Uday K Bhatt, MN Abdul Karim, Jeremy I Prydal, Senthil V Maharajan, Usama Fares

Ocular herpes is a viral infection of the eye caused by the herpes simplex virus (HSV), a double-stranded DNA virus. Corneal scarring caused by herpes simplex keratitis (HSK) is the leading infectious cause of penetrating corneal graft in high-income countries. Acyclovir is an antiviral drug known to have a protective effect against recurrences in herpetic eye disease. While there are some studies which have evaluated the effects of intervention with oral antiviral in preventing such recurrences in people with corneal grafts, a systematic review of all comparative clinical trials has not been previously undertaken. To assess the efficacy of oral antivirals such as acyclovir in any dosage when taken for six months or more, in preventing recurrence of herpetic keratitis in people having corneal graft surgery for herpetic keratitis. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2016), Embase (January 1980 to June 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 1 June 2016. We handsearched conference proceedings and contacted authors of the included studies and researchers active in the field. We included randomised controlled trials (RCTs). People enrolled in these trials had corneal grafts for HSK. The intervention was oral antivirals for six months or more following the corneal graft surgery, and this was compared to no treatment or placebo. Two review authors independently assessed trial quality and extracted data. We contacted trial investigators for any clarification or missing information. We graded the certainty of the evidence using GRADE. We included three trials, involving 126 participants, comparing the use of oral acyclovir to no treatment or placebo. Two studies were conducted in single centres in Turkey and the USA, and one was multi-centred in the Netherlands. In general, the studies were poorly reported and it was difficult to judge the extent to which bias had been avoided.Oral acyclovir may reduce the risk of recurrence of herpetic keratitis (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.13 to 0.64, 126 people, low-certainty evidence). Based on data from the included trials, this corresponds to approximately 23 fewer cases of HSK recurrence (95% CI 29 fewer cases to 12 fewer cases) per 100 corneal graft operations if oral acyclovir is used.Oral acyclovir may reduce the risk of graft failure (RR 0.40, 95% CI 0.16 to 0.97, 126 people, low-certainty evidence). Based on data from the included trials, this corresponds to approximately 13 fewer cases of graft failure (95% CI 18 fewer cases to 1 fewer cases) per 100 corneal graft operations if oral acyclovir is used.None of the studies reported any serious side effects of the antivirals necessitating stoppage or change. None of the trials reported outcomes over the long term (more than two years) or any data on quality of life. Compared to placebo or to no treatment, oral antiviral (acyclovir) may reduce the risk of recurrence of herpetic keratitis in the first 12 months in eyes that have undergone corneal graft surgery.