**5. Management**

Major advances in the treatment of HSV keratitis have been provided by the evidence-based results and conclusions of the Herpetic Eye Disease Study (HEDS) randomized clinical trials, which were multicenter, characterized by doublemasking with placebo controls studies. Based on this knowledge, further treatment guidelines were proposed and published [12, 29–37]. Although the HEDS clinical trials directly addresses multiple clinical concerns, the studies have also several limitations. These include: inadequate sample size in case of HSV stromal keratitis with epithelial ulceration to determine the optimal course of therapy, relatively high rate of follow up failure within the study group. Also, the corticosteroid regimen was standardized and fixed in the study group, thus lacking the evidence of benefit of delivery of personalized care. Finally, the concerns regarding the dose and the optimal period of antiviral prophylaxis have not been resolved.

## **5.1 Active keratitis**

Nowadays, the main treatment line of the active keratitis is a combination of the antiviral and corticosteroids drugs, depending on the epithelial and stromal involvement. The general rule to follow is to avoid corticosteroids in epithelial keratitis, because the entity of this form is virus activation and to treat with corticosteroids in stromal and endothelial keratitis without epithelial involvement, because those forms are strongly connected with the significant reaction of the immune system.

Antiviral drugs are used in two main forms: topical and oral. Topical anti HSV-1 drugs include: trifluridine solution (1%), ganciclovir gel (0.15%), and acyclovir ointment (3%). Oral anti HSV-1 drugs include: acyclovir, valacyclovir, and famciclovir. Historically, other systemic drugs were also used, such as idoxuridine, vidarabine, valganciclovir, foscarnet, and cidofovir, but they were withdrawn from the market or are relatively too toxic in combination with the achieved therapeutic effect.

Most common antiviral drug worldwide is acyclovir used either orally or topically or in combination. Common side effects of the prolonged oral acyclovir include nausea, vomiting, diarrhea, headache and weakness. Potentially serious, but very rare side effects include renal failure and hematology complications, such as: thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS).

In recent years, there have been an increasing interest in valacyclovir, due to its proven improved bioavailability and steadier plasma concentration compared to acyclovir. Valacyclovir is considered a prodrug of acyclovir. The lower frequency of dosing (2 times daily versus 5 times daily) may be a strong benefit for some patients. However, there is a lack of strong evidence, that treatment with valaciclovir provides leads to better results and less ocular and systemic complications. Comparing to herpes zoster ophthalmicus, the authors of the systematic Cochrane report indicated uncertainty of the relative benefits and harms of valacyclovir over acyclovir [38]. All topical antiviral drugs are characterized by ocular surface toxicity, could cause allergic reactions, and punctal and nasolacrimal duct stenosis, therefore the prolonged usage of those formulas is not advised. Authors of the Cochrane systematic review on HSV keratitis treatment, published in 2015 also assessed other methods of HSV keratitis treatment, such as manual debridement of the corneal epithelium or experimental biologic agents. Manual debridement alone has been proved to be not effective. Also, topical treatment with interferon has only a modest benefit over placebo [39]. In case of epithelial keratitis, the mainstay of treatment is antiviral agents. Corticosteroids excessive usage may lead to geographical ulcers

#### *Recent Advances in the Diagnosis and Management of Herpetic Keratitis DOI: http://dx.doi.org/10.5772/intechopen.96898*

and delay healing of the epithelium. When stromal involvement is present, the mainstay of treatment is the use of corticosteroids with the combination of antiviral agents. The HEDS clinical trials have brought solid rationale for the treatment of the stromal keratitis with corticosteroids. Nowadays, there are several available topical corticosteroids formulas with different anti-inflammatory potency and different potential for adverse reactions: Dexamethasone 0,1%, Betamethasone at concentrations ranging from 0.01% to 0.1%, Prednisolone 1%, Loteprednol Etabonate 0.5%, Rimexolone 1%, Dexamethasone 0.1%, Hydrocortisone 0.335%, Fluorometholone 0,1%. The strongest anti-inflammatory effect is demonstrated by dexamethasone, the weakest by hydrocortisone. This should be taken into consideration, when choosing the medication depending on the level of the corneal inflammation. Moreover, steroid medication must be withdrawn gradually, tapering the doses generally over few weeks' time. During the drug withdrawal, instead of sudden discontinuation of the stronger corticosteroid, one may consider replacing it with a relatively weaker one to avoid a rebound increase in inflammation and a disease recurrence immediately after drug cessation. The recommended treatment for HSV stromal keratitis without ulceration should include a topical corticosteroid for at least a period exceeding ten weeks in conjunction with a prophylactic oral antiviral. A treatment period greater than ten weeks has been recommended, because of the high treatment failure rates six weeks after a ten-week prednisolone taper in the HEDS clinical trial. The most concerning side effects of topical steroids include: increase of the intraocular pressure, cataract and secondary infections (including bacterial, fungal, and also viral infections). Therefore, patients must be monitored carefully when treating with topical steroids.

## **5.2 Recurrence prevention**

The HEDS study on recurrence rate clearly demonstrated that short-course oral during an active HSV epithelial keratitis does not prevent later stromal keratitis or iritis. On the other hand, a 12-month course of prophylactic oral acyclovir (400 mg) twice daily significantly decreased a recurrence rate of the stromal involvement. Although the HEDS study authors did not recommend a prolonged, beyond 12 months acyclovir prophylaxis, clinical practice recommendations and observations seem to postulate a positive role of a long-term prophylaxis, especially in patients with a high recurrence rate, significant corneal thinning at risk of corneal perforation, with comorbidities, such as atopy, autoimmune diseases or in immunocompromised patients. Also patients with history of HSV keratitis undergoing surgical procedures, such as corneal transplant, photorefractive procedures or cataract surgery may benefit from acyclovir prophylaxis, until the level of inflammation associate with the procedure and the risk of recurrence is decreased [12, 29–37].

One of the future treatment strategies is to enhance patient's immune system resistance to the infection through a vaccine against HSV-1. Nowadays there are no approved vaccine available, but there are ongoing studies regarding this subject. In the recently published study in 2020, the authors identified 15 viral-encoded proteins, which could serve as candidates for further testing for the HSV-1 vaccine [40].

## **5.3 Neurotrophic keratitis**

There are several methods of treatment depending on the severity level of keratitis. First line therapy includes discontinuing potentially toxic topical medications, tear replacement products and oral supplementation with omega-3 fatty acids. The next step of treatment is immunomodulatory therapy including:

lifitegrast, cyclosporine and steroids at different frequency and concentrations, and also autologous serum eye drops at concentrations from 20–100%. Autologous serum eye drops are characterized by multiple benefits: biochemical characteristics, including pH, nutrient content, vitamins, fibronectin, growth factors such as epithelial growth factor (EGF) or nerve growth factor (NGF), are similar to that of human tears, the serum eye drops also inhibit the release of inflammatory cytokines and increase the number of goblet cells and mucin expression in the conjunctiva. Prolonged use of serum eye drops is proved to restore homeostasis of the ocular surface.

In the last few years, there have been an increasing interest in the implementation of the Nerve Growth Factor (NGF) in the sub-basal nerve plexus regeneration, leading to the complete healing of the neurotrophic ulcers. NGF is an endogenous protein involved in the differentiation and maintenance of all systemic neurons, while in corneal tissue it is established to play a role in corneal innervation, tear secretion mechanism, and corneal epithelial cell growth and stability. Cenegermin is a recombinant human Nerve Growth Factor (rhNGF) that is structurally identical to the human NGF protein made in ocular tissues, it was introduced in the ophthalmic solution at concentration of 0.002% (20 mcg/mL). Two controlled clinical trails in Europe (REPARO) and USA (NGF0214) provided strong evidence on its effectiveness. 72% and 65% of patients with neurotrophic keratitis receiving cenegermin were completely healed in Europe and USA trails respectively [41–44]. Matrix regenerating agent (ReGenerating Agent; RGTA), mimicking natural heparan sulfate within the corneal tissue, is also a recent topical agent showing promising results in the treatment. RGTA eye drops (Cacicol; Thea) are preservative-free, well-tolerated, proved to promote regeneration of damaged tissues and to enhance corneal tissue healing [45, 46].

Novel emerging treatment approaches also include thymosine β4, CODA001, topical insulin, Substance P and insulin-like growth factor 1 (IGF-1). Thymosine β4 and CODA001 are in the most advanced evaluation undergoing clinical trials. Thymosin beta 4 is a 43-amino acid peptide, a major constituent protein of macrophages, and platelets. Currently, third-phase, multi-center, randomized, double masked, placebo controlled clinical study is ongoing regarding its role in ocular surface healing. Insulin at 3 different concentrations. CODA001 is an antisense oligonucleotide (antisense deoxynucleotide oligomer) that modulates and downregulates the expression of the gap junction protein Cx43 (Connexin-43), which is increased in persistent epithelial defects [47].

Other procedures implemented at different severity levels of neurotrophic keratitis include: therapeutic contact lenses, lacrimal punctual occlusion, amniotic membrane contact lens or transplantation, partial or complete tarsorraphy, corneal transplant, conjunctival flap transplant or direct neurotization.

Amniotic membrane transplantation (AMT) is proved to provide many benefits in the treatment of neurotrophic keratitis. AMT inhibits the activity of inflammatory cells, extends the life of corneal epithelial stem cells and maintains their ability to regenerate epithelial cells, promotes healing of the corneal wounds, blocks the TGF-ß cytokine system activation and the transformation of fibroblasts into myofibroblasts, also creates a protective membrane covering the affected ocular surface tissues. In dry eye disease, it is used in case of serious complications, such as corneal ulcer or microperforation. An interesting solution to consider is a sutureless, adhesiveless amniotic membrane transplant (AMT; ProKera; Bio-Tissue, Inc.) implantation. It is a corneal–epithelial device that consists of a polycarbonate ring conformer containing cryopreserved amniotic membrane. Advantages of this design include: shorter surgical time and prevention of suture-related complications [48].

To summarize neurotrophic keratitis treatment: a stepwise approach should be implemented with careful exclusion of the active infection. Topical treatments should be the first line therapy over the surgical interventions.
