Ganciclovir Ophthalmic Gel in the Treatment of Herpes Simplex Keratitis
Clinical Trials Evidence for the Use of Ganciclovir in the Treatment of Herpes Simplex Keratitis Preclinical studies of GCV gel have demonstrated effective treatment of herpetic keratitis. Experimental models of herpetic keratitis in rabbits and mice have shown treatment with GCV 0.15% prevented lesion formation and had greater efficacy than ACV.47–50
Additionally, chronic administration
of GCV in rabbits with HSK resulted in clinical efficacy and a significant reduction of corneal ulcer area, clouding, and vascularization.51
GCV was developed for the treatment of acute superficial herpetic keratitis as a replacement for earlier, less effective, or less tolerated antivirals. Studies have found topical GCV gel treatment to be safe and well tolerated.29
Two further clinical trials in France examined
GCV ophthalmic gel in randomized, double-masked studies evaluating pharmacokinetics and tolerance in healthy volunteers. All volunteers completed the studies and reported good tolerance and no significant discomfort with only mild anomalies of no clinical consequence following the application of the GCV gel.8
Phase II/III trials of GCV gel all occurred in treatment centers outside North America and have not included any patients with HSK from US centers. Clinical studies conducted in Europe, Asia, and Africa involving over 370 patients, comparing the efficacy and tolerability of GCV ophthalmic gel with ACV ointment in herpetic keratitis, showed that, although not always statistically significant, GCV-treated patients tended to have higher overall healing rates accompanied with lower relapse rates than the ACV-treated patients (see Table 1, Figures 3 and 4).8,22,29
The first randomized, prospective phase II clinical trials occurred in the early 1990s, involving 66 patients from across Africa and a further 37 patients from Europe. Patients with herpetic keratitis were treated with either GCV (0.15%, 0.05%) gel or ACV (3%) petrolatum-based ointment five times daily until healing and then three times daily for one week. In the African study, the rate of healing was 82.6% for GCV 0.15%, 77.3% for GCV 0.05%, and 72.7% ACV 3%, whilst the median healing time was seven days for the GCV treated patients and eight days for the ACV patients. Greater tolerance and compliance were observed, accompanied by less stinging and burning sensations in the GCV treated groups compared to the ACV treated groups.29
In the European study,
patients experienced less blurring in the GCV groups compared to ACV treatment (38.5% and 76.9%, respectively), while less burning/stinging sensations were reported by patients receiving the GCV (0.15% and 0.05%) treatment compared to ACV (16.7% and 50%, respectively).29
A
third clinical study undertaken in Karachi, Pakistan, involved 109 patients in a similar randomized, controlled trial design as the European and African trials. Similar to the earlier trials, this study reported GCV to have generally improved healing rates, and lower incidences of relapse and withdrawal when compared to ACV treatment.8
The elevated
withdrawal rate in the ACV treated patients was due to treatment failure relating to worsening condition or reduced therapeutic efficacy.
There has been one large multicenter, prospective, randomized phase III study examining the effects of topical GCV gel and ACV ointment for the treatment of HSV herpetic keratitis.22
across 28 study centers within Europe. Analysis of the clinical study results indicate that GCV 0.15% was at least as effective as ACV 3% for
US OPHTHALMIC REVIEW
Trifuridine (diphosphate)
Trifuridine (monophosphate) Trifuridine
Cellular and viral thymidine kinase
P
Cellular and viral kinase
P P
Cellular and viral kinase
Trifuridine (triphosphate)
P P P
Ganciclover (triphosphate)
Ganciclovir (diphosphate)
Ganciclovir (monophosphate) Ganciclovir
Viral thymidine kinase
P
Cellular and viral kinase
P P
Cellular and viral kinase
P P P
Figure 2: Trifluridine and Ganciclovir Mechanism of Action Trifluridine
Ganciclovir
Extracellular Intracellular
Extracellular Intracellular
Incorporation into cellular or viral DNA
Competitive inhibition of viral DNA polymerase
Viral DNA chain termination
Prevents further cellular or viral replication
Prevents further viral replication
P = phosphate. Source: Zirgan monograph, Bausch & Lomb 2010.
treating acute herpetic keratitis with similar median time to healing. Patients treated with GCV did however report less blurring and fewer incidences of stinging or burning sensations.8,22
Complete resolution of herpetic keratitis was noted in all patients. The six patients on prophylactic GCV did not develop recurrence of herpetic keratitis, including three patients who had undergone penetrating keratoplasty.52
The lack of clinical controls or
masking notwithstanding, this study demonstrates the potential value of GCV in the treatment and prophylaxis of HSV herpetic keratitis, including in those patients that have undergone corneal grafts.
Ganciclovir in Clinical Use for Viral Keratitis Treatment
This study involved 164 patients
The commercial availability of GCV 0.15% gel across Europe, Asia, Africa, and South America has led to a considerable number of patients with herpes infections being treated by physicians. The proportion of cases where the investigator judged the tolerance to the product as excellent
65
GCV can penetrate the corneal stroma following topical application which results in therapeutic levels of GCV in the aqueous humor. Results from the previous clinical studies demonstrate that GCV is as effective as ACV for treating herpetic keratitis in humans, and, when applied in gel form, causes less blurring of vision than the petrolatum-based ointment applications, leading to greater tolerance of the treatment and potentially, to better compliance. A further non-randomized clinical study examined the potential efficacy of GCV for treating patients with herpetic keratitis.52
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