Herpes simplex virus (HSV) keratitis is the leading cause of corneal blindness in developed as well as developing countries. The ocular disease affects approximately 10 million people worldwide.

Herpes viruses are a group of double-stranded DNA viruses with three subfamilies: alpha-, beta- and gamma- herpes viruses. HSV-1, HSV-2, and varicella-zoster virus (VZV) belong to the alpha-subfamily.

HSV spreads by direct contact with virus shed by saliva or genital secretions. During primary infection, HSV-1 infiltrates the corneal epithelial cells. Here it lyses the host cells and releases virions which in turn infect neighboring cells. Then the HSV travels via neuronal cells to trigeminal ganglion and establishes a latent infection. HSV can remain latent for lifetime by storing its genome in the nucleus of the host neuronal cell. While latent, it produces latency-associated transcripts (LATs) that maintain the integrity of the viral genome.

The latent HSV-1 can reactivate and return to the site of initial infection due to various triggers or disease modifiers.

Various disease modifiers reported in published literature are:

The HSV-1 corneal infection is classified simply classified on the basis of anatomical location of principle site of keratitis:

In the past, there had been uncertainty about the appropriate treatment for different variants of anterior segment disease caused by HSV. The debridement of corneal epithelium was considered first-line therapy in HSV epithelial keratitis. The use of corticosteroids, oral, and topical antiviral drugs was not defined by any large-scale clinical trial. This uncertainty existed for many decades until the Herpetic Eye Disease Study was published in 1996.

The Herpetic Eye Disease Study (HEDS)

The Herpetic Eye Disease Study (HEDS) was a series of prospective, randomized, double-masked, placebo-controlled, multi-center trials. It was divided into three therapeutic, two preventive, and one cohort trials. The guidelines proposed by HEDS are still considered as Gold standard for the treatment of anterior segment HSV disease.

The HEDS was conducted in two parts, HEDS-I, which started in May 1989 and was divided into three clinical trials, and HEDS-II, which started in October 1992 and was divided into two clinical trials and one epidemiologic study.

The HEDS-I was developed to assess the efficacy of oral acyclovir and topical corticosteroids for treating HSV stromal keratitis and Iridocyclitis.

HEDS was designed around the following questions which the trials strove to explain and to offer a protocol for the treatment of HSV anterior segment disease:

Are topical corticosteroids effective in treating herpes simplex stromal keratitis in conjunction with topical trifluridine?

The first study of HEDS I- Herpes Stromal Keratitis, Not on Steroid Trial (HEDS-SKN)- was based on this question. 106 Patients with active HSV stromal keratitis who were not on topical corticosteroid in the last 10 days were randomized to treatment with topical prednisolone phosphate drops or topical placebo drops. Treatment was started with 8 drops a day of 1 percent prednisolone phosphate for 7 days and decreased over 10 weeks. Placebo drops were followed the same schedule. All patients also received topical trifluridine drops.

Treatment was deemed successful if, after completion of 10 weeks course of medication, there was resolution of active inflammation. Also, after stopping medication after 10 weeks, there was no recurrence till the 16 weeks follow up period.

Treatment failure was defined as either of these occurrences, worsening of inflammation, no change in inflammation, or occurrence of an adverse event.

The study concluded that as compared to the patients in the placebo group, the patients who received prednisolone phosphate 1% drops had faster resolution as well as the reduction in progression of the stromal keratitis and fewer treatment failures as defined in the study. During the ten-weeks of follow up, the rate of treatment failure was 26% in the corticosteroid group compared to 73% in the placebo group. There was 68% decrease in the progression of stromal keratitis. Delay in the prescription of topical corticosteroids did not affect the final outcome of the disease, as the final visual acuity at 6 months was similar in the two groups.

Should oral acyclovir be added concomitantly along with topical steroids and trifluridine in the treatment of stromal keratitis?

The second part of HEDS I was designed for this premise - Herpes Stromal Keratitis, on Steroid Treatment (HEDS-SKS)- 104 Patients with active HSV stromal keratitis who were already on topical corticosteroid treatment, were randomized either to oral treatment with acyclovir capsules 400 mg five times daily for 10 weeks or to the similar dose of placebo capsules. All Patients received additional topical prednisolone phosphate in the schedule as given by SKN trial. Patients also received topical trifluridine 4 times a day for 3 weeks and tapered to twice a day till the 10^th week.

Over the 16-week follow-up period, treatment failure was noted in 84 days on an average in the oral acyclovir group as compared to 62 days in the placebo group, although, there was no statistical difference in the rate of treatment failure between the two groups. The rates of treatment failure within the ten-week follow up were 38% in the acyclovir group and 48% in the placebo group.

Does oral acyclovir help in better resolution of HSV iritis which is already treated with topical corticosteroids and trifluridine?

Herpes Simplex Virus Iridocyclitis, Receiving Topical Steroids (HEDS-IRT) was the third part of HEDS I. 50 Patients with active HSV iridocyclitis were randomized either to oral acyclovir 400 mg five times daily for 10 weeks or to oral placebo. All Patients received additional topical prednisolone phosphate and topical trifluridine in the schedule as given by SKN trial. The patients were followed up weekly for 10 weeks, then every 2 weeks for the next 6 weeks post-treatment and lastly at 26 weeks.

Out of the originally planned 104, only 50 patients enrolled in the study over a 4 year period. The trial was stopped because of a small sample size and statistically conclusive results were not formulated from this trial.

The trial showed a higher rate of treatment failure in the placebo group (68%) as compared to the acyclovir group (50%).

Does early treatment of herpes simplex virus (HSV) epithelial keratitis with oral acyclovir prevent progression to the blinding complications of stromal keratitis and iridocyclitis?

287 patients with acute HSV epithelial keratitis (dendritic or geographical) were enrolled in the trial within 7 days on the onset of symptoms. Patients were randomized to receive oral acyclovir 400 mg five times a day for 3 weeks or a placebo. All patients were given standard treatment of topical trifluridine.

Patients were followed up for 1 year and had eight visits in that period. The outcome measured was the time of recurrence of stromal keratitis or iridocyclitis in the eye with epithelial keratitis in the beginning of the trail.

In the 1 year of follow up, stromal keratitis or iridocyclitis developed in 11% in the acyclovir group and in 10 % in the study group. Also, stromal keratitis or iridocyclitis was found to be more frequent in patients with a history of previous episodes of stromal keratitis or iridocyclitis (23%) than in the patients without such history (9%). The study found that the overall risk of stromal keratitis or iritis after an episode of epithelial keratitis was much lower than what was previously reported, except when the patient had a history of HSV keratitis or iridocyclitis.

Is low-dose oral acyclovir prophylaxis effective in preventing recurrent HSV eye infection in patients with previous episodes of herpetic eye disease?

This question was studied in the Acyclovir Prevention Trial: HEDS-APT – 703 patients with a recent history of HSV ocular disease but no active disease during recruitment were included in the study. Inclusion criteria was patients with history of any variant of ocular HSV infection viz blepharitis, conjunctivitis, keratitis or iridocyclitis, in the last 1 year. The infection must have been inactive, and the patient not on any treatment, in the last 1 month.

Out of the 703 patients, 357 were randomized to the acyclovir group (400mg twice daily), and 346 to the placebo group. The treatment continued for 1 year, with 5 follow up visits during treatment period and 3 more follow up visits during the 6 month post-treatment period. The patients were evaluated for all forms of ocular and non ocular recurrences during the 18 months of follow up period.

The primary outcome measured was the time of recurrence of any form of HSV ocular disease. Recurrences during the trial were treated with a standard regimen according to the ocular disease, but the patients continued oral acyclovir or placebo for the entire 1 year.

The study reported that, the rate of recurrence of any variant of HSV ocular disease was 19% in the acyclovir group and 32% in the placebo group. There was 50% reduction in the recurrence of stromal keratitis in patients with previous episodes of the infection in the previous year. This effect on prevention of recurrence of stromal keratitis was seen only in patients with history of the same. In patients with a history of other variants of ocular HSV, 4% developed HSV stromal keratitis, while in placebo group it occurred in 3% patients. Additionally the study found that oral acyclovir prophylaxis reduced the incidence of epithelial keratitis from 11% to 9% and that of stromal keratitis from 13% to 8%. Regarding multiple recurrences, 4% of the patients from oral acyclovir group and 9% in the placebo group had more than one recurrence.

How long does the effect of prophylactic oral acyclovir lasts in preventing recurrence of HSV stromal keratitis?

Total 703 immuno-competent patients were recruited for the HEDS-APT study and were randomized for oral acyclovir 400 mg twice daily and placebo for 1 year. These studies evaluated risk of recurrence in patients with history of ocular HSV. The results were evaluated at 12 months and 18 months as previously mentioned. Subgroup analyses that the patients treated with low dose oral acyclovir had 50% less recurrences of ocular HSV as compared to the placebo group during the 12 month treatment period.

However, this preventive action of low dose acyclovir disappeared after cessation of treatment. There was no statistical difference in recurrence of ocular HSV between the two groups over the 6 months once the patients were off the medication.

Does previous HSV eye disease affect the risk of recurrent HSV keratitis? What are the risk factors for recurrent HSV keratitis?

346 patients from the placebo group of HEDS-APT, who had a history of HSV eye disease in the last 1 year, were followed up to 18 months. Demographic data like age, sex, ethnicity, was noted. All recurrences were noted as per the type of involvement. Rates of recurrence were compared for types and number of previous ocular and non-ocular infections.

58 (18%) patients developed epithelial keratitis and 59 (18%) developed stromal keratitis over the 18 months of follow up. Statistical analysis showed that, while the previous episodes of epithelial keratitis did not significantly increase the risk of epithelial keratitis ( p = 0.84 ), previous stromal keratitis increased the risk of recurrent stromal keratitis 10-fold ( p < 0.001 ). This risk was also strongly related to the number of previous episodes ( p < 0.001 ). Age, gender, ethnicity, and non-ocular HSV was not associated with significant increase in risk of recurrence of ocular HSV.

What are the predictors for the development of epithelial keratitis in cases of HSV stromal and/or iridocyclitis?

260 patients who had active stromal keratitis and/or iridocyclitis but no epithelial disease and who were enrolled in the Herpetic Eye Disease Study were evaluated. Patients were given either topical placebo with topical prednisolone phosphate or oral acyclovir with topical prednisolone phosphate for 10 weeks. All patients also received topical trifluridine four times daily for 3 weeks tapered to twice daily for 7 weeks. Patients were followed up for development of HSV epithelial keratitis for 16 weeks.

Epithelial ( dendritic or georaphical ) keratitis occurred in 4.6% of the total patients ( 12 out of 260 ) during 16 weeks follow up. Epithelial keratitis occurred in 6.5% of patients treated with topical steroids without oral acyclovir and 2.7% of patients treated with topical steroid with oral acyclovir. The difference was not statistically significant.

The study concluded that oral acyclovir has similar efficacy as a topical antiviral in preventing recurrence of epithelial keratitis during the treatment of stromal keratitis. It may have an additional suppressive effect in patients using topical steroids.

In some cases, despite combined treatment with oral and topical antivirals, epithelial keratitis recurred. In such cases, antiviral resistance is supposed to be responsible.

It was noted that dendrite often occurred near the site of stromal inflammation, which might be because of shedding of virus from the same corneal nerves or by reactivation of latent virus.

Is there any role of external factors (such as ultraviolet light or corneal trauma) and behavioral factors (such as life stress) in recurrences of HSV eye disease?

Various stressors have been suggested in the literature as triggers for recurrent orofacial and genital HSV, like fever, menstruation, psychological stress, and upper respiratory infection.

308 patients were enrolled in the study to analyze the relationship between external triggers and ocular HSV infection. Out of these 308 patients, 155 were in the acyclovir treatment group and 153 in the placebo group. The patients were required to submit a weekly log of potential triggers. The triggers included were psychological stress, sunlight exposure, systemic infection, contact lens wear, menstrual period, and eye injury.

Out of total 308 patients, 67 experienced recurrences, and out of these 67, only 35 patients submitted a valid weekly log. None of these 35 patients reported stress during the exposure week before onset of symptoms. Patients, who completed the log after the onset of symptoms, over-reported high stress and systemic infection due to recall bias, and were excluded from the final analysis.

Ultraviolet light exposure, contact lens wear, systemic infections were not found to be associated with recurrence of ocular HSV disease. No association was found between the onset of the menstrual period and recurrence of HSV. Eye injuries reported were not enough to form a valid statistical conclusion.

Pitfalls, limitations, and omissions in HEDS

The investigators believe that many of the patients might have been incorrectly diagnosed.

The data in the HEDS-SKN trial was difficult to analyze as many of the patients from the placebo group were given corticosteroids after failing.

In the HEDS-SKN study, after cessation of steroids, 50% of the patients failed during the 6 weeks follow up. The question, which was not answered was, did the patients fail because the steroids were tapered too fast (over 10 weeks)? So, while the study concluded that steroids help in better resolution of stromal keratitis, it didn’t give any guidelines for how the steroids should be tapered to prevent treatment failure.

Conclusion in effect of oral acyclovir on recurrent epithelial keratitis study had low power because of small study population and concurrent use of topical trifluridine by all patients.

In HEDS-IRT the study had to be stopped because of low enrollment. Only 50 patients were studied and thus the conclusions have low power.

In the HEDS-RFS study, only 35 patients submitted a valid weekly log. Thus the sample from which the conclusions were drawn was very small.

There were very fewer reports of corneal injury, which was one of the variables of HEDS-RFS study, and hence no conclusions could be drawn on effect of injury on rate of recurrence of HSV.

HEDS investigators evaluated the effect of patient compliance on the risk of recurrence. They found that 89% of patients of the treatment group were 80% compliant and 72% were 90% compliant. But the compliance rates were similar in patients who developed recurrence to those who did not.

Patients, less than 18 years of age were not included in the study. Children generally have severe disease with more recurrences and more sequelae of the infection leading to amblyopia. Children are more likely to present with bilateral disease compared to adults. Also, the dosage of antiviral drugs is different in children than adults. So it is an open question whether the conclusions provided by HEDS can be applied to children.

Endothelial keratitis as a disease variant was not included in the HEDS.

Therapeutic options since HEDS

Currently, three topical and three oral antivirals are in use.

The topical antiviral medication used in HSV epithelial keratitis includes:

The oral antiviral medications used in HSV keratitis are:

Conclusion

Ocular HSV infection is an infection for life. No therapy exists for eradication on virus from the trigeminal ganglia. Currently approved treatment modalities can only control the severe manifestations of infection, till the treatment is continued. Often corticosteroids are needed for a long time. Physician adherence to the guidelines provided by the HEDS can prevent severe sequelae of the recurrent HSV-1 infections and thus reduce burden of HSV-1 related corneal blindness.

Ready reckoner – HEDS I & HEDS II