For a long time, we have used syndromic thinking, that is, what patients tell us during their medical history and what we see clinically, to determine the way we manage genital herpes.

In fact, many more people are infected than actually have classically appearing herpes (i.e. a vesiculoulcerative lesion on an erythematous base) and this raises a number of important issues both in terms of clinical care and counseling.

Much of this material is relatively new and has been drawn from studies and insights gained over the past decade.

This is an electron micrograph of the herpesvirus.

The herpesvirus family includes 8 viruses. We're going to discuss 2 of them today: herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2). This family of viruses also includes varicella-zoster virus (also known as chickenpox virus), Epstein-Barr virus, cytomegalovirus, Kaposi's sarcoma (KS) virus, among others. The virus has a large double-stranded core of deoxyribonucleic acid (DNA), which is surrounded by an envelope. Not all viruses are enveloped. Fortunately the herpes virus is, and the envelope proteins have allowed us to develop a new test that tells us accurately who's infected and who isn't.

This family of viruses can be divided into 3 groups: the alpha-, beta-, and gamma-herpesviruses. Alpha- and beta-herpesviruses both exhibit latency. When you're not having clinical disease, the virus is present in sensory neuronal ganglionic tissue, located either in one of the cranial nerves or in one of the dorsal root ganglion in the back.

The latency sites for gamma-herpesviruses are thought to be B- and T-lymphocytes.

From a clinical perspective, we are principally dealing with recurrent infection. All patients have primary infection but most primary infections with these viruses are either asymptomatic or unrecognized by both the patient and health care provider.

The main concern in clinical care is the issue of recurrent infection. Most painful and annoying recurrent genital herpes is due to HSV-2, and almost all recurrent cold sores or fever blisters are due to HSV-1. Although genital herpes also can be caused by HSV-1, this type of genital herpes is much less frequently recurrent and each recurrence usually lasts only a few days. As a result, even though new cases of genital herpes are as much as one third due to HSV-1 (especially in adolescents and young adults), more than 95% of recurrent disease is due to HSV-2.

How do you become infected? It's pretty straight-forward. Someone places the virus either on your mucosal surface or your keratinized skin, and you end up with the virus traveling retrograde up the same nerve pathways sensory nerves travel to the skin. You end up with a latent HSV infection in the cranial nerves or dorsal spinal ganglion.

In this slide, you see the virus attaching to the skin, fusing with the skin, traveling to the nerve tissue, and then being periodically reactivated.

We would all like to better understand why HSV-infected patients reactivate virus. It probably has to do with the fact that some small change occurs in our immune system, particularly in our cell-based immunity (i.e. T-helper 1 lymphocyte (Th-1) type immunity) or circulating immunity (Th-2 immunity) or both. Exactly how this happens is unknown.

Issues such as psychological stress, physical stress, being immunocompromised, or having a menstrual period can contribute to lowered immune competence.

Here's the progression of lesions. Most patients start with some erythema, or redness. Interestingly, when you have primary infection, the virus presents in ganglionic tissue very quickly. As a result our ability to prevent acquiring infection after having been exposed is very limited. Instead, most of our efforts clinically have been directed toward managing this infection once it's already established.

After the initial redness, you develop a vesicle. Initially, the vesicle is filled with a clear fluid, and it may then become filled with white cells. The result is a pustule. Un-roofing of vesicles and pustules results in an ulcer.

You usually see some crusting, then scabbing, and ultimately completely healed skin. This whole sequence of 6 steps usually takes somewhere between 4 to 10 days for recurrent lesions and up to two weeks for primary lesions.

We're going to talk about 3 presentations of genital herpes infection. The 6 pictures I just showed represent classic genital herpes, which is recurrent and most often painful and irritating. But there are 2 other kinds of genital herpes presentations. One is unrecognized, or inapparent infections, and the other is subclinical HSV shedding. The first involves clinical lesions that do not look like classic herpes but are caused by HSV infection. The second, subclinical shedding, occurs when people have virus that is retrievable from the skin, but there is no manifestation of disease. In other words, there are no classic ulcers, and there is no unrecognized or inapparent infection.

Let's talk first about subclinical shedding. When I was trained in the 1970s, I was told that if you had a herpes outbreak 4 times a year (once every 3 months) and there were 90 days between outbreaks, you shed virus asymptomatically perhaps 1% of those days or 1 in 90 days.

It turns out that this was a significant underestimate. We now know that within the first few years of being infected, most people are shedding somewhere between 10% and 20% of days; in some cases, individuals shed considerably more than that.

The reason we now have at least 50 million Americans infected with HSV-2 has to do with sexual transmission from infected individuals who do not have classic genital herpes lesions to uninfected partners. Responsibility for most transmission has to do with transmission while people either are asymptomatic, but shedding virus, or alternatively have atypical or unrecognized clinical herpes.

I want to mention perianal herpes, which often includes perianal itching and irritation. When people end up with herpes in the perianal area it's either because of autoinoculation from the front of the genitals or spread to the perianal region along closely related nerves in the sacral area.

In other words, the HSV on the front of your genitals can be spread to other areas through toweling, wearing clothes, sexual foreplay and sharing of sex toys.

When patients have an outbreak on their vulva or the shaft of the penis, they may also have outbreaks on the cervix, the scrotum and the perianal area as well.

This is a graph of age vs prevalence of this virus. Using new accurate antibody tests, we find that by the age of 30, almost 25% of Americans have HSV-2 antibodies. That breaks down to about 30% of women and 20% of men.

So if there were 100 of you, and I drew blood on all of you, about 25 would have HSV-2 antibodies. Of those 25 who have HSV-2 antibodies, 10% of the 25% (or 2-3% of the total number) will have a history of classic genital herpes. And that is what we have been aware of over the last 5 decades - that is, patients having classic painful recurrent genital lesions.

Also, another 10% of those infected, will have purely asymptomatic disease; their immune system largely prevents the clinical appearance of infection. The middle group have unrecognized or inapparent herpes. These presentations of herpes, nonclassical in appearance, actually are 8 to 10 times more common than classic genital herpes.

I think one of the most important issues to recognize is the degree to which herpes is usually quite atypical in its appearance. Why haven't we known about this before? Because when infectious diseases are initially discovered, the most obvious and classic manifestations are the ones we classify as a particular disease. As time goes on, we have developed better tests and gained a more accurate picture of the full spectrum of genital herpes infection.

Between 1976 and 1994, the percentage of patients infected with HSV-2 rose from 18% to 22%. Today, I would estimate that at least 25% of Americans are HSV-2 infected.

Where does this fit in the context of other sexually transmitted disease (STD) in terms of how many Americans are currently infected? Herpes simplex virus 2 is the number one sexually transmitted infection, followed by human papillomavirus (HPV).

In terms of new cases every year, however, HPV is the most common; HSV-2 is third, after chlamydia.

Let me start by giving credit to Dr. Rhoda Ashley, who helped us better understand, through improved laboratory testing, what people actually tell us when they have herpes, but don't know they have herpes -- and physicians often don't know either. These are the kinds of complaints patients have when unrecognized or inapparent genital herpes is the culprit.

There are a large number of conditions that female patients tell us they have when they may have genital HSV-2 infection.

These basically break down into 2 categories: lower genital tract inflammatory disease, and pain syndromes in the low back and upper aspects of the lower extremities.

HSV-2 infected men have a similar but somewhat different spectrum of complaints for unrecognized or inapparent genital herpes infection.

The figures on this pie chart are approximate. For example, if we take a hundred people who are sexually active, about one quarter of them will have HSV-2 antibodies. These infected individuals are represented in the pie chart: 10-20% are asymptomatic, 10-20% have recognized classic symptomatic genital herpes and the remaining 60-80% have atypical genital herpes which is frequently referred to as unrecognized or inapparent disease.

The height of the bars on this chart show that patients with asymptomatic infection and classic symptomatic herpes are considerably less common than those with unrecognized symptomatic infections.

In the past few years, the Food and Drug Administration (FDA) approved 2 new tests to diagnose genital herpes. In May 2002, the Centers for Disease Control and Prevention (CDC) published the new 2002 STD Treatment Guidelines and recommended that HSV-2 antibody testing be available when patients are diagnosed with genital herpes.

Let's talk about how herpes has been commonly managed in the past. When we see a patient, and the patient says, "I have burning and pain down there," and they have some vesicles or ulcers, we make a syndromic diagnosis of genital herpes. The patient usually tells us this has happened before, maybe a few months ago, and we say this is recurrent genital herpes.

Some of us have done cultures for herpes, and I certainly recommend them, because there are 2 kinds of genital herpes that are classic, either HSV-1 or HSV-2. Herpes simplex virus 2 is the most common presentation in terms of recurrent disease, and HSV-1 is less common. One of the benefits of culture is knowing which virus is causing genital herpes because this will affect your counseling message. Genital herpes due to HSV-2 can be a very frequently recurrent disease while genital herpes due to HSV-1 is a much less frequently recurrent disease and each outbreak is shorter and somewhat less painful.

In the United States today, if a 27-year-old female patient says she has burning down there, and she's never had it before, and she has the signs of genital herpes, she's going to have an average of 4 to 5 outbreaks in the first year. She's going to lose approximately half an outbreak a year, and at 5 years, she's going to be having 2 to 3 outbreaks. If she has HSV-1 infection, she's going to have 1 to 2 outbreaks in the first year and very few by 5 years.

What's wrong with culture? You need a lot of virus to get a positive culture. Cultures are frequently falsely-negative when the patient has genital herpes. This can be difficult for patients. A negative test usually means you don't have something. In this case, a negative test does not mean that. It usually means the test wasn't able to detect the virus. This can be confusing to patients who naturally want to hear that they don't have genital herpes..

Now let's talk about the 2 blood tests that have recently become available. The HerpeSelect test is sent to the laboratory. It's type-specific and differentiates between HSV-1 and HSV-2 infection with high accuracy. This is an immunoglobulin G (IgG) antibody. It becomes positive in at least half of people at 3 weeks, and in 98% of people by 6 weeks.

This is the point-of-service HSV-2 antibody test; also a very good test with high sensitivity and specificity. This particular test becomes positive in a few weeks for most patients. It can be administered and read in a few minutes in the office.

Who is a candidate for testing? The first category is people who have suspicious symptoms or a history suggesting unrecognized or inapparent herpes.

The second category is patients with classic herpes, who you'd like to be able to tell that they definitely have herpes. We are aware of the communication problems with patients who have herpes. If you tell patients they definitely have herpes, they hear that they probably have herpes; if you tell them they probably have herpes, they hear that they might have herpes; if you tell them they might have herpes, they hear that it's unlikely they have herpes. So there is a deflation of what people hear relative to what we tell them. This is true for all disturbing information, especially sexually transmitted diseases. One of the benefits of blood testing is that it reinforces to patients that they actually have a problem. We wouldn't consider treating patients with AIDS or hepatitis C without a confirmatory laboratory test, and I think we need to bring that same level of diagnosis to the HSV-testing area.

The next issue is that of individuals requesting an STD screening and those at risk for HIV infection. When the typical patient comes to our office and says, "I need an STD test," or "I'm worried because of my spouse's behavior. I need an STD test," what should we do? We do a chlamydia test. In females, we do a wet prep for trichomoniasis. We'll offer an HIV test depending on the circumstances. We might do a gonorrhea or syphilis test depending on specific risk factors and the level of those diseases in the local community. We might consider a hepatitis B test.

If you want to screen your patients for STDs, the most common, unrecognized STD infection is not chlamydia, it's not trichomoniasis, it is genital HSV-2 infection. So, a blood test for HSV-2 antibodies should be done as part of the routine STD evaluation.

The other issue I want to mention is when patients have genital herpes, their partners are often unaware that they may also have herpes. This is a highly contagious disease and offering blood testing to the spouse or sex partner is appropriate and may well detect unrecognized HSV-2 infection.

There are old and new ways of thinking about herpes. We used to think that herpes was an infection that occurs 4 to 5 times a year for 4- to 6-day outbreaks, and subclinical shedding was infrequent or unusual. Today, our thinking is that 75% of shedding episodes are subclinical. That is, most people who are shedding virus do not have classic disease. Also, reactivation rates for herpes in terms of total days of shedding virus is much higher than previously suspected, in the range of 15% to 20% of total days. Genital herpes infection is more like hepatitis C, in that it should be seen as a continuous infection, rather than an intermittent infection.

Let's talk about treatment. We direct our treatment to relieving symptoms and healing lesions as well as reducing the frequency of recurrent episodes. I want to emphasize that suppressive therapy provides the opportunity to go from 4 to 6 outbreaks a year to 1 or fewer outbreaks. If you are in the high recurrence group (1 outbreak a month or 12 a year), suppression can reduce outbreaks by 80% to 85% for a total of perhaps 1 to 2 outbreaks per year. There is also a strong suggestion that by treating people with antiviral therapy for herpes, you significantly reduce the likelihood of viral transmission, perhaps as much as 80%. This undoubtedly occurs due to reduced lesional disease and reduced asymptomatic shedding.

There are a number of agents available for treating herpes. Valacyclovir and famciclovir are second-generation drugs. They are converted to first-generation forms of anti-HSV medication. This class of drug was discovered in the 1970s. The herpesvirus produces an enzyme called thymidine kinase. It turns on the acyclovir or penciclovir molecule so that it attaches to DNA in infected cells and prevents the virus from using DNA to further replicate itself.

These are the various medications that are available to treat genital HSV.

The treatment for initial infection or first clinical episode genital herpes is shown on the slide. If the decision is to use episodic therapy, then the simplest regimen for the patient is the recently approved three-day treatment course using Valacyclovir 500 mg twice a day. This approach is two days shorter than the standard regimen, is equally effective, and is likely to result in higher compliance and hence better outcomes. A shorter treatment course undoubtedly works because most viral replication takes place either during the prodrome (i.e. prior to the appearance of vesicles or ulcers) or in the first few days of the appearance of lesions.

If we want to suppress virus in patients, we routinely start with 500 mg a day. In some patients who break through on 500 mg, we use either 500 mg twice a day or 1 g once a day.

This is a single clinical trial; the results of a multi-year research project published by Goldberg in 1993. In the green, people with genital herpes who are treated episodically go from having 12 outbreaks a year in the baseline year to about 12 outbreaks a year in year 1. Episodic therapy has no effect on the frequency of recurrences, only on the duration of each outbreak.

The patients in yellow are treated with suppressive therapy and they have about an 80% to 85% reduction in number of outbreaks. Those treated initially with episodic therapy were then switched to suppressive therapy, and you see again an 80% to 85% reduction in the frequency of recurrences.

I want to cover 4 or 5 tips on suppressive therapy. Number one, although the package labeling talks about using suppressive therapy if you have 6 or more outbreaks, in many practices today, clinicians will offer people suppressive therapy at the second or third visit. This is especially true for patients in the transportation industry (flight attendants, pilots, bus drivers, and truck drivers) and in sales positions. These are individuals who have limited control over their schedule and may have to delay treatment of their genital herpes lesions. Also, they often have increased pelvic pressure due to extended periods of sitting and this may cause reactivation of their genital herpes.

We also ask very pointed questions about the impact of HSV on the patient's life. We are increasingly aware that a number of patients end up on Paxil (paroxetine) or Prozac (fluoxetine) or other psychotropic medications because of depression and anxiety associated with having recurrent genital herpes.

In terms of length of suppressive therapy, I don't want to commit young patients to a lifetime of anti-viral therapy. On the contrary, the average duration of suppressive therapy is between 9 months and 2 years in my practice. I find that over two-thirds of patients can be successfully transitioned from suppressive to episodic therapy. We give all our patients an extra month or two supply of medication so they can restart their suppression prior to coming back to see us if they start having frequently recurring lesions.