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State of the art: Treatment prospects for herpes simplex disease
John A. Hovanesian, MD, FACS, talks with Herbert E. Kaufman, MD, about the Herpetic Eye Disease Study, testing, cultures and regimens.
 John A. Hovanesian |
John A. Hovanesian, MD, FACS: We are joined by a highly honored and respected leader in the cornea community, Herbert E. Kaufman, MD. Dr. Kaufman maintains an active research interest in virology and joins us to talk about herpes simplex disease. Dr. Kaufman, thanks for joining us.
Herbert E. Kaufman, MD: It is my pleasure.
Dr. Hovanesian: Dr. Kaufman, how has our thinking about herpes changed in the past 10 years?
Dr. Kaufman: A lot of exciting stuff has happened. Some years ago, through the National Institutes of Health, we organized the Herpetic Eye Disease Study (HEDS), and we tried to answer several questions that were really debated at that time. First of all, do oral drugs have anything to offer us? We treated stromal disease and iritis — some patients with and some patients without. And the answer was, “No, it was not of any benefit.”
 Dendritic corneal ulcer caused by HSV keratitis. Images: Used with permission from Yves Lachkar, Hôpital Saint-Joseph | ||
Then we asked the second question, “If you have herpes epithelial disease and you treat early with oral acyclovir, does it prevent stromal disease from developing?” And the answer in patients, some treated and some not, was, “No, the incidence was the same.” The acyclovir did not do anything.
 Herbert E. Kaufman |
Then we asked the third question, “If you give oral acyclovir, does it prevent recurrences of herpes?” And the answer to that was, “Yes, but not as good as we’d like.” It prevents about half the recurrences of herpes. In patients who get only epithelial disease, it may not be worth it. But in patients who are getting recurrent stromal disease, certainly it seemed to be worth it.
Then we asked some more questions that were debated. For example, in the past I suggested using antivirals and steroids for disciform edema and for treatment of stromal disease, but there was always this nagging question, “Does the addition of steroids that suppress the immunity really cause increased recurrences, further damage, spread of the virus?” There were laboratory studies one way or another. So we decided it was time to find out in patients. What we found basically was, “Yes, adding steroids really improves disease.” Patients see, they become asymptomatic, the disease clinically either goes away or is much improved. Then we followed them for at least 6 months after the cessation of steroids, and we found that there was no penalty. There was no increase in epithelial disease. There was no increase in stromal disease. That is, the steroids benefitted the acute disease, and there was no damage caused by them in this study in which they were also covered by an antiviral during the treatment.
Dr. Hovanesian: That study certainly changed the standards of practice for both general ophthalmologists and cornea specialists because it defined what we need to do in these broad categories of disease. But when you have a patient who develops recurrent, isolated epithelial keratitis, do you routinely prescribe oral antivirals, whether it is oral acyclovir or one of the others?
Dr. Kaufman: It depends on how often it recurs. If I have a patient who gets a recurrence once every couple of years, I often do not. If I have someone who is really troubled by the disease, I know that oral acyclovir or, better now, Valtrex (valacyclovir, GlaxoSmithKline), which is basically the same drug but absorbed more reliably, will reduce the risk of recurrences and yet is almost a harmless drug. The risk of oral Valtrex is so small despite the cost that I will prescribe it for someone who is really troubled.
Dr. Hovanesian: In cases in which a patient does not tolerate topical antiviral therapy, do you feel comfortable, particularly with Valtrex, using oral agents alone for epithelial disease?
Dr. Kaufman: That is an important question because there is a subset of patients who have trouble taking eye drops, such as people with arthritis and some older people. Some years ago, Collum in Ireland showed that oral acyclovir actually is excreted in tears and can treat epithelial disease. We do not know if it is as effective as Viroptic (trifluridine, Monarch Pharmaceuticals), and in general I prefer topical therapy with known efficacy. But certainly, in people who have trouble taking drops, I use oral Valtrex. When I have a child who has herpes, it is so important to clear that up, and they have so much trouble with drops that I usually prescribe both the Viroptic and the oral Valtrex.
Dr. Hovanesian: What about patients who have recurring stromal disease in which there is the threat of permanent scarring and loss of corneal clarity? Do you prescribe ongoing steroid as well as antiviral?
Dr. Kaufman: I use steroid as long as the disease is active, but premature cessation can cause additional scarring. Once I start steroid for stromal disease, I continue with at least a minimal dose for at least 3 months before stopping. Once the disease becomes inactive, I prescribe an oral antiviral. One of the awful questions that nobody answers is once you prescribe an oral antiviral to reduce recurrences, how long do you keep it up? What we found in the HEDS study is that when you give the oral antiviral, it reduces the risk of recurrence. As soon as you stop it, the risk comes back to just what it was before. No more — there is no overshoot — but no less. And so you can ask yourself once you put people on a suppressive regimen, does it make sense to keep them on for the rest of their life? There is no answer to that, but maybe yes.
Dr. Hovanesian: It seems that some patients go through periods of their life where they are prone toward recurrences and progressive damage and then go through long periods where there is no activity of disease. Can you help explain this?
Dr. Kaufman: No. The question is a good one. The observation is correct. Sometimes people have bouts of recurrences, and then it just goes away. And we do not understand why.
Dr. Hovanesian: Like many good studies, HEDS answered many good questions, but it also posed many other questions that we still do not have answers to — is that correct?
 Geographic corneal ulcer caused by HSV keratitis. |  Stromal damage caused by HSV keratitis. |
Dr. Kaufman: That is absolutely correct. There are a bunch of new observations that really make you crazy. I studied people who have never had disease, and I did herpes cultures on them. I found that a small proportion was actually excreting live virus. Doing cultures is a very insensitive technique, you need a ton of virus to pick it up the way I did. So now we use polymerase chain reaction (PCR), which is a much more sensitive technique.
Dr. Hovanesian: What about other sources of herpes or patients who have no clinical herpes of any sort?
Dr. Kaufman: No clinical herpes of any sort — you take just a little bit of tears and a little bit of saliva morning and night for 30 days. More than 90% will have herpes DNA in their tears and their saliva, at least some of the time. Not all the time, but sometime during the month, you and I and most of the people reading this article will be excreting herpes virus DNA.
Dr. Hovanesian: So there is probably a spectrum of disease activity that only PCR can detect.
Dr. Kaufman: What we know is that, many years ago, we took isolates from different people, and we found that some cause severe disease in rabbits, some cause virtually no disease in rabbits and some are just there and they are part of your body and they live happily with you unless you get a renal transplant or HIV. It is as if there are good viruses and bad viruses, as well as the changes in your own immune response, and we do not understand all of this very well, but most of us presumably have been infected and the virus is happily there and it does not bother us.
Dr. Hovanesian: How often do we see true bilateral, clinically apparent herpes simplex in the eye?
Dr. Kaufman: It is rare, but it happens often enough so that it is a source of malpractice suits and that sort of thing. It certainly can occur. For example, in people who have no history of clinical herpes and who are probably excreting tiny amounts of virus, occasionally after cataract surgery or corneal transplant surgery they will suddenly come down with a herpes infection. It may not look typically dendritic, but if you are a clinician and you do surgery on someone and you see a funny epithelial defect that you are having trouble healing, you better think, “Maybe it’s herpes.”
Dr. Hovanesian: When you think that, would your first step be to treat it empirically with Viroptic or to perhaps attempt to culture it or do PCR? What would your clinical approach be?
Dr. Kaufman: It depends on your own set-up. For example, I would culture it or look for a herpes antigen. But that is just because I am set up to do it. In the real world, I think you would be perfectly justified putting people on an antiviral for a couple of weeks and doing a therapeutic test.
Dr. Hovanesian: Often the treatment of epithelial disease with Viroptic leads to an ongoing epitheliopathy that seems just not to heal for many weeks. Often there is less pain, but with or without staining epithelial defect, Viroptic seems to provide no help and yet clinicians are inclined to want to continue Viroptic. Are these purely sterile “meta-herpetic” lesions?
Dr. Kaufman: The observations are fascinating. First, as far as Viroptic as an antiviral is concerned, the problem with Viroptic, which I developed, is that it is toxic to tissue. It is not totally selective. So you may say, “Why don’t we use acyclovir ointment?” The problem with acyclovir ointment is that it is an ointment, and it blurs your vision and you need to take it several times a day. So basically, the patient is blind while he is being treated.
There is a new hope. Ganciclovir, which works in many ways like acyclovir, is available in Europe and will soon be available here. It is a gel that does not blur vision and yet avoids the toxicity of trifluridine because it inhibits viral DNA synthesis and not that of normal corneal cells. I think that will be a big step forward. In addition, there is evidence that ganciclovir can be effective in treating adenovirus infections.
The second thing is, usually if you have treated an ulcer for 3 weeks, there is no virus there anymore. On the other hand, if you are worried, what I will do is stop the Viroptic and put patients on oral Valtrex. In the future, I would use ganciclovir instead of Viroptic.
New directions in treatment
Dr. Hovanesian: Let’s move now to new directions in treatment of herpes simplex. You maintain an active research role in this. Tell us what is most exciting and please give us a little detail on the things that you think are most promising.
Dr. Kaufman: One of the things we are most excited about is a new antiviral that is a helicase-primase inhibitor. And what that does is prevent the viral DNA, which is a double strand, from unwinding and starting its new multiplication. So it works differently from the present antivirals, which are like building blocks but just a little bit abnormal. This is a whole prevention of unwinding and multiplication. It seems nontoxic, and at least in the laboratory, and it is more effective than acyclovir. The other thing is, we have found, in the laboratory at least, that Viroptic and ganciclovir are actually synergistic. What that means clinically, we do not know yet, but that is interesting.
Dr. Hovanesian: In other words, there may be some role for using both drugs simultaneously.
Dr. Kaufman: Yes, and we are testing the possibility that we can use the helicase-primase inhibitor or the synergistic topical combination to treat stromal disease.
Dr. Hovanesian: Interesting. And this helicase-primase inhibitor, how would you anticipate delivering it to the eye?
Dr. Kaufman: We know that it is nontoxic orally, at least in animals, and you may just be able to take it orally. But that is a question that has not been solved yet, what is the best way to get it. Nobody knows yet.
Dr. Hovanesian: We are probably several years from any human approval, but are we close to starting some human trials of these drugs?
Dr. Kaufman: Yes, I think we are.
Dr. Hovanesian: Is there a particular company that has an interest in this?
Dr. Kaufman: It was originally developed by Bayer in Germany, but it has sort of delegated to another separate company, and I am not sure where that stands.
Dr. Hovanesian: Any other technologies on the horizon that look promising for herpes simplex?
Dr. Kaufman: I thought that if people are excreting virus in tears — normal people — maybe you could use this as a way to test antivirals. Maybe, for example, you could show that acyclovir or Valtrex reduces the amount of virus actually being put out. We have not been able to show that, even though it reduces the risk of recurrent disease.
Dr. Hovanesian: So treatment with a drug in healthy individuals does not reduce shedding of virus that is asymptomatic in tears and saliva?
Dr. Kaufman: In genital disease it seems to do it somewhat, but we have not been able to show that in ocular disease, although the study is ongoing.
Dr. Hovanesian: Any other last thoughts for clinicians on any changes to their approach to herpetic disease that you would recommend?
Dr. Kaufman: The only thing we have not mentioned is what happens after corneal surgery. For example, oral antivirals allow me to do refractive surgery on people who have had a history of herpes. I start them before and continue them for a few weeks after their refractive surgery. Similarly, in corneal transplants, they have been wonderful in preventing recurrences of herpes and improving the prognosis of corneal transplant. Ganciclovir should be less toxic that Viroptic and should be useful after surgery.
Dr. Hovanesian: Help me understand the specifics in the way you practice. If a patient had a history of epithelial herpes, otherwise a good candidate for refractive surgery, what procedure would you lean toward? How long would you wait from an active episode until you would be comfortable performing surgery?
Dr. Kaufman: Most of the procedures I have done have been LASIK. I usually start at least a couple of days before LASIK, and I keep it up for 2 weeks after LASIK. Nobody knows that that is the right way to do it, but that is what I do and it has worked well. In patients with some slight superficial scarring, I have done PRK to remove the scar as well as correct the error and treat them with the same prophylactic regimen.
Dr. Hovanesian: How long do you wait after an active episode before you would recommend surgery? Is 6 months enough? Do you wait a year?
Dr. Kaufman: There is no answer to that. I do not wait a long time. I figure that if they are asymptomatic for a few weeks, I go ahead.
Dr. Hovanesian: You said you will continue the antivirals for a couple of weeks after surgery. How high a dose do you use and what route do you deliver them?
Dr. Kaufman: I give 500 mg of oral Valtrex twice a day.
Dr. Hovanesian: So 500 mg of oral Valtrex twice a day for a few days before and up to 2 weeks after surgery. And you have not noted recurrences of herpes in these patients with LASIK?
Dr. Kaufman: Not so far. That is correct. I feel it is safe. Now, a large-scale study needs to be done, and there are all of the usual qualifiers, but so far I am comfortable with this.
Dr. Hovanesian: Dr. Kaufman, thank you so much for joining us. It has been a pleasure talking with you.
For more information:
- John A. Hovanesian, MD, FACS, is a clinical instructor at the UCLA Jules Stein Eye Institute and is in private practice in Laguna Hills, Calif. He can be reached at Harvard Eye Associates, 24401 Calle De La Louisa, Suite 300, Laguna Hills, CA 92653; 949-951-2020; fax: 949-380-7856; e-mail: drhovanesian@harvardeye.com. Dr. Hovanesian is a consultant for Sirion Therapeutics.
- Herbert E. Kaufman, MD, is a professor of ophthalmology, pharmacology and microbiology at Louisiana State University. He can be reached at LSU Eye Center, 2020 Gravier St., Suite B, New Orleans, LA 70112; 504-568-2414; fax: 504-568-2385; e-mail: hkaufm@lsuhsc.edu. Dr. Kaufman works for Sirion Therapeutics.