Topical Tacrolimus as an adjunct to Conventional Therapy for Stromal Herpetic Keratitis: a Randomized Clinical Trial


Purpose: This study investigates the effects of 0.05% topical tacrolimus as an adjunct therapy for patients with non-necrotizing herpetic stromal keratitis (HSK).

Methods: Patients with non-necrotizing HSK, referred to the Cornea Clinic at Hospital in Rasht, Iran, between September 2016 and February 2018, were randomly assigned to two groups. The case group (N = 25) and the control group (N = 25) received conventional treatment with systemic acyclovir and topical prednisolone. The case group (N = 25) additionally received 0.05% tacrolimus eye drops four times a day for one month. Complete ocular examinations, including best-corrected visual acuity (BCVA) assessment, intraocular pressure (IOP) measurement, slit lamp biomicroscopy, and photo slit lamp imaging, were performed before treatment, and 3, 7, 14, 21, and 28 days after the intervention.

Results: The mean age of the patients was 46.2 ± 12.9 years, and 70% of the patients were male. There was no difference between the groups in terms of age, sex, and baseline ocular measurements (P > 0.05). The case group had a lower mean logarithm of the minimum angle of resolution (LogMAR) for BCVA, lower grading scores, and steeper decreasing trends for corneal haziness, edema, neovascularization, and epitheliopathy compared to the control group after the second week (P < 0.05), while IOP remained unchanged between groups (P > 0.05).

Conclusion: The addition of 0.05% topical tacrolimus enhances visual acuity and reduces corneal inflammation, neovascularization, and scarring; thus, it can used as an appropriate adjunct treatment for patients with HSK.


Corneal Haziness, Corneal Neovascularization, Corneal Sequel, Herpes Simplex Keratitis, Herpetic Stromal Keratitis, Tacrolimus

1. Looker KJ, Magaret AS, May MT, Turner KM, Vickerman P, Gottlieb SL, et al. Global and regional estimates of prevalent and incident herpes simplex virus type 1 infections in 2012. PLOS ONE 2015;10:e0140765.

2. Pebody RG, Andrews N, Brown D, Gopal R, de Melker H, Francois G, et al. The seroepidemiology of herpes simplex virus type 1 and 2 in Europe. Sex Transm Dis 2004;80:185– 191.

3. Gupta R, Warren T, Wald A. Genital herpes. Lancet 2007;370:2127–2137.

4. Arduino PG, Porter SR. Herpes Simplex Virus Type 1 infection: overview on relevant clinico–pathological features. J Oral Pathol Med 2008;37:107–121.

5. Al–Dujaili LJ, Clerkin PP, Clement C, McFerrin HE, Bhattacharjee PS, Varnell ED, et al. Ocular herpes simplex virus: how are latency, reactivation, recurrent disease and therapy interrelated? Future Microbiol 2011;6:877–907.

6. Kaye S, Choudhary A. Herpes simplex keratitis. Prog Retin Eye Res 2006;25:355–380. 7. Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol 2012;57:448–462.

8. Tsatsos M, MacGregor C, Athanasiadis I, Moschos MM, Hossain P, Anderson D. Herpes simplex virus keratitis: an update of the pathogenesis and current treatment with oral and topical antiviral agents. Clin Exp Ophthalmol 2016;44:824–837.

9. Knickelbein JE, Hendricks RL, Charukamnoetkanok P. Management of herpes simplex virus stromal keratitis: an evidence–based review. Surv Ophthalmol 2009;54:226– 234.

10. Wilhelmus KR. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database Syst Rev 2015:9;1:CD002898.

11. Yoon K–C, Heo H, Kang I–S, Lee MC, Kim KK, Park SH, et al. Effect of topical cyclosporin A on herpetic stromal keratitis in a mouse model. Cornea 2008;27:454–460.

12. Rao SN. Treatment of herpes simplex virus stromal keratitis unresponsive to topical prednisolone 1% with topical cyclosporine 0.05%. Am J Ophthalmol 2006;141:771–772.

13. Zabawski EJ, Costner M, Cohen JB, Cockerell CJ. Tacrolimus: pharmacology and therapeutic uses in dermatology. Int J Dermatol 2000;39:721–727.

14. Keadle T, Morris J, Pepose J, Stuart P. CD4+ and CD8+ cells are key participants in the development of recurrent herpetic stromal keratitis in mice. Microb Pathog 2002;32:255–262.

15. Biswas PS, Banerjee K, Kim B, Rouse BT. Mice transgenic for IL–1 receptor antagonist protein are resistant to herpetic stromal keratitis: possible role for IL–1 in herpetic stromal keratitis pathogenesis. J Immunol 2004;172:3736–3744.

16. Li H, Zhang J, Kumar A, Zheng M, Atherton SS, Yu FS. Herpes simplex virus 1 infection induces the expression of proinflammatory cytokines, interferons and TLR7 in human corneal epithelial cells. Immunology 2006;117:167–176.

17. Eris E, Yuksel N, Pirhan D, Karadenizli A, Aslan M, Gacar G, et al. Evaluation of effect of topical tacrolimus treatment on herpetic stromal keratitis in a rat model. Eye Contact Lens 2016;42:163–170.

18. Park JH, Joo CK, Chung SK. Comparative study of tacrolimus and bevacizumab on corneal neovascularization in rabbits. Cornea 2015;34:449–455.

19. Gupta PC, Ram J. Comparative evaluation of tacrolimus versus interferon alpha–2b eye drops in the treatment of vernal keratoconjunctivitis: a randomized, double– masked study. Cornea 2018;37:1.

20. Zhong J, Peng L, Wang B, Zhang H, Li S, Yang R, et al. Tacrolimus interacts with voriconazole to reduce the severity of fungal keratitis by suppressing IFN–related inflammatory responses and concomitant FK506 and voriconazole treatment suppresses fungal keratitis. Mol Vis 2018;24:187–200.

21. Liesegang TJ. Herpes simplex virus epidemiology and ocular importance. Cornea 2001;20:1–13.

22. Remeijer L, Duan R, van Dun JM, Wefers Bettink MA, Osterhaus AD, Verjans GM. Prevalence and clinical consequences of herpes simplex virus type 1 DNA in human cornea tissues. J Infect Dis 2009;200:11–19.

23. Mott KR, Bresee CJ, Allen SJ, BenMohamed L, Wechsler SL, Ghiasi H. Level of herpes simplex virus type 1 latency correlates with severity of corneal scarring and exhaustion of CD8+ T cells in trigeminal ganglia of latently infected mice. J Virol 2009;83:2246–2254.

24. Shtein RM, Garcia DD, Musch DC, Elner VM. Herpes simplex virus keratitis: histopathologic inflammation and corneal allograft rejection. Ophthalmology 2009;116:1301– 1305.

25. Keating AM, Jacobs DS. Anti–VEGF treatment of corneal neovascularization. Ocul Surf 2011;9:227–238.

26. Miyazaki D, Fukushima A, Ohashi Y, Ebihara N, Uchio E, Okamoto S, et al. Steroid-sparing effect of 0.1% tacrolimus eye drop for treatment of shield ulcer and corneal epitheliopathy in refractory allergic ocular diseases. Ophthalmology 2017;124:287–294.

27. Heiligenhaus A, Steuhl KP. Treatment of HSV-1 stromal keratitis with topical cyclosporine A: pilot study. Graefes Arch Clin Exp Ophthalmol 1999;237:435–438.

28. Shoughy SS. Topical tacrolimus in anterior segment inflammatory disorders. Eye Vis 2017;4:7.