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Genital Herpes: Framing the Problem, Diagnosing the Disease (Slides With Transcript)

Authors: H Hunter Handsfield, MD; Peter A Leone, MDFaculty and Disclosures

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  • Genital Herpes: Framing the problem

    Slide 1.

    Genital Herpes: Framing the problem, Diagnosing the Disease. Prevention and Management for Healthcare Providers

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  • Michelle Manzo, MPH: Hello everyone; I'm Anne Michelle Manzo with Medscape Infectious Diseases, and I would like to welcome you to our Live Web Conference entitled: "Genital Herpes: Framing the Problem, Diagnosing the Disease." This is a continuing education activity made possible by an independent educational grant from GlaxoSmithKline. Before we begin, let me take a few minutes to go over the format of today's program. Dr. Handsfield and Dr. Leone will alternate in the presentation of 4 segments on genital herpes. Each presentation will last approximately 10 minutes, and at the completion of all 4 presentations, there will be a question and answer session. At the end of the program, a pop-up will appear with the link to the post-test where you can answer questions to obtain CME and CE credit.

    Now I would like to introduce our first faculty presenter. H. Hunter Handsfield, MD, is Senior Research Leader at the Battelle Centers for Public Health Research and Evaluation, and a Clinical Professor of Medicine at the University of Washington Center for AIDS and STD. Dr. Handsfield, good afternoon, and thank you for joining us, and we'll commence the educational series with your presentation on the epidemiology and clinical presentation of genital herpes.

  • Slide 2.

    Welcome, Moderator, Michelle Manzo, Medscape

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Genital Herpes: Epidemiology and Clinical Presentation

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  • H. Hunter Handsfield, MD: Thank you, everybody, and greetings. Thanks for joining this presentation. Just as a bit of a preamble, I'll just make the point that genital herpes is probably the most complex of certainly all the commonest STDs [sexually transmitted diseases]. I suppose you could argue syphilis and HIV have similar issues, but there is a significant problem with the relative complexity -- both epidemiologically, clinically, -- and understanding herpes is not a trivial exercise in clinical acumen and epidemiologic understanding. This program sort of reflects that. There are a lot of slides, maybe even more than is easy to absorb, and Dr. Leone and I will go through them quite quickly, but this will only scratch the surface for many of you. You're probably going to need to really fill in your knowledge; some additional reading and so on probably is a good idea.

  • Slide 3.

    Genital Herpes: Epidemiology and Clinical Presentation. H. Hunter Handsfield, MD

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STDs Are Sexist

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  • So whenever I speak about STDs at all, whether it's herpes or anything else, I always start with the point that STDs are biologically sexist. The transmission efficiency for most STDs is greater from men to women than the reverse. If you think about it, internal inoculation of an infectious secretion has to be an efficient way to transmit any infection, whereas a male generally does not leave a sexual encounter with internalized inoculum of his partner's secretions. Now women more commonly are asymptomatic; they tend to have typical nonspecific symptoms; they don't seek care properly; [and] the diagnosis is inherently more difficult. Just think of the relative ease of working up a urethral discharge in a guy vs a vaginal discharge in a woman and feeling pretty confident at the end of a brief office visit that you know what's going on. And finally, partly for those reasons, but really because of anatomy and physiology, the complications are more frequent in a woman and often permanent or severe.

  • STDs are Sexist

    Slide 4.

    STDs are Sexist

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  • The next slide shows a World War II era poster that really reflects the nontruth, exact opposite of what we just discussed: It shows an obviously masculine hand being bloodied by the thorns of a rose smashing into the face of a woman and dripping blood. [This characterization] is completely opposite of what the truth is as we've just implied. I would point out that it is as a reflection of its time, namely, the 1940s, and aimed at an essentially all-male audience, and perhaps it had some educational value, but it certainly was off the mark of what the truth really is.

  • Graphic

    Slide 5.

    Graphic

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  • This is the cover of the German magazine Der Speigel. This picture on the cover, which is obviously about herpes -- and I'm sure there are people there who can read the German better than I can -- is useful to illustrate which of these individuals looks more concerned about the events that are about to transpire, and who looks concerned about getting those events under way as promptly as possible. And that's not a bad paradigm, as to the way sex works and the way who is at risk for the outcomes for importance whether it's herpes or most other STDs.

  • Slide 6.

    Graphic

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Herpes Simplex Virus and Genital Herpes

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  • So getting into the meat of what we're talking about today, this slide on herpes simplex viruses is microbiology 101. You've all seen this before, and you should already know that herpes simplex viruses cause an initial mucocutaneous infection. There's retrograde infection on sensory nerves. It used to be said that the virus activated intermittently. It's actually, we now know, more continuous viral replication; although it's clinically latent, there's actual biologically probably continued viral replication not only in cranial and spinal ganglia, but also in peripheral nerve endings. And as you'll see, that translates into much more frequent episodes of subclinical viral shedding than has not been understood until very recent research.

    There are 2 viruses, cleverly called types 1 and 2. Note that the proper terminology is Arabic numerals and not Roman for those who care about that sort of thing. Second, the numbers refer to the virus, not the disease [so it is not] proper to say I have herpes type 1 -- meaning oral herpes -- or I have herpes type 2 -- meaning genital -- because either virus can affect either part of the body. But it's not even. HSV-1 [herpes simplex virus type 1] is very dominantly the cause of orolabial herpes, but it does cause rising proportions of initial genital herpes, probably because of increasing frequency of oral sex among sexually active people. HSV-2 [herpes simplex virus type 2] by contrast is almost entirely genital, and oral [HSV-2] infection is relatively uncommon and recurrent oral HSV-2 is very uncommon. HSV-2 accounts for more than 90% of recurrent genital herpes. We'll talk about this more in a little bit.

  • Slide 7.

    Herpes Simplex Virus

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Genital Herpes: Disease Impact

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  • The next slide shows it's not a reportable disease, [thus] you have to use indirect measures to understand the epidemiological frequency. This is a measure going back 3 plus, 4 decades really, showing number of initial visits to clinician offices for genital herpes. The upper trend is undoubtedly a combination of increased disease incidence, increasing patient concerns, and increasing diagnostic understanding by providers, and the proportion of those contributions can be noted, these particular data.

  • Genital Herpes: Initial Visits to Physician's Offices, 1966-2005 [Graph]

    Slide 8.

    Genital Herpes: Initial Visits to Physician's Offices, 1966-2005 [Graph]

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  • The next slide shows the prevalence of genital HSV infections serologically in randomly selected population-based samples in the United States for 3 time periods -- the late 70s, the early 90s, and most recently the period from 1999 to 2004. And the take-home message is that although there's been some up and down, and there's some debate and lack of understanding as to why it went up and then down, but the take-home message is at the very bottom. At least 20% of the US adult population harbors HSV-2. An unknown proportion, roughly half the population among adults, is HSV-1-infected. What proportion of those millions and millions of people have genital infection is really not known, but if you make an admittedly very rough guess, and it's only my guess that it's 10 million, you're talking about millions and millions of people infected with genital HSV infections in the United States. Most of those are subclinical.

  • Prevalence of Genital HSV Infection in Adults in the United States [Table]

    Slide 9.

    Prevalence of Genital HSV Infection in Adults in the United States [Table]

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  • Now the next slide just makes the point that herpes is looked on with horror by many people with new infection or who are worried about getting herpes. And this bar graph shows the results of a garden variety telephone poll, just like the political polling -- same sort of sample size that's so well known these days -- and the verbatim question in this health-related questionnaire, which is asked only of people aged 18-40, so it's not the general population, it is the younger half from an age standpoint: "I'm going to read you a list of items that people may or may not consider traumatic. Tell me how traumatic it would be for you if you had this problem." And of course almost 100% said that acquiring AIDS would be a very big deal. But having general herpes is really very traumatic by two thirds, and that was more than the proportion who rated it is very traumatic to break up with the significant other or to get fired from the job. Now that's crazy. Herpes is just not that severe; infact, so many cases are asymptomatic you can argue that in most people it's not severe at all. But it does reflect how patients who might have been exposed or who think they might be infected are likely to react to this, and so part of your job as clinicians is to help ameliorate the level of concern people start with and help them come to understand that it's just not quite that big a deal.

  • Perceived Trauma of Contracting Genital Herpes [Graph]

    Slide 10.

    Perceived Trauma of Contracting Genital Herpes [Graph]

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  • The next slide summarizes the key issue that herpes has evolved to be understood now as the single most important STD there is in terms of an HIV transmission, and in the interest of time, I won't go through the entire slide bullet by bullet; you can go back online and take a look again. I would point out that it is possible that as much as 50% of all sexually transmitted HIV infections worldwide would not have occurred had one other partner not been infected with HSV-2. The importance of that is critical in terms of current therapeutic studies that are going on to learn whether antiherpetic therapy will prevent HIV transmission and acquisition. Very large studies have been funded by NIH [the National Institutes of Health] and the Gates Foundation, and others will begin to emerge to answer some of those studies in the next couple of years.

  • Genital Herpes and HIV Transmission

    Slide 11.

    Genital Herpes and HIV Transmission

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  • The next slide is the summary from the single most important research study that shows the data behind some of those statements, and the 4 quadrants of this meta-analysis show that after you look at various studies, if you look at the risk of HIV acquisition as a variable dependent on whether one is HSV-2-seropositive, notice that in 3 of the 4 groups -- the general population of women; general population of men; and in the lower right, men who have sex with men -- on average herpes doubles to triple the risk of HIV acquisition. The only reason that appears not to be an effect in the upper right quadrant, female sex workers, is that that's obviously a group that's at such high risk to begin with that any cofactors probably have less influence in that population.

  • Slide 12.

    Relative Risk of HIV Acquisition in HSV-2 Positive vs. HSV-2 Negative Persons

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Clinical Presentation of Genital Herpes

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  • The next slide introduces the clinical spectrum of the disease. The first episode of infection is defined as either primary if it's the first infection of that person with either of the HSV viral types, and that's around 20%. Nonprimary, first episode if the person who previously infected with the opposite type. In the genital STD arena, this almost always means somewhat chronic, oral -- whether symptomatic or recognized or not -- HSV-1 infection who now gets infected with HSV-2 in the genital area. And that unbalance probably counts for something like 40% of all first episodes. Now very important is that third subbullet, the first recognized episode of long-standing infection. The available research, and it's not the best research in the world but it's the best we have, suggests that around 40% of people who come in with a new herpes problem, and say I've never had this before, in fact, have been infected for at least several months and sometimes for years. Very important to understand that, to know that in counseling people, and it is that occurrence that results in all of the stories that are now passé about toilet seat transmission, moist towels, fomites, and nonsexual acquisitions because someone would be seen who was obviously not at risk for a new sexual acquisition and yet had this infection. But delayed onset of first symptoms is not all that good. Recurrent infection by definition is the second or subsequent outbreak, and that's much more likely to occur with HSV-2 than -1, and very important to understand that somewhere, over half, up to 90% of genital HSV infections are subclinical. It depends on how you ask the question. If you just ask, "have you ever had genital herpes to a seropositive person," 90% say no. If you ask more detailed questions about symptoms, you uncover more and more individuals, and about two thirds of people who are told they're seropositive having previously had no symptoms, in fact later come to recognize those symptoms, so a lot of asymptomatic infection is unrecognized but not truly asymptomatic, and Dr. Leone will address that.

  • Clinical Spectrum of Genital Herpes

    Slide 13.

    Clinical Spectrum of Genital Herpes

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  • Clinical manifestations of initial infection are generally more severe. This is now slide 14, with multiple vesiculopustular lesions, which tend to be bilaterally distributed in the genital area, or often are. With recurrent outbreaks, almost all are unilateral or up to and including the midline; that's because they are emanating from an infected nerve or nerve root and nerves don't cross midlines. Some symptoms are nonspecific, such as genital discharge or dysuria; there's often a neuropathic prodrome, numbness, tingling, etc, in the general area where the outbreak will occur, typically for just a day or two before the outbreak, and the duration of lesions tends to be shorter. Common misdiagnoses include most of the other things that cause genital irritation or ulcerations -- so Candida, syphilis, chancroid, sometimes dysuria only, and genital trauma; a lot of people will complain of [for example] I think I tore myself because I wasn't lubricated. I had genital lesions; in fact, I have herpes.

  • Clinical Manifestations of Genital Herpes

    Slide 14.

    Clinical Manifestations of Genital Herpes

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  • HSV-2 is maybe the most common in younger people, the younger adults, and certainly among the most common causes of asymptomatic meningitis, but the cause is often not specifically evaluated. Erythema multiforme and the Stevens-Johnson syndrome are complications of herpes, complications that itself are complicated by the fact that Stevens-Johnson syndrome itself causes genital ulceration. The issue of perinatal morbidity and neonatal herpes is a very big deal; it could be a topic for an entire separate CME program, and I won't dwell on that further today, but it's one of the more critical, important elements of this problem. A chronic disabling ulceration of the genital area, face, or elsewhere in HIV-infected people is common. We already mentioned the HIV transmission risk, and there is the rare but definite case of people who die of initial herpes infection due to encephalitis, hepatic necrosis, and things of that sort.

  • Biomedical Complications of HSV Infection

    Slide 15.

    Biomedical Complications of HSV Infection

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  • The first to several clinical photos just makes the point of what classical herpes is supposed to look like, with intact, clear, fluid-filled vesicles and erythematous base -- nothing but herpes causes that appearance.

  • Picture

    Slide 16.

    Picture

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  • The next slide is the typical appearance in a woman, illustrating the fact that in moist mucous areas, the lesions unroof early, and so ulceration as opposed to attack vesicles is one of the reasons women have more severe symptoms than men or complain more severely of their symptoms than most men do. If in a woman with that kind of initial herpes, if you were able to get a speculum in, you might see a cervix like the third picture shows with an overt angry eroded cervicitis, not the subtle kind of cervicitis that you tend to see with gonorrhea or Chlamydia.

  • Picture

    Slide 17.

    Picture

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  • The next slide is a typical recurrent herpes lesion, [with] more localized of vesicular lesions in this gentleman. And then all of the rest of the clinical photos we're going to go through very quickly, make the point that most herpes doesn't look as classically typical as the ones we just saw. So [here] we have a non-specific-looking excreted lesion on this woman's labia.

  • Picture

    Slide 19.

    Picture

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  • The next slide shows a woman who has a lesion, [which] she might have thought was traumatic, this ulcerative lesion with the posterior fourchette. Now she also has a more typical lesion on the right labia minor, but that lesion near the fourchette is the kind of thing that a woman might mistake for trauma as a result of vigorous intercourse or intercourse without sufficient lubrication, but it was culture-positive for HSV.

  • Picture

    Slide 21.

    Picture

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  • The next one showing the patients -- not my clinical staff's ungloved finger --holding a lesion. This is a woman who's totally asymptomatic, came to our HSV clinic because she was exposed to gonorrhea, had this lesion that she didn't know was there, and it was culture-positive for HSV, and then we have a lesion of a guy right on the underside of the penis, along the median, you can see the median raphe on the left side. He thought he caught his penis in his zipper. In fact, it was culture-positive for HSV-2. It could be that trauma actually stimulates HSV outbreaks in people; we don't know that for a fact, but in any case don't disregard; don't assume that all history of trauma necessarily is really trauma; you need to consider the other remaining differential diagnosis of genital ulcer.

  • Picture

    Slide 23.

    Picture

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  • The next slide shows a very tiny 1-mm lesion on this woman's vulva; [It's] easy to understand how this woman would be totally asymptomatic, or have a minor nonspecific itch that she didn't otherwise think of as significant. [Here's] another lesion like that of this woman's labia on the left side, again showing how trivial herpetic lesions can be in explaining some asymptomatic cases.

  • Picture

    Slide 24.

    Picture

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  • I have only just 1 more slide before Dr. Leone takes over. So the recurrence rate after initial genital herpes, when you follow people prospectively after their initial infection with HSV-2 genitally, you find that men have an average of 5 and women 4 episodes per year.

  • Slide 25.

    Picture

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Recurrent Genital Herpes

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  • The true rates are probably similar in both, but it's probably easier to recognize subtle lesions in men than it is in the vulva. Up to 20% have 10 or more recurrences in the next year, so it's a pretty frequent problem for those who have symptomatic initial herpes. The rate does gradually decline over several years, and I personally don't see very many patients who've had herpes more than 5 or 8 years, who are still having frequent occurrences. The story is very different for HSV-1, and we already alluded to this. When you follow HSV-1-infected people prospectively, you find the mean recurrences are 1.3 in the first year and only 0.7 per year in the second year and after that, and 38% of these 83 people had no recurrences whatsoever, so the important take-home message is: You always want to know virus type because it has very important implications for therapy, counseling, and transmission risk for the patient.

  • Recurrence Rate After Initial Genital Herpes

    Slide 26.

    Recurrence Rate After Initial Genital Herpes

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  • What triggers recurrent outbreaks? [It's] important to understand that although clear triggers are well understood for oral HSV-1 infections, the very name cold sore and fever blister reflects the role of intercurrent infections; sunburn is an issue as well; and ENT [ear, nose, and throat] docs and ophthalmologists have learned that there's a risk of herpes recurrence in HSV-1-infected people after you do facial surgery. But genital HSV-2, despite a lot of folklore that put emphasis on menstruation, stress, and things of that sort, in fact, the data suggest that there are no clearly documented triggers. If there is, and there may be, a neuropsychobiological access that's operating here, it is not sufficiently predictive to be remotely useful in advising or counseling patients or treating them.

    Thank you very much. The first segment's done.

    Michelle Manzo, MPH: Thank you, Dr. Handsfield, for that overview of epidemiology and clinical manifestations of HSV-2, and furthermore for underscoring its role in enhancing HIV transmission.

  • Slide 27.

    What Triggers Recurrent Outbreaks

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Asymptomatic Viral Shedding in Transmission and Acquisition of HSV-2

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  • And now I would like to introduce our second faculty presenter, Dr. Peter A. Leone, who is an Associate Professor of Medicine at the University of North Carolina and Medical Director of the HIV/STD Prevention and Care Branch in the North Carolina Department of Health and Human Services. Hello, Dr. Leone, and welcome.

  • Asymptomatic Viral Shedding in Transmission and Acquisition of HSV-2. Peter A. Leone, MD

    Slide 28.

    Asymptomatic Viral Shedding in Transmission and Acquisition of HSV-2. Peter A. Leone, MD

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  • Peter A. Leone, MD: Thank you. It's a pleasure to be here with all of you. Hunter has covered the clinical aspects of genital herpes and some of the epidemiology, and I'm going to probably raise your degree of paranoia. After Hunter's talk, you think my God, everything looks like herpes or at least it's going to be hard to sort this out. I'm going to probably make the matter worse, so the next time you go to the bathroom, you're going to be convinced that there's herpes everywhere, including probably on your own genitals. But not to make light of the issue, the point that I think we're going to be making here with this next segment is that the emphasis has been for years on the clinical presentation of herpes, and that is important and it's important to the individuals who have outbreaks. However, the disease states that we see associated with herpes, such as HIV or neonatal herpes, are really related, in transmission are really related to what we call asymptomatic viralshedding. That means -- and we'll go to the next slide -- finding virus on the surface of the skin or mucosa in the absence of any signs or symptoms.

  • Asymptomatic Viral Shedding

    Slide 29.

    Asymptomatic Viral Shedding

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  • Our knowledge about herpes has really evolved dramatically over the last several years, and we now have an understanding that we will come back to, that this is a disease of almost continual viral replication with leakage basically of the virus across mucosal surfaces intermittently, almost all of the time. That the appearances of lesions are really only the tip of the iceberg, but what drives transmission is asymptomatic viral shedding.

    So what are the key facts for patients with the diagnosis of genital herpes that I think is important for them to understand that we should be communicating to every patient? The first point is that patients frequently spread genital herpes between outbreaks. So even though you may be aware of when an outbreak occurs and you saw all the signs and symptoms listed that Hunter went through as well as clinical pictures, people can recognize outbreaks when they occur. However, transmission does occur away from those outbreaks. It's important that every patient understand that. Virtually all patients shed virus asymptomatically. If you are infected with genital HSV-2, you will shed virus. The third point is that you can't predict when those shedding events will occur. Fourth point [is that] all patients are at risk for asymptomatic viral shedding, and it really isn't pegged to the frequency of outbreaks. So we can't unfortunately tell someone that if you have 3 outbreaks a year you'renot so much at risk for asymptomatic shedding vs someone with 7 or 8. This is something that occurs regardless of the frequency of outbreaks, unless you get into very high-frequency outbreaks, and as we'll also talk about unless this is an infinite infection. The fifth point, recent data suggests that shedding is a more continuous process than previously realized; some recent data that was presented would suggest that most episodes of asymptomatic shedding are short episodes, burst of shedding that are quickly cleared from mucosal surfaces and that breakthrough occurs all the time. The data that we're going to be presenting on asymptomatic viral shedding was primarily driven by once-a-day swabbing of the genital tract in the absence of signs or symptoms to look at whether or not virus is present. We now know that once-a-day swabbing grossly underestimates the frequency of shedding, so when you look at the data that we're going to present here in a second, they're actually much morecommon than what we even cite with some of our PCR [polymerase chain reaction] data. And then the final point on this slide is that safer sex practices should be used. Even with safer sex, you can still transmit herpes. Condoms do work; they [however] are not 100% effective. We'll come back to that towards the end about ways to reduce transmission.

  • Key Facts for Patients

    Slide 30.

    Key Facts for Patients

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  • The next slide is on asymptomatic viral shedding; how common is it? It's a little bit of a complicated slide; I'm going to walk you through it very quickly. If you look at the first line in terms of the percentage of patients with at least 1 day in which virus was detected, the 2 columns you look at detection by culture, which is the less sensitive way of finding herpes simplex, vs PCR, where a swab is obtained to look for the DNA of the virus itself. If you look at that, this is a study or a group of studies that were conducted in women, in which they swab their genital tract daily -- meaning the labia, vaginal tract, and perianal area -- every day for a 2-month period; 72% to 88% of the women had at least 1 day of asymptomatic shedding. If we did more frequent swabbing, we would find that virtually all of them have at least 1 day of asymptomatic shedding. If we go to the next line, percentage of days, you can see by PCR the percentage of days over that 60-day period in which youcan find virus present varies from about 8% to nearly 27%, and again this is a gross underestimation of the frequency of which we can find this. The bottom line is that if you're infected, you will shed. Shedding is nearly universal, and it occurs at some degree of high frequency anywhere from around 8% to 10% of days to 30% or more of days.

  • Asymptomatic Viral Shedding Is Common and Can Occur Frequently

    Slide 31.

    Asymptomatic Viral Shedding Is Common and Can Occur Frequently

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  • This is a complicated slide; I'm going to walk you through it, but I think it illustrates a couple of points. The slide written out here follows a patient from a study that was published by Anna Wald in 1997, in which the patient swabbed her genital tract daily, and noted whether or not she was having an outbreak. If you look at the line underneath the data on the first bar here, looking at days going from 0 to 80, you can see that the solid lines underneath that refer to when genital lesions were present. So during this 80-day period, this woman had 3 outbreaks. Now she swabbed her vulva area and the cervical area, and this was done by culture and by PCR. The dots here represent positive cultures, but the bars that are represented here represent whether or not virus is detected by PCR and the amount of virus, so the height of the bars reflects how much virus is actually detected. And you can see that although she had 3 outbreaks, there was high frequency of shedding in this woman,and the amounts of virus that were present on days which asymptomatic shedding occurred were high, so that you really can see from just looking at this that this can be an issue: that if we told this person you only have to worry about transmission when you're having an outbreak, we actually would be setting herself up for transmission to her partners. The line below which shows what happens with daily suppressive therapy, in this case with acyclovir, and you can see the dramatic difference in terms of no outbreaks occurring from day 90 after she had been on therapy for a little while, and only a few breakthroughs of virus, but the height of the bars markedly diminished. Now we'll come back to what the significance of that slide is in a second in terms of biological plausibility being set up in terms of reducing the risk of transmission through daily suppressive therapy.

  • Viral Shedding Patterns Are Unpredictable and Influenced by Therapy

    Slide 32.

    Viral Shedding Patterns Are Unpredictable and Influenced by Therapy

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  • Now understanding that asymptomatic shedding is common and that high amount of virus can be shed during these periods, you can understand the role that this may play in transmission. Older data from 1992 looked at discordant couples that were followed for nearly a year in which the person with herpes knew that they had herpes was avoiding sex or at least educated to avoid sex during outbreaks, and then they were followed to look at whether transmission occurred to the noninfected partner. Transmission during that period was about 10%, but if they looked at when transmission occurred based on the diary of when outbreaks occurred and when that couple had sex, up to 70% of transmission occurred during these periods of asymptomatic viral shedding, so the driving force for transmission is asymptomatic shedding.

  • Up to 70% of Transmission May Occur During Asymptomatic Viral Shedding

    Slide 33.

    Up to 70% of Transmission May Occur During Asymptomatic Viral Shedding

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  • Coming to the frequency of shedding based on the frequency of outbreaks, looking at a simple bar graph here of individuals who report 0-3 outbreaks a year compared to 4-9 outbreaks a year, you can see no difference statistically in terms of asymptomatic viral shedding based on reported history of outbreaks.

  • Asymptomatic Viral Shedding* Can Occur Regardless of Outbreak Frequency

    Slide 34.

    Asymptomatic Viral Shedding* Can Occur Regardless of Outbreak Frequency

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  • So where are we with all of this? If a person is infected with HSV-2, that means detecting it either by culture or PCR from the genital tract or by antibody testing, type-specific antibodies, then they're infected. And if they are infected, they will shed virus. Asymptomatic viral shedding is frequent, and it's difficult to predict when and where it will occur in the genital tract. Asymptomatic viral shedding does decrease with time, but remains high over time, enough so that we are concerned that people may transmit herpes to an uninfected partner over the lifetime of that relationship. So asymptomatic viral shedding is the driving force for transmission. I'm going to turn it back over to Hunter at this point to discuss general herpes diagnosis.

  • Slide 35.

    Summary of Asymptomatic Viral Shedding

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Genital Herpes: Diagnosis

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  • H. Hunter Handsfield, MD: Thank you very much, Peter.

  • Genital Herpes: Diagnosis. H. Hunter Handsfield, MD

    Slide 36.

    Genital Herpes: Diagnosis. H. Hunter Handsfield, MD

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  • So the first slide here just looks to the general issue of the etiology, differential diagnosis of genital ulcer disease. And these data are from the single best, and really the only good study of this issue in the past couple of decades in the United States; there are more in some developing countries. But importantly, this study was done in populations and settings that were specifically selected to have specifically high rates of syphilis, STD clinics number 1, and number 2, STD clinics in the cities which at the time had the highest syphilis rates. People with classical herpes atypical vesticulopustular lesions were excluded. In fact, if you include the total of the second 2 lines, 77 people with syphilis, herpes was present in about a fifth of them or a sixth of them, so having syphilis didn't exclude the notion of having a dual infection. So the take-home message is that herpes is the horse; other causes are the zebra; and if you see genital ulcer disease, you always must think of and test for herpes. It doesn't matter what the lesion looks like.

  • Etiology of Genital Ulcer Disease

    Slide 37.

    Etiology of Genital Ulcer Disease

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  • Now the next, the first clinical photo in the series of 4, shows a classical case and a culture-positive case of the rate genital ulcer disease called chancroid, as I said, very rare in the United States.

  • Picture

    Slide 38.

    Picture

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  • The next one after that shows another case that it's a very good mimic of chancroid. For anybody who has worked in countries who have seen that infection, they will say, "Sure, it looks like a pretty good case, but this guy was culture-positive for HSV and not chancroid. He happened to be HSV-1 in that particular patient."

  • Picture

    Slide 39.

    Picture

    (Enlarge Slide)
  • The third picture in this series shows another case, a very classical chancroid that, in fact, was herpes.

  • Picture

    Slide 40.

    Picture

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  • The fourth picture shows a dual lesion, which is uncommon with syphilis, but that's what this guy had; otherwise this is typical syphilitic chancres, and the final picture in this series shows a fairly non-specific-looking ulceration even when it started to epithelialize around the edges. This guy was positive for syphilis but also culture-positive for herpes, illustrating exactly the point I made in the etiologic study slide.

  • Picture

    Slide 42.

    Picture

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  • So the next slide gets into the more specifics of how you go about diagnosing this infection. So as I've already implied, you want to test anybody with a genital ulcer for HSV, and that includes the clinically obvious cases. Not only is the clinical diagnosis sometimes long, even by very experienced herpes researchers, but the virus type as we've already said has an important role in determining clinical prognosis, the potential for transmission, and therefore counseling and therapy of the patient. [Virologic testing, which is a direct detection of HSV] is the way to go, when you have an overt genital ulcer. Polymerase chain reactions technically are the test of choice; they're more sensitive than culture. They are increasingly available, but do beware that there are no FDA [US Food and Drug Administration] approved or validated PCR tests. A culture will miss a lot of active cases, particularly if the lesion has even started to heal, [or] more than a couple of days old, but it's the primary test that will be available to you in most settings. If a culture is done, you always want to go to the lab to type the virus. Some labs will do it on the assumption, and some clinicians may believe it doesn't matter which type -- it's herpes, it's herpes. You do want to know virus type for the reasons we talked about. Forest antibody tests are available, but some don't provide virus type, and in general, they are a lot less sensitive than either culture or PCR, and I really don't recommend them unless it's the only thing available in your particular laboratory. Cytology; looking under the microscope; the old what was called the "Tzanck prep" to look for cells typical of herpetic infection is a lousy test, and I see no valid reason for its use in today's world. Serologic testing has an important role, and we're going to discuss that in the next couple of slides.

  • Diagnosis of Genital Herpes

    Slide 43.

    Diagnosis of Genital Herpes

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  • So the next slide lists the available types of specific serological tests in the United States. Western blot is the historic gold standard. It's still available as a confirmatory assay from selected labs. The one that does most testing in the country is in my hometown of the University of Washington Clinical Laboratories in Seattle [Washington]. Focus Technologies has 2 different assays called HerpeSelect: One is an ELISA [enzyme-linked immunosorbent assay]; the second is an immunoblot. The ELISA has been more frequently studied; it's highly reliable. The immunoblot probably has similar performance since it uses the same biology, just a different detection system, but it hasn't been as extensively studied. The Trinity Biotech Company has an assay whose trade name's Captia. And then the Biokit USA test has a point-of-care test that you can do in the office, but it's only for HSV-2, not HSV-1.

  • Type-Specific HSV Serologic Tests

    Slide 44.

    Type-Specific HSV Serologic Tests

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  • If someone tests twice and they get a 0.3 OD [optical density] ratio one time and a 0.7 the next, it doesn't mean that they've got a little bit of herpes antibodies developed. Those variations have to do solely with the chemistry of the test. Some values between 1.1 and 3.5 are false-positive if someone is also HSV-1-tested, so there is some potential advantage to simultaneously test for HSV-1 when you test for HSV-2.

  • Interpreting HSV-2 HerpeSelect

    Slide 45.

    Interpreting HSV-2 HerpeSelect

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  • The next slide makes the point that IgM [immunoglobulinM] testing, even though it is offered automatically by some labs when you routinely order an HSV serology, is simply a useless test. You should ask the lab not to do it, and you should ignore any results that you get. IgM testing is not titer-specific for HSV-1 vs -2. It does not distinguish early from late infection, despite the fact that biologically that's what it's supposed to do and what you've been taught that IgM antibody is supposed to do. Many people with initial HSV infections do not develop measurable IgM antibody. Many with recurrent disease do have IgM antibody, and even in people without HSV at all, false-positive results are common, so it's not an easy test to do well. So I think there's no valid indication for use in adults, [but in] pediatric infectious diseases -- diagnosing neonatal herpes -- they do still have a role.

  • HSV IgM Testing is Not Clinically Useful

    Slide 46.

    HSV IgM Testing is Not Clinically Useful

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  • Options for confirmatory testing, if you get someone whose test does not make a lot of clinical sense to you, or they're in that gray zone, not as strongly positive as you'd like but technically positive, you can order a Western blot. You can flex to a different test using also looking at glycoprotein G antibodies, so you could try the Focus Immunoblot, and there are confirmatory assays -- by rumor -- being developed by various diagnostic companies. Repeat and convalescent testing will often get you out of the woods; simply doing another test with the same technology a few weeks later sometimes will sort things out.

  • Options for Confirmatory Testing of the Focus HSV-2 ELISA

    Slide 47.

    Options for Confirmatory Testing of the Focus HSV-2 ELISA

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  • The next slide makes the point of the time to seroconversion. The HerpeSelect actually seroconverts more rapidly than the Western blot does, and half of the people will become infected, will be positive within 3 weeks of a new infection, although you're going to get out to about 3 or 4 months before you approach certainty of the validity of the results.

  • Time to HAV-2 Seroconversion

    Slide 48.

    Time to HAV-2 Seroconversion

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  • Uses of the test, unequivocal indications include the diagnosis of genital ulcer disease, someone who's got a second or third episode of genital ulceration who's HSV-2-seropositive; you've nailed it; if you're not theoretically sure, you can have the antibody also have something else causing you genital ulceration. Statistically you all understand that that's not very likely. Certainly managing the sex partners of some person... Most commonly this comes up in the monogamous relationship where one person's infected and the other one wants to know are they infected or not, and you can learn whether someone is susceptible and that couple needs to continue to take precautions, or already infected with or without symptoms -- often without symptoms -- and therefore don't need to take any precautions, because people do not ping-pong their HSV infections back and forth. Once you're infected with either HSV-1 or HSV-2, you are either totally immune or at least highly resistant to reacquiring infection with the same virus type. We've mentioned before the potential value of letting people at high risk for HIV, such as injection drug users, gay men, and certain others can know that they are HSV-infected because they can learn and know that the risk of acquiring HIV is a lot higher than it otherwise would be. I don't know that knowing that would make very many people alter their sexual behavior, but I do know that not telling them will have no effect, and the effects can only be positive even if not quantitative. There are other uses that are the subject of a certain amount of debate among experts in the STD and infectious disease arenas. There are potential uses in helping prevent neonatal herpes by testing pregnant women and perhaps their partners. There are issues about people who would like a truly comprehensive STD evaluation; say their single days are over and they're about to get married. There are some potential issues there regarding the positive predictive value. The test is not perfect in people at fairly low risk for disease, and it is that issue about specificity and positive predictive value that generates the debate about when and how these tests should be used in that manner. I think everybody would agree that it would be premature with the current state of knowledge and the current performance of tests to routinely screen every sexually active person as a matter of automatic routine, but do keep in mind the diagnostic uses if not the screening uses for these tests. Thank you.

  • Slide 49.

    Uses of Type-Specific HSV Serology

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Prevention and Available and Emerging Treatments for HSV-2 Infection

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  • Michelle Manzo, MPH: Thank you, Dr. Handsfield, for stressing the importance of diagnostic testing and, furthermore, the importance of choosing the accurate diagnostic test technology when testing for genital herpes even when it's clinically obvious, and before that Dr. Leone for underscoring the importance of the role of asymptomatic shedding in HSV-2 transmission. And so now we conclude with our fourth and final presentation on prevention and treatment for HSV-2 from Dr. Leone.

  • Prevention and Available and Emerging Treatments for HSV-2 Infection. Peter A. Leone, MD

    Slide 50.

    Prevention and Available and Emerging Treatments for HSV-2 Infection. Peter A. Leone, MD

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  • Peter A. Leone, MD: So let me go ahead and move to the next slide on transmission. And where we're getting or moving towards in wrapping things up here is we really laid out a lot of information about how to make the diagnosis, and it gives someone the information which will hopefully guide them to steps that will reduce the risk of transmission. There is hope; there are lots that we can do, but you have to make the diagnosis first. There is good news here, and we'll go through both the sort of cheap and quick ways that we can reduce transmission and also ways that with interventions you can reduce transmission through pharmacologic intervention. So the first slide, "Transmission Reduction: What Can Be Done?" Well, first you gave advice to patients to avoid sexual contact when they're having outbreaks. It seems sort of obvious, but given the subtleties of the presentation of general herpes, until we actually say, "Look, these lesions tingling or itching that last for acouple of days is a good indication you're having an outbreak; avoid sex during that period." People can be taught quite easily to recognize outbreaks even though the signs and symptoms are rather subtle.

  • Transmission Reduction: What Can Be Done?

    Slide 51.

    Transmission Reduction: What Can Be Done?

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  • Inform patients about transmission risk during periods of asymptomatic shedding, which you've already talked about.

  • Transmission Reduction: What Can Be Done?

    Slide 52.

    Transmission Reduction: What Can Be Done?

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  • Offer suppressive therapy that patients, as an option, as an option for them to have some outcome, which you have discussed with them. What are the 2 outcomes here that we want to try to achieve? One is try to control disease; episodic treatment does not reduce the frequency of outbreaks; suppression does. Second, is reduce the risk of transmission, which is just as valid a reason to go on daily suppressive therapy, in controlling outbreaks. Point is, you have to have a discussion with the patient about what they hope to achieve by treatment and then tailor that treatment or those options, a menu of options that we'll go through that will give them the results that they want.

  • Transmission Reduction: What Can Be Done?

    Slide 53.

    Transmission Reduction: What Can Be Done?

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  • So what about suppressive antiviral therapy to reduce transmission risk?

  • Suppressive Antiviral Therapy to Reduce Transmission Risk

    Slide 54.

    Suppressive Antiviral Therapy to Reduce Transmission Risk

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  • [This was taken from a] study that's now several years old, 2004, New England Journal article, Larry Corey looking at discordant heterosexual couples. Now mind you, these are couples in which one person knows that they have herpes; the other one is not infected, so we sort of screened out a couple that are already transmitted, and I'll come back to why that's important in a second. They were enrolled in a double-blind, placebo-controlled trial in which the person with herpes was put on either a placebo or daily suppressive therapy. The at-risk partner was seen if they had signs or symptoms suggestive of an outbreak, and they were also screened monthly for serologic conversion looking for a transmission of herpes from the infected partner, and this was done for 8 months. Now couples were told to abstain from sex when they had an outbreak, to use condoms with every sexual encounter, although frankly, condom use was not particularly great in this study. And on either arm of the trial, if the source partner had an outbreak, they were put on episodic treatment. So the study was really looking at whether or not our standard approach of abstaining from outbreaks, use of condoms, episodic therapy, how did that compare to adding suppressive therapy to that regimen. This is not looking at suppression in the infected individual and doing nothing in the other set of couples. This is absolutely looking at whether suppression offered an added advantage. So if anything, we may see reduced transmission potential in the study, which we did. Remember we saw a 10% transmission rate in this study of looking at asymptomatic shedding that I cited before. In this trial, in the placebo arm there was a 3.6% transmission rate from the infected person to the noninfected individual in the placebo arm. There was a 48% reduction with the use of daily suppressive therapy in the person with genital herpes, so we're looking at here a 1.9% transmission rate. If you look at these susceptible individuals developing a general herpes outbreak, that was reduced by 75%.

  • Proportion of Susceptible Partners With Overall Acquisition of HSV-2 Infection

    Slide 55.

    Proportion of Susceptible Partners With Overall Acquisition of HSV-2 Infection

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  • So the advantages here of daily suppressive therapies is that it does offer an advantage above and beyond the standard approach: It did result in at least a 50% reduction. And this is looking at a low transmission population to begin with because these couples had been together for on average about 2 years and had not transmitted during that period leading up to the study.

  • Slide 56.

    Proportion of Susceptible Partners With Symptomatic Genital Herpes

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Treatment Guidelines

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  • Now we'll go to the next slide. The CDC [US Centers for Disease Control and Prevention] and ACOG [The American College of Obstetricians and Gynecologists] made recommendations based on that study and all the biological plausibility that went before it, which we'll quote the CDC recommendations from the 2006 STD treatment guidelines: "Discordant couples should be encouraged to consider suppressive antiviral therapy as part of a strategy to prevent transmission, in addition to consistent condom use and avoidance of sexual activity during recurrences should be encouraged." ACOG said, "For couples in which one partner has HSV-2 infection, suppressive antiviral therapy should be recommended for the partner with HSV-2 to reduce the rate of transmission." So any time you make this diagnosis, you really need to extend that to discuss the partnership that that person is in.

  • CDC Sexually Transmitted Diseases Treatment Guidelines and ACOG Recommend Daily Therapy

    Slide 57.

    CDC Sexually Transmitted Diseases Treatment Guidelines and ACOG Recommend Daily Therapy

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  • So you're really looking at then a slide here that you can spend some time looking at more in detail deciding whether to, or trying to, control disease and how you go about doing that vs reducing transmission. Either way, or either arm here, daily suppressive therapy is reasonable and that you can use this sort of template to help decide who would be eligible for daily suppressive therapy.

  • Candidate for Antiviral Suppressive Therapy [Table]

    Slide 58.

    Candidate for Antiviral Suppressive Therapy [Table]

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  • Now what are treatment options? Taking strictly straight out of the STD treatment guidelines, the possible dosing regimens here are for acyclovir, famciclovir, and valacyclovir. Now for controlling disease, all 3 of these are equivalent; the main differences are in the frequency of dosing and the cost. However, for suppressive therapy to reduce the risk of transmission, the only data that's out there is for valacyclovir, and personally, I think that acyclovir and valacyclovir probably are going to be equally efficacious in reducing transmission. However, there are 2 studies that have been published within the last several years suggesting that famciclovir may not offer as much of an advantage in reducing asymptomatic viral shedding and is not equivalent to the benefit seen with valacyclovir. The mechanism of action is different for famciclovir, and that may be the reason why we see differences in asymptomatic viral shedding. Although we don't know whether or not those differences lead to clinically significant differences in terms of reducing transmission, it's enough for me to pause in saying that if the desire here is to reduce the risk of transmission, I am not so sure that famciclovir is equivalent to either acyclovir or valacyclovir. However, if the desire here is to control disease, then I think these are all equivalent.

  • Slide 59.

    Treatment Options: Suppressive Therapy

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Transmission Reduction

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  • What other options can be done? Transmission reduction. We should be encouraging patients to share their HSV status with their sexual partners and promote condom use because condom use does not only result in a reduction in herpes transmission, but there's also an advantage in reducing the risk for other sexually transmitted infections being transmitted.

  • Transmission Reduction: What Can Be Done?

    Slide 60.

    Transmission Reduction: What Can Be Done?

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  • What is the data that's out there to suggest disclosure results and any difference? Now the obvious things to say: "Well, gee, if you tell someone you have genital herpes, guess what. They're not going to have sex with you." That may be true, but in this study in which Anna Wald looked at couples in which transmission occurred, and then went back and looked at whether or not disclosure had been made prior to these folks having sexual intercourse, there was a statistically significant delay in transmission. To note, for nondisclosers, the median time was 60 days of transmission; for disclosers that was 270 days, yet there was no difference statistically in the frequency of sexual intercourse, the types of sexual intercourse, or the use of condoms. So for some reason, and we can speculate why, sharing that diagnosis does result in terms of benefit in reducing transmission.

  • Transmission Reduction: Disclosure to Sexual Partners

    Slide 61.

    Transmission Reduction: Disclosure to Sexual Partners

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  • What about condoms? While condoms are not 100% effective, condom use does appear to offer about a 50% protection against HSV-2 acquisition in both men and women.

  • Slide 62.

    Condom Sense

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Future Prevention and Treatment Strategies

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  • What's on the horizon? Well, unfortunately, we don't have a long list here, but I do think it is worth mentioning 2 things. One, there is a herpes vaccine trial, which currently finished enrollment on Friday of last week. However, that study will not be completed until 2010, and even if that study does show a protection in reducing the risk of HSV-2 acquisition, it is limited in that it's only for women, and the vaccine in previous studies only was beneficial in women who did not have HSV-1 or HSV-2 infections, so they had to be double zero negative. So this vaccine, even if it comes to market, will have a somewhat limited benefit overall. In terms of new therapy, well, unfortunately, there's not much that's out there. There is a new drug that is entering into phase 2 clinical trials, but even if this drug looks to be effective, we're looking at probably a good 3-5 years before it will actually come to market.

  • What Is On The Horizon?

    Slide 63.

    What Is On The Horizon?

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  • So in conclusion, while genital herpes is common, it's underrecognized; shedding -- asymptomatic shedding -- is the norm and it's responsible for transmission of infection. And that treatment really should be designed to control disease and/or transmission, but that comes back to counseling the patient and tailoring the course of therapy accordingly. And with that, I complete my section of the talk.

  • Slide 64.

    Conclusions

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Questions and Answers

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  • Michelle Manzo, MPH: Thank you, Dr. Leone. We enjoyed and appreciated your presentation on treatment of HSV-2. Now we'd like to invite all of our listeners and viewers to submit questions for our faculty, and for the first question that we have coming in from a clinician, this is for you Dr. Leone: "Would you please speak to the guidelines on therapy, use of the suppressive therapy during pregnancy, and also any recommendations for testing of newborns?"

    Peter A. Leone, MD: At this point, all of the drugs... All of the oral therapies that are available are category B drugs, and there won't be any clinical trials looking at trying to get an indication in pregnancy. But I think that they're safe to use in pregnancy. The recommendations right now are that like any time we should be avoiding the use of drugs during the first trimester if at all possible, but for individuals in which transmission is a potential issue to their partner, or if a woman has frequent outbreaks then I would certainly put her on treatment. If she has an outbreak, I would treat her. If there's a high frequency of outbreak, I would put her in suppression and leave her in suppression. Now there are 5 studies that have been published in a meta-analysis looking at whether or not suppression late in pregnancy for women with a history of genital herpes outbreaks will reduce the frequency of outbreaks and the need for Caesarean section. The conclusion of those studies and the meta-analysis is that it does. There are no studies to look at whether or not treatment of a pregnant woman will reduce the risk of transmission from mother to infant. Those studies will not be done, but it is reasonable to conclude that that would be an added benefit for suppression. At this point, the data that's out there would suggest that the dosing for acyclovir is 400 mg 3 times daily in pregnant women, and we would recommend a higher dose of valacyclovir in pregnant women of 500 mg twice daily. Many individuals now, that when I speak to communities, the norm of the behavior is to put women with a history of genital herpes outbreaks on suppression at about 36 weeks until the completion of pregnancy, and Hunter, feel free to comment on that if you have anything else to add.

    H. Hunter Handsfield, MD: I agree with that. The only thing I would add is that ACOG gives what amounts to permissive recommendation. They don't say you must do it, but they say, considerations should be given and that such suppression during the last few weeks of pregnancy makes sense.

    Michelle Manzo, MPH: Thank you. Another question. This is for Dr. Handsfield: "You had mentioned during your presentation about the role of HSV-2 in the transmission of HIV. Would you please speak to the role of HSV-2 in the role of transmission of other sexually transmitted diseases, for example, gonorrhea and Chlamydia?"

    H. Hunter Handsfield, MD: I'm unaware of any data that specifically looks at it. Given the biophysiology of those infections, I don't think there's a lot of suspicion, but that's an issue -- but it hasn't been studied. I don't think we can say anything definitive. I would make the same statement about HPV [human papillomavirus], no data available.

    Michelle Manzo, MPH: Thank you. This is a question that I will put out there for both of you, and Dr. Leone, if you would please answer first: "What, if any, study is done with long-term effect for the use of valacyclovir," and if you could please comment?

    Peter A. Leone, MD: Well, in terms of transmission, I think what the question is alluding to is that the indication is for a limited time. The study was done for 8 months, and so the indication is not for more than a year. However, there's safety data that goes out to 24 months suggesting that side-effect profile actually decreases over time, and there's no biological reason to believe that the efficacy of the drug would diminish over time. Probably the conclusion we can draw is based on acyclovir, in which there's data published looking at suppression for 10 years and finding no increase in resistance of herpes simplex and nonimmunocompromised patients on suppression, finding a decrease in side-effect profiles reported over that time period and continued benefit of daily suppression. And being that valacyclovir is a prodrug of acyclovir, I think it's also reasonable to conclude that the same thing would be seen with valacyclovir. And I have no reason to believe that famciclovir would have any untoward effect for long-term suppression.

    H. Hunter Handsfield, MD: And I'll add that the standard of recommendation is to stop suppressive therapy after a year, which goes back to what the package insert says, but it's really not a clinical issue; it's really just one of recognizing that in terms of symptomatic disease control leaving transmission aside for the moment, we know that over time transmission or symptomatic outbreaks become less frequent. So it's not a bad idea to stop periodically to see whether that natural course is coming to fruition, and that the need for therapy is less than it might have started; whether that's 1 year, 2 years, 3 years is personal. The other point that is worth making, in terms of preventing transmission, is you always want to consider; don't start with the assumption that this patient must take rigid precautions to prevent. If she or he is in a monogamous relationship with someone who is already HSV-2-infected, for example, then the only indication for suppressive therapy issymptom control and maybe the symptoms for that person aren't all that bad. Even in other settings, the silver lining around subclinical shedding, in asymptomatic herpes, the fact that so many cases are subclinical, is that if transmission occurs, of the newly infected person may be so mildly infected that he or she doesn't even know that it's happened. So again, leaving aside the dating situation where you have this extremely important psychological fear and overlay of transmitting and the ability to forge a rewarding sexual relationship, in the monogamous setting, it may not be that big a deal. And then finally, I will say that suppressive therapy is partly determined by the patient's psychological state of affairs. The person whose lip is quivering with the knowledge of his or her new diagnosis when you start therapy a few weeks later might be in a situation where the relationship helped her get her okay; the outbreaks when they do break through are not bad, and no, I don't need it. And the person who badly needed suppressive therapy initially doesn't need it 3, 4, or 6 months down the line. So you need to continually reassess with the patient considering his or her relationships and consider the dyad of the couple in terms of how you manage suppressive therapy for all of these indications.

    Michelle Manzo, MPH: Thanks to both of you for answering those questions concerning patient-centered and evidence-based therapies for genital herpes. And that concludes our Web conference for today, and I would like to thank our faculty, Drs. Handsfield and Leone, for participating in the Web conference as well as all of those who logged on to listen to these enlightening presentations. And this program will be available as an audio and slide archive for those of you who would like to refer to this session in the future, and for your colleagues who are not able to take part in the live event. In approximately 3 weeks a full-text transcript of the program will also be published. Participants of this live event will now be able to take the CME post-test, and once again, thank you for participating, and have a good day.

    Supported by an independent educational grant from GlaxoSmithKline

  • Questions & Answers

    Slide 65.

    Questions & Answers

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