RECOMMENDED: ZIRGAN

Ganciclovir ophthalmic gel 0.15% is a recommended first-line treatment for dendritic HK, based upon the following evidence:

  • Topical ophthalmic antiviral agents allow for high concentration of drug on the cornea and in the tear film, with negligible systemic uptake1
  • As a second generation antiviral, ganciclovir gel is preferentially activated in virus-infected cells, sparing host cells2
  • Ganciclovir gel has been proven comparable in efficacy and safety to acyclovir ointment (available outside the US) in the treatment of HK3
    • Ganciclovir gel has been in use outside of the US since 19954
  • Ganciclovir gel is preserved with BAK, a non-mercury based preservative1
    • Mercury-based preservatives have been associated with ocular toxicity and allergy5,6
    • Ganciclovir gel is the only topical ophthalmic antiviral agent with a nonmercury-based preservative
  • Ganciclovir gel has an established safety profile, a convenient dosing schedule, and does not require refrigeration.1,7

REFERENCES

  1. Zirgan (ganciclovir ophthalmic gel 0.15%) prescribing information. Tampa, FL: Bausch & Lomb, Inc; 2010.
  2. Villarreal EC. Current and potential therapies for the treatment of herpes-virus infections. Prog Drug Res. 2003;60:263-307.
  3. Colin J. Ganciclovir ophthalmic gel, 0.15%: a valuable tool for treating ocular herpes. Clin Ophthalmol. 2007;1(4):441-53.
  4. Zirgan (ganciclovir ophthalmic gel) 0.15% NDA application no. 22-211. Center for drug evaluation and research, medical review. Letter date: November 14, 2008.
  5. Tosti A, Tosti G. Thimerosal: a hidden allergen in ophthalmology. Contact Dermatitis. 1988;18:268-73.
  6. Tripathi BJ, Tripathi RC, Kolli SP. Cytotoxicity ophthalmic preservatives on human corneal epithelium. Lens Eye Toxic Res. 1992;9:361-75.
  7. Foster CS. Ganciclovir gel—a new topical treatment for herpetic keratitis. US Ophthalmic Review. 2008;3:52-6.

INDICATION

ZIRGAN® is a topical ophthalmic antiviral that is indicated for the treatment of acute herpetic keratitis (dendritic ulcers).

IMPORTANT RISK INFORMATION ABOUT ZIRGAN®

• ZIRGAN® is indicated for topical ophthalmic use only.
• Patients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during the course of therapy with ZIRGAN®.
• Most common adverse reactions reported in patients were blurred vision (60%), eye irritation (20%), punctate keratitis (5%), and conjunctival hyperemia (5%).
• Safety and efficacy in pediatric patients below the age of 2 years have not been established.

Click here for complete prescribing information for Zirgan

REFERENCES

  1. Zirgan (ganciclovir ophthalmic gel 0.15%) prescribing information. Tampa, FL: Bausch & Lomb, Inc; 2010.

REGIMEN

Zirgan (ganciclovir ophthalmic gel 0.15%) should be applied five times daily (or every three hours while awake). The initial dosing should be continued for the duration of time required for the corneal ulcer to heal. (Healing can be defined as an absence of fluorescein uptake at the ulcer site; this typically, but not invariably, occurs within 1 week.) Once the ulcer has healed, the ganciclovir dose should be reduced to three times daily and continued for 7 days thereafter.1

Patients should be advised to avoid wearing contact lenses while experiencing signs and symptoms of HK and during the course of treatment with ganciclovir gel.1

REFERENCES

  1. Zirgan (ganciclovir ophthalmic gel 0.15%) prescribing information. Tampa, FL:    Bausch & Lomb, Inc; 2010.

FOLLOW-UP

Patients should be reexamined 1 to 2 weeks following initiation of treatment or sooner at the discretion of the clinician. If the diagnosis is in question, or if the ulceration is severe, follow up as early as 48 to 72 hours to assess initial response to treatment may be appropriate. Typically, healing is first evident at the sites of actively replicating virus in the terminal bulbs of the ulcer; however, various patterns of healing may be observed. Patients who are responding well to therapy will have substantial reduction in the size of the ulcer or full reepithelialization at follow-up. Once the ulcer is healed, patients should continue on ganciclovir gel at a reduced dosing frequency of three times daily for an additional 7 days. 1

Patients who are improved but not fully healed should continue on ganciclovir gel five times daily until the ulcer is healed and then reduce the dosage to three times daily for an additional 7 days.

Most patients respond well to topical antiviral therapy; however, occasionally follow-up examination will reveal a lack of improvement or progression of the ulcer. This may be attributable to factors related to the disease, the host, the treatment, or a combination of factors. Leading considerations in such cases include lack of patient compliance with treatment or an inaccurate diagnosis. If one is confident that neither the diagnosis nor compliance is in question, referral to a corneal specialist may be warranted to confirm the diagnosis, rule out antiviral resistance, and/or modify the treatment regimen.

REFERENCES

  1. Zirgan (ganciclovir ophthalmic gel 0.15%) prescribing information Tampa, FL: Bausch & Lomb, Inc; 2010.

A RECOMMENDED TREATMENT FOR
EPITHELIAL HERPETIC KERATITIS


CONTINUE TO ALTERNATIVE

ALTERNATIVE

As the only selective antiviral formulated for topical application, Zirgan (ganciclovir ophthalmic gel 0.15%) is an appropriate first-line treatment for dendritic HK. Alternatives to Zirgan include trifluridine 1% ophthalmic solution or, under circumstances in which a topical agent is not advisable, oral antiviral therapy.1

REFERENCES

  1. Wilhelmus KR. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database of Systematic Reviews 2010, Issue 12.

INDICATION

ZIRGAN® is a topical ophthalmic antiviral that is indicated for the treatment of acute herpetic keratitis (dendritic ulcers).

IMPORTANT RISK INFORMATION ABOUT ZIRGAN®

• ZIRGAN® is indicated for topical ophthalmic use only.
• Patients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during the course of therapy with ZIRGAN®.
• Most common adverse reactions reported in patients were blurred vision (60%), eye irritation (20%), punctate keratitis (5%), and conjunctival hyperemia (5%).
• Safety and efficacy in pediatric patients below the age of 2 years have not been established.

Click here for complete prescribing information for Zirgan

THE EVOLUTION OF TREATING
HERPETIC KERATITIS

TRIFLURIDINE

Trifluridine 1% ophthalmic solution is a reasonable alternative choice for the acute treatment of HK, particularly when low medication cost is a top priority. Trifluridine should not be used for longer than 21 days due to the potential for ocular toxicity.1

Trifluridine is an example of a non-selective antiviral. Non-selective antiviral agents inhibit not only virus reproduction but also cellular DNA synthesis in uninfected cells. As such, non-selective antiviral agents can interfere with wound healing and contribute to ocular surface toxicity. Associated complications are rare, but can be serious when viral infection produces large corneal ulcers that require significant cell division to heal.2 Trifluridine is preserved with thimerosal, a mercury-based preservative. 1

REFERENCES

  1. Viroptic Ophthalmic Solution, 1% Sterile (trifluridine ophthalmic solution) Archived Drug Label. Accessed on 9/4/12.
  2. Kaufman HE. Part three: the historical perspective. Advances in the management of ocular herpetic disease. Candeo Clinical/Science Communications 2011;16-18.

ORAL

There is a dearth of data on the use of oral antiviral therapy as a substitute for topical antiviral therapy in the treatment of acute HK.1 This is understandable, as topical treatment is a well accepted form of pharmaceutical administration for ophthalmologic conditions. A randomized, double-blind, controlled trial found that treatment of HK with oral acyclovir was associated with similar efficacy and speed of healing compared with topical acyclovir, suggesting that oral antiviral therapy (with acyclovir, valacyclovir, or famciclovir) was a reasonable alternative to topical among patients who might not tolerate the topical.2

REFERENCES

  1. Wilhelmus KR. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database of Systematic Reviews 2010, Issue 12.
  2. Collum LMT, McGettrick M, Akhtar J, et al. Oral acyclovir (Zovirax) in herpes simplex dendritic corneal ulceration. Br J Ophthalmol. 1986;70:435-8.

THE ROLE OF TOPICAL AND ORAL
ANTIVIRALS IN TREATING HERPETIC
KERATITIS


CONTINUE TO ADJUNCTIVE

ADJUNCTIVE

Zirgan (ganciclovir ophthalmic gel 0.15%) is an appropriate first-line treatment for dendritic HK and can be administered as a single agent. Adjunctive measures may include preliminary ulcer debridement, the addition of a systemic antiviral medication, or the addition of interferon.1

Systemic antiviral medication may be used as an adjunct to topical treatment of HK, although evidence for added benefit over topical treatment alone is lacking. Select patients may benefit from adjunctive oral antiviral therapy, such as those with large dendritic lesions, geographic lesions, significant iritis, or who are immunocompromised. Patients with comorbid HSV dermatoblepharitis warrant adjunctive treatment with systemic antiviral therapy. Recommended therapies include oral acyclovir (400 mg five times daily) or valacyclovir (500 mg three times daily).1

Several studies have reported successful treatment of HK with interferon, either alone, or in combination with debridement or antiviral therapy. As an adjunct to antiviral therapy, interferon may speed healing of HK ulcers, however it has not been consistently shown to improve healing rates.1 For this reason, interferon is not generally recommended as first-line therapy for uncomplicated HSV keratitis.

REFERENCES

  1. Wilhelmus KR. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database of Systematic Reviews 2010, Issue 12.

INDICATION

ZIRGAN® is a topical ophthalmic antiviral that is indicated for the treatment of acute herpetic keratitis (dendritic ulcers).

IMPORTANT RISK INFORMATION ABOUT ZIRGAN®

• ZIRGAN® is indicated for topical ophthalmic use only.
• Patients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during the course of therapy with ZIRGAN®.
• Most common adverse reactions reported in patients were blurred vision (60%), eye irritation (20%), punctate keratitis (5%), and conjunctival hyperemia (5%).
• Safety and efficacy in pediatric patients below the age of 2 years have not been established.

Click here for complete prescribing information for Zirgan

DEBRIDEMENT

Various physical methods of debridement to reduce viral load have been used since the pre-antiviral era and remain in use in some settings today. For the most part, however, such techniques have been abandoned due to the time and effort required, the risk of damaging Bowman layer, and the potential to increase inflammation and scarring. When used without concomitant antiviral therapy, debridement alone is associated with an increased risk of recrudescent epithelial keratitis.1

The diverse methodologies, surgical techniques, and skill levels of the participants make comparing clinical trials of physicochemical debridement techniques for the treatment of HK challenging; and few have compared physical techniques to placebo.1,2 Thus, reviews of the literature that have sought to offer evidence-based guidelines on the matter have been largely inconclusive. There may be some improvement in speed of healing when debridement is used prior to topical antiviral therapy.2

REFERENCES

  1. Wilhelmus KR. The treatment of herpes simplex virus epithelial keratitis. Tr Am Ophth Soc. 2000;98:505-32.
  2. Wilhelmus KR. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database of Systematic Reviews 2010, Issue 12.

ORAL

Some clinicians report the use of oral antiviral therapy as an adjunct to topical antiviral therapy in the treatment of acute HK.1 A meta-analysis of HK therapies revealed that combination oral and topical antiviral therapy had similar efficacy compared to topical antiviral monotherapy (relative risk [RR]=1.08; 95% confidence interval [CI] 0.99 to 1.17). Authors concluded that it remains unclear whether the addition of a second antiviral agent to a baseline topical antiviral regimen is useful in accelerating healing. Further studies are needed to assess the role of adjunctive oral antiviral therapy in the treatment for dendritic epithelial keratitis.2

  1. Guess S, Stone DU, Chodosh J. Evidence-based treatment of herpes simplex virus keratitis: a systematic review. Ocul Surf. 2007;5:240-50.
  2. Wilhelmus KR. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database of Systematic Reviews 2010, Issue 12.

THE ROLE OF TOPICAL AND ORAL
ANTIVIRALS IN TREATING HERPETIC
KERATITIS


CONTINUE TO ANTIVIRAL RESISTANCE

ANTIVIRAL RESISTANCE

HSV resistance to acyclovir and related antiviral compounds, valacyclovir, famciclovir, and penciclovir, has remained low since introduction of these agents starting in the early 1980s. Resistance is far more common among immunocompromised patients—estimated 3.5% to 10% compared with 0.1% to 0.7% among immunocompetent patients—as viral replication is typically prolonged in such patients, and impaired host responses allow for virus with lower pathogenicity to survive and replicate.1,2 In fact, infection with an HSV-1 strain that is resistant to acyclovir raises the concern of immunodeficiency.3

The vast majority of HSV-1 strains with clinical resistance to acyclovir contain a mutation in the gene that encodes for the key enzyme TK. While some TK-mutant strains remain highly pathogenic, others have reduced “viral fitness” as a result of the mutation compared with wild-type strains. Rarely, the mechanism of antiviral resistance relates to an altered DNA polymerase. The low rates of acyclovir resistance despite decades of widespread use may be a result of compromised pathogenicity in HSV-1 strains with mutant TK or DNA polymerase.1

Though rates are low overall, increased antiviral prescribing may be driving up acyclovir resistance in patients with herpetic eye disease. A recent study of sequential corneal HSV-1 isolates from patients with recurrent HK revealed an acyclovir resistance rate of 6.4%, surprisingly high for an immunocompetent population.2 All patients in this study with an acyclovir-resistant HSV strain had received treatment with acyclovir within the past year. Lack of clinical responsiveness to treatment—slow healing over several weeks or frequent recurrences—was associated with antiviral resistance.4

Acyclovir-resistant HSV strains are resistant to acyclovir’s prodrug valacyclovir, and most are cross-resistant to famciclovir.3 Ganciclovir and acyclovir share similar structures and mechanisms of action, therefore cross-resistance is possible.5 In Duan and coworkers’ study of corneal HSV isolates, 45% (5/11) of acyclovir-resistant strains were resistant to ganciclovir.2

Recovery of HSV and in vitro resistance assays and molecular characterization of isolates should be performed prior to switching therapy in patients who are refractory to initial therapy.2 This may necessitate a referral to a corneal specialist with expertise in infectious disease management.

REFERENCES

  1. Piret J. Boivin G. Resistance of herpes simplex viruses to nucleoside analogues: mechanisms, prevalence, and management. Antimicrobiol Agents Chemother. 2011;55:459-72.
  2. Duan R, de Vries RD, Osterhuas ADME, Remeijer L, Verjans GMGM. Acyclovir-resistant corneal HSV-1 isolates from patients with herpetic keratitis. J Infect Dis. 2008;198:659-63.
  3. Bacon TH, Levin MJ, Leary JJ, Sarisky RT, Sutton D. Herpes simplex virus resistance to acyclovir and penciclovir after two decades of antiviral therapy. Clin Microbiol Rev. 2003;16:114-28.
  4. Duan R, de Vries RD, van Dun JM, et al. Acyclovir susceptibility and genetic characteristics of sequential herpes virus type 1 corneal isolates from patients with recurrent herpetic keratitis. J Infect Dis.2009;200:1402-14.
  5. Croxtall JD. Ganciclovir ophthalmic gel 0.15%: in acute herpetic keratitis (dendritic ulcers). Drugs. 2011;71:603-10.

CONTINUE TO VIRUS TO ANTIVIRAL: A TIMELINE

 

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