV strains, and favorable tolerability in both mice and humans elevate it as a superior candidate. Amenamevir demonstrates consistent effectiveness against infected cells, whether it’s during immediate infection or in the later stages characterized by extensive viral DNA synthesis. In contrast, Acyclovir’s efficacy is primarily observed post-infection and before the initiation of viral DNA synthesis, yet it proves ineffective against cells with significant viral DNA synthesis underway. It has successfully completed phase III part of clinical trials (NCT01959295).

6. Current challenges and emerging drugs

6.1. Current challenges

The existing therapies for HSK encounter numerous difficulties owing to the ongoing emergence of drug-resistant viral strains. Moreover, the concerns are exacerbated by the toxicities and side effects linked to the current treatments and diagnostic procedures. The current treatments primarily revolve around impeding viral DNA replication by integrating synthetic nucleoside analogs into viral DNA, eventually leading to chain termination of viral DNA synthesis. The future research should identify novel host pathways affected by HSV that can be explored for the development of new drugs. This approach has been previously investigated by alleviating virus-mediated endoplasmic reticulum (ER) stress using the chemical chaperone 4 PBA, resulting in the successful repurposing of 4 PBA as a novel antiherpetic drug [83,84]. Similarly, recognizing the significance of virus-induced reactive oxygen species in facilitating viral replication has led to the repurposing of several antioxidants as antiherpetic agents that primarily work by quenching this oxidative stress. Thus, beyond directly impeding viral DNA replication, the identification of crucial factors within the virally controlled host cellular environment, necessary for productive viral replication, and manipulating these factors can contribute to the development of novel antivirals equally effective against resistant viruses [72].

6.2. Emerging drugs

Nucleoside analogs, such as ACV and TFT, continue to serve as the primary treatments for HSV keratitis. The continuous evolution of drug-resistant viral strains and increasing numbers of side effects have fueled the drug discovery process in the field. The identification of various host pathways altered by viral infections has paved the way for recognizing novel targets, which later proved to be significant tools in drug discovery. A virus utilizes host machinery for successful completion of its lytic life cycle, beginning with entry, followed by replication, and concluding with its release from infected cells [85]. Identifying host factors that facilitate the progression of the viral lytic life cycle at each step, followed by their manipulation and pharmacological modulation, presents extensive opportunities for the discovery of novel anti-herpetic drugs [86] (see Figure 2).

Figure 2.

Schematics of different emerging inhibitors in HSV-1 life cycle.

Molecules that can aim host cell receptors (including 3-O-sulfated heparan sulfate) and viral glycoproteins (gD) can restrain HSV entry and spread. These molecules engage in competitive binding with either host or viral glycoprotein receptors, effectively obstructing viral attachment and entry into cells. Cationic membrane-infiltrating peptides such as G1 and G2, attach to 3-O-sulfated heparan sulfate (3-OSHS) and block the attachment of HSV glycoprotein, gD, thereby inhibiting viral entry into cells in both in vitro and ex vivo models [87–89]. An additional prospective antiviral therapy involves a DNA or RNA aptamer that binds to gD. This approach prevents HSV entry and general infection by limiting viral spread, proving effective in both prophylactically and therapeutically ways [90].

HSV manipulates the host cellular environment and alters the state of different cell organelles for productive replication. For instance, the identification of virus mediated induction of ER stress and disarmed UPR raised the curiosity about the fate of virus on alleviation of ER stress. Treating infected cells with 4-Phenylbutyric acid (4PBA), an FDA-approved drug known as a chemical chaperone that alleviates ER stress, unexpectedly resulted in a significant reduction in viral replication. Moreover, its effective synergy with ACV and TFT, leading to a dose reduction of individual drugs, can offer additional renal protection, especially in cases where higher amounts of antiviral drugs need to be administered systemically [83]. Moreover, it inhibits inflammation in preclinical ocular inflammation models by preventing the production of pro-inflammatory cytokines through the inhibition of NF-κB [84]. Due to its possession of both antiviral and anti-inflammatory activities, when administered with ACV, it eliminates the need for topical corticosteroids, which was earlier recommended by HEDS-1 trials. Similarly, a small molecule inhibitor of TANK-binding kinase 1 (TBK1), BX795, demonstrates the suppression of HSV viral protein synthesis with antiviral activity comparable to TFT in animal models of ocular HSV infection [91]. The virus-mediated induction of oxidative stress is recognized as a factor necessary for productive replication. Thus, the mitigation of oxidative stress via treatment with antioxidants is also known to inhibit viral replication [92,93]. The disruption of signal transduction host signaling pathways needed for HSV growth and survival using a bacterial component prodigiosin has also been reported for unique anti-herpes activity [94]. After a productive replication cycle, inhibiting the release of progeny virions from infected cells offers another avenue for drug discovery. The virus is known to exploit various host factors, with heparanase being a major player, to facilitate its release from infected cells. Pharmacological inhibition of HPSE using OGT 2115 has demonstrated a significant reduction in infection [95–97].

Nanotechnological interventions in the field of medicine are emerging as a significant branch, primarily focusing on drug delivery. These drugs aim to inhibit multiple stages of the viral life cycle. Recently, Yadavalli et al.. (2019) from our group demonstrated that highly porous activated carbon can trap HSV-1 virions in its nanopores, effectively blocking the viral entry process [98]. In addition to its inherent ability to inhibit viral replication, it was discovered to be an excellent vehicle for loading ACV, achieving a drug loading efficacy of greater than 99%. The drug release occurred in a controlled manner triggered by virus infection. When tested in murine models, a single topical dose of DECON on alternate days effectively restricted HSV-1 replication in vivo. Furthermore, the treated mice did not exhibit any signs of blepharitis, corneal keratitis, or any disease scores throughout the infection period.

CRISPR, a groundbreaking gene-editing technology, shows great promise in treating diverse diseases by precisely modifying genetic sequences to correct mutations, regulate gene expression, and develop novel therapies. It has demonstrated potential in addressing genetic disorders, cancer, infectious diseases, and more in both preclinical and clinical research. With its versatility, efficiency, and specificity, CRISPR is a powerful tool for targeted gene editing, enabling personalized medicine and innovative treatments. However, the broader safety and efficacy of in vivo CRISPR therapy are still being explored. To tackle some of these challenges, a recent clinical trial (NCT04560790) introduced engineered virus-like particles capable of transporting mRNA or ribonucleoprotein for transient gene editing in patients with HSV infections. These particles, including the mRNA-carrying lentiviral particle (mLP) and the HSV-1-erasing lentiviral particle (HELP), target essential genes for the HSV-1 life cycle. In mouse models, a single intracorneal injection of HELP significantly reduced HSV-1 levels in corneas and trigeminal ganglia. Combination therapy with HELP and corneal transplantation in refractory herpes simplex keratitis (HSK) cases led to sustained viral suppression without observable CRISPR-related adverse effects over an average follow-up period of 18 months. Laboratory data demonstrated efficient reduction of HSV-1 in infected corneas without off-target cleavage in the human genome or immune responses induced by HELP injection. These findings suggest that HELP could be a promising approach for controlling HSV-1 replication in human corneas with minimal CRISPR-associated side effects.

7. Potential development issues

Despite continuous efforts in drug discovery and repurposing existing drugs for HSK, the evident global failure and inadequacy of existing drugs are reflected in the 80–90% seropositivity of HSV. One of the major developmental challenges in developing countries remains the inadequacy of diagnostic measures, where the distinction between HSK and other forms of keratitis is often unclear. Diagnostics that can provide clear differentiation are either prohibitively expensive or time-consuming. Moreover, the reporting of the disease for medical diagnosis remains uncommon among patients due to economic constraints in accessing treatment. Currently, the drugs going into clinical trials for limiting HSK are still represented by nucleoside analogs, thus there is a requirement for the advancement of novel agents with enhanced characteristics. This is essential to address concerns such as endurance, inadequate oral bioavailability, lasting toxicity, and population-based variability that demands dose modification. Recent clinical trials have emphasized the importance of topical corticosteroid application alongside oral nucleoside analogs. The use of corticosteroids is often linked to potentially serious adverse events, including the recurrence of herpetic disease, increased intraocular pressure, and the development of cataracts. Administering corticosteroids alongside oral ACV or VACV, especially at a frequency of at least five times a day, could potentially lead to multiple pathologies in the kidney due to ACV’s nephrotoxicity and adverse effects on the corneal surface caused by corticosteroids. Further, the unpredictability of stress-triggered recurrence and the renal toxicities associated with nucleoside analogs limit their usage for prolonged prophylactic treatments. Other drugs recently repurposed for treating HSV, such as 4-PBA and BX795, have not been specifically evaluated in the context of HSK [99–101]. Additionally, they lack human data and clinical trials. Given their recent repurposing, there is a greater risk of off-target effects associated with these drugs, potentially leading to the generation of other pathologies. In addition to drug development, extending drugs to low-income and uneducated communities and gaining acceptance for drug treatments beyond their orthodox religious beliefs remain a challenge for certain segments of society.

8. Conclusion

Despite the widespread adoption of the primary frontline treatment, HSK remains associated with elevated recurrence rates and inadequate disease manifestation. Tailored medications targeting specific viral pathways and designed for the relevant disease manifestation have the potential to attain optimal resolution of the condition. Several active clinical trials are concentrated on repurposing drugs and investigating synergies among drugs already available in the market. The strategy of developing new therapeutics through this approach lacks a broader perspective and specificity. Nevertheless, specific emerging drugs discussed in this review article hold the potential to provide superior benefits against HSK compared to the drugs currently undergoing clinical trials.

9. Expert opinion

Given the unpredictable nature of herpes recurrence episodes, prophylactic drug administration appears to be the sole feasible remedy. Administering ACV or its analogs orally for prophylaxis to patients with HSV cannot be prolonged indefinitely due to their nephrotoxic nature. Therefore, repurposing drugs such as 4-PBA, which are already part of daily consumption for other diseases and have demonstrated acceptability with minimal side effects, may limit HSK in cases of HSV patients [102–104].

Following each episode of HSV recurrence, the inflammatory response from the host immune system inadvertently damages a section of the cornea, leading to permanent scars on the eye. The limitations linked to existing corticosteroids significantly constrain their application to a broader segment of the affected population. Hence, the utilization of a chemical chaperone such as 4-PBA, possessing both antiviral and anti-inflammatory properties, eliminates the need for additional drug treatments, each with its own set of limitations. Likewise, the regular intake of antioxidants is a common and well-established practice in other diseases. Currently, there are no clinical trials concentrating on recommending antioxidants to HSK patients, which could potentially enhance the use of corticosteroids. Given that the virus relies on reactive oxygen species (ROS) for its productive replication and successful recurrence, another area of treatment could be explored involving antioxidants. As the regular consumption of antioxidants is a firmly established practice, it attests to their widespread acceptance and nontoxic nature, even in the absence of clinical trials. Moreover, the extensive array provided by the antioxidant market renders the development of resistant strains highly improbable. Furthermore, addressing multiple pathways also presents innovative avenues for combinatorial therapy, a current and highly researched topic.

A widely overlooked aspect of HSV recurrence is the establishment of latency during the primary infection [105]. Inadequate diagnostics during the initial infection, due to common disease symptoms or the shared morphology of multiple pathologies, frequently result in delayed or incorrect treatment. This provides the virus with sufficient time to replicate and successfully establish latency. Identifying specific biomarkers that clearly distinguish ocular herpetic infection from other microbial infections will greatly enhance the initial treatment and restrict the latency of the virus.

Since the approval of ACV in 1982 for the medical treatment of HSV, current clinical trials continue to focus on the prophylactic and therapeutic use of these nucleoside analogs. Yet, the consistent use of the same drug for the past five decades has created a distinctive environment for the emergence of ACV-resistant virus strains, leading to numerous instances of treatment failure.

As a potential alternative, TFT was introduced to address ACV-resistant viruses, but it also falls within the same class of drugs. This raises the possibility of the evolution of a virus that may develop resistance to the entire pathway targeted by nucleoside analogs. Hence, addressing viruses through multiple pathways is of paramount importance. Therefore, the emerging studies that focus on multiple pathways, as highlighted in the review article, should be advanced to clinical trials.

Article highlights.

• HSV-1 infects the human eye causing HSK.

• HSK is a prominent cause of infection-related blindness, globally.

• Despite the high seropositivity, there is currently no vaccine available for HSK.

• New drugs are needed to more effectively treat HSK.

• The current pipeline includes future drugs that target new steps in the HSV-1 lifecycle.

Abbreviations

HSK

Herpes Simplex Keratitis

HSV-1

Herpes Simplex Virus-1

ACV

Acyclovir

AAO

American Academy of Ophthalmology

HEDS

Herpes Eye Disease Study

TFT

Trifluorothymidine or trifluridine

AVP

Antiviral Prophylaxis

VACV

Valacyclovir

ACVR

ACV-resistant

TK

Thymidine Kinase

DNA

pol DNA polymerase

GCV

Ganciclovir

FDA

Food and Drug Administration

WHO

World Health organization

NSAIDs

Non-steroidal anti-inflammatory drugs

dGTP

Deoxyguanosine triphosphate

PED

Persistent Corneal Epithelial Defects

PCED

Primary congenital glaucoma Defects

DNA

Deoxyribose Nucleic Acid

RNA

Ribose Nucleic Acid

AVP

Antiviral prophylaxis

NICE

National Institute for Health and Clinical Excellence

EMA

European Medicines Agency