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Although rarely a cause of severe systemic disease in otherwise healthy adults, HSV infection may be severe or even fatal in neonates and those who are immunocompromised. The incidence of herpes infection has risen so rapidly largely because this is a silent pandemic.
Unfortunately, the gold standard of laboratory diagnosis--the Western blot--is expensive and may be difficult to obtain. In the past, primary care physicians who were not content to rely on cultures had to resort to one of several enzyme-linked immunosorbent assays (ELISAs), which--although approved by the U. At $15 to $30 per test, the new tests are roughly one-fifth the cost of the Western blot, and much faster and easier to administer. After HSV enters the mucosa or abraded skin, it replicates within epithelial cells, producing cell lysis and inducing a local inflammatory response that may be clinically apparent within two to 21 days. Typically, the lesions of true primary herpes begin as papules and progress to thin-walled vesicles on an inflamed base (Figure 2).
For the majority of patients with genital herpes, recurrences represent only a nuisance, and episodic antiviral treatment is satisfactory. Asymptomatic shedding--an important contributor to HSV spread--is common in both sexes, particularly in the period immediately surrounding a symptomatic episode.
While there is no cure for genital herpes at this time, we are fortunate in having a number of selective antiviral agents--acyclovir, famciclovir.
Topical antiviral agents are never indicated for the treatment of genital herpes when an effective oral agent is available. Unfortunately, many physicians remain suspicious of chronic antiviral therapy, recalling the unacceptable toxicity that accompanied chronic use of vidarabine and other early examples of the class.
Continuous use of either acyclovir or famciclovir has been shown to suppress both symptomatic and asymptomatic HSV shedding by 80% to 90%. In a dose-range study that compared valacyclovir, acyclovir, and placebo, 250 mg bid of valacyclovir was equivalent to 400 mg bid of acyclovir in reducing the frequency of recurrences. It is important for physicians to emphasize that use of antivirals should not become an excuse to abandon safer sex practices.
When counseling patients experiencing their first episode of genital herpes, a balance must be struck between reassurance that the disease is not going to cause serious harm and validation of the physical and psychological suffering that it can produce.
Patients who are experiencing a particularly severe primary episode need to be assured that it is likely to be a once-in-a-lifetime event, and that recurrences are often mild and transient. New classes of agents that show promise in the treatment of genital herpes include nucleoside analogs, antisense compounds, and agents that act on HSV envelope glycoproteins. Recent research on herpes vaccines has focused on development of viral subunit vaccines containing the immunogenic HSV glycoproteins gD and gB as well as vaccines containing replication-incompetent viruses.
In summary, there is no evidence that an established latent HSV infection can be reversed or diminished with any of the existing antiviral agents. Sacks SL et al: Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. Spruance S et al: A large-scale, placebo-controlled, dose-ranging trial of peroral valacyclovir for episodic treatment of recurrent herpes genitalis. Tyring SK et al: A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. The Content is not intended as a substitute for professional medical advice, diagnosis, or treatment.
Sacks is Professor, Department of Pharmacology and Therapeutics, University of British Columbia Faculty of Medicine, and founder of Viridae Clinical Sciences Inc., Vancouver. The vast majority, perhaps 44 million, are infected with herpes simplex virus type 2 (HSV-2), but a rapidly growing minority--roughly four million--are infected with HSV type 1 (HSV-1) (Figure 1). Seroprevalence was considerably higher among women than among men, and higher among African Americans than among other ethnic or racial groups. Moreover, the presence of herpes lesions has been shown to facilitate HIV transmission; a 10-city survey conducted in 1996 showed a 7% rate of HSV-HIV coinfection.
Today, the infection is rampant not only in that age group but throughout our high schools as well, with the fastest increases occurring among white adolescents aged 12 to 19.
Many teenagers have grown up thinking that they can change partners indiscriminately as long as they use a condom.
In the NHANES III study, nine of 10 HSV-positive subjects did not know that they were infected.
Their role in STD clinics and other settings of high HSV prevalence, however, remains to be determined. In patients with no preexisting antibody to either HSV-1 or HSV-2, such primary first episodes have a range of presentations, from asymptomatic to severe with systemic symptoms. These break down to form ulcers and then dry to crusts and heal, leaving a faint discoloration. Once established in the host, HSV maintains lifelong latency in the sensory ganglia, from which it may periodically migrate back to the epithelium to cause recurrent infection.
What is insufficiently appreciated, however, is that a large minority--perhaps 40%--experiences six or more recurrences a year, and fully half of that group experiences at least 10 a year. Studies employing viral culture suggest that patients with genital herpes experience viral shedding on 1% to 5% of asymptomatic days.
Treatment should be individualized to suit the patient's needs, with chronic suppressive therapy recommended if symptomatic episodes are frequent or especially bothersome, or if they cause significant psychosocial and obsessive sequelae. But years of experience with acyclovir and its successors have shown that these are benign drugs that should not be restricted to acute use in all but the most severely affected patients. The data suggested that a once-daily dose of 500 mg of valacyclovir was also effective in a carefully chosen subgroup of patients who had less than 10 recurrences a year while off therapy.

Condom use should remain consistent, and couples should be abstinent (even from oral-genital sex) during periods of active infection. For example, a patient whose primary relationship has just ended may want to suspend antiviral therapy until sex is contemplated with another partner.
The first physician contact can have lasting effects--patients often tell me that the diagnosing physician did not take adequate time to explain the natural history of the disease, failed to take a proper sexual history, or either exaggerated or understated the potential impact of recurrent episodes on social relationships and sexual function. Those who are not already in stable relationships may avoid potential romantic situations out of fear of having to inform new partners about the risk of asymptomatic shedding.
There are exceptions, however, and it is unwise to assume that all is well simply because the patient is in a long-term relationship. Regimens combining older agents that target viral DNA polymerase with immunomodulators or ribonucleotide reductase inhibitors are also in development. On the positive side, the existing drugs are safe and effective for symptom control, and drug resistance does not appear to be increasing even among immunocompromised hosts. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition.
Chronic suppressive therapy in patients with frequent recurrences reduces viral shedding and may reduce transmission. HSV seroprevalence has risen sharply during the past decade despite a barrage of warnings aimed at preventing the spread of AIDS and other sexually transmitted diseases (STDs). Seroconversion during pregnancy may also be hazardous to the fetus, particularly if it occurs in the last trimester. White adolescents are nearly five times more likely to have herpes today than they were in the 1970s. But sex with a condom--although much safer than without--does not provide total protection, especially against chronic viral infections that are easily transmitted through skin-to-skin contact. Although HSV culture is quite specific, sensitivity varies according to the stage of the lesion (wet, vesiculo-ulcerative lesions being the most likely to yield a positive result) as well as the experience of the physician, transport conditions to the laboratory, and culture techniques used.
Even the Western blot may provide a false-negative result if performed prematurely, since antibodies to HSV envelope glycoproteins do not fully emerge until three to four months after exposure. By making rapid testing available to large numbers of high-risk, asymptomatic patients, the new serologies are expected to increase utilization of antiviral therapy and could have a real impact on disease spread.
However, most patients who present with first-episode HSV infection are already seropositive, having been exposed to one or both forms of the virus in the past, and their first episodes are generally milder than symptomatic primary episodes. Outbreaks are generally bilateral and may be associated with local erythema and swelling as well as itching, tingling, and burning. Between 60% and 90% of patients who have had symptomatic primary genital herpes are subject to these outbreaks. The psychological ramifications can be significant for any patient with genital herpes, but frequent symptomatic recurrences can cause repeated physical discomfort and almost constant awareness of risk. However, a recent crossover study of women with early recurrent genital herpes using a sensitive HSV-DNA PCR assay found viral shedding in the cervicovaginal or vulvar region on an average of 28% of asymptomatic days sampled. Acyclovir has the longest history and is the least expensive, but the two prodrugs, famciclovir and valacyclovir, have also been thoroughly studied and have significantly greater bioavailability (Figure 4). Some patients may want the benefit of reduced asymptomatic viral shedding, even though suppressive therapy has not yet been shown to reduce transmission (studies are under way).
Given the large number of patients who are subject to frequent recurrences and the propensity of HSV to be shed on a regular basis, I feel that chronic therapy is an option that has not been adequately explored. And in a recently reported, randomized, double-blind, placebo-controlled trial involving 30 referral centers in Canada and Europe, median time to recurrence in patients treated with famciclovir (250 mg bid) was 222 to 336 days, compared to 47 days for placebo recipients. Promotion of condom use may lead to greater patient selectivity in choosing sexual partners and increased dialogue with physicians concerning STDs in general.
Although many experts suggest an initial regimen of six months to a year, there are no data suggesting that toxicity increases or efficacy decreases beyond that point.
Or, if an uninfected partner has taken a job abroad and will return infrequently, episodic treatment or selected periods of abbreviated suppressive therapy may be preferred. Women who are pregnant or considering pregnancy should receive additional information concerning the risk of neonatal transmission and rationale for cesarean delivery if lesions are active. Partners who initially reject the patient can be reminded that, with 20% or more of sexually active persons currently infected, genital herpes is difficult to avoid. Since first reported in 1982, acyclovir-resistant strains of HSV have remained stable in this group and have only rarely been identified in immunocompetent individuals. Never disregard professional medical advice or delay in seeking it because of Content found on the Website. First episodes of maternal HSV-2 infection have been associated with premature labor, intrauterine growth retardation, spontaneous abortion, and neonatal death.
A man who has herpes lesions at the base of the penile shaft or on the scrotum places his partner at risk even if a condom is used. They range from a generalized flu-like illness to neurologic manifestations such as aseptic meningitis, lymphadenopathy, skin edema, and transient autonomic neuropathy. In patients with mild or atypical presentations, cultures often are negative, since HSV may be present at the nerve roots yet remain undetected in urine or cervical mucus. The polymerase chain reaction (PCR) technique, which can detect viral DNA from lesions that are culture-negative, is too sensitive to reflect true reactivation and too costly for routine clinical use. A more reliable ELISA with a sensitivity of about 95% and specificity of 96% to 98% has been developed and is awaiting release. However, their usefulness as a general screening tool for pregnant women and their partners is likely to be limited by an unacceptably high proportion of false-negative and -positive responses. Indeed, a significant proportion of first episodes are really recurrences that are reflected in mild symptoms and minimal systemic sequelae.

The mean annual rate of recurrence for patients with HSV-2 infection is four episodes but may eventually decrease in some patients.
Episodic treatment of such cases involves 10 or 12 separate courses of medication, which may speed healing of individual outbreaks but is not preventive and has only a modest effect on viral shedding. When the same specimens were evaluated by both methods, the rate of HSV detection by PCR was 3.5 times higher than by culture--suggesting that genital reactivation and shedding occur with greater frequency or longer duration than standard techniques demonstrate.
Furthermore, they are simpler to take as episodic treatment because only two daily doses are required, compared with the standard acyclovir regimen of five daily doses.
Suppressive therapy with any of the three agents is more effective than episodic therapy and generally well-tolerated. At six months, the proportion of patients remaining completely free of recurrences was approximately three times higher in the famciclovir group (79% to 86%) than in the placebo group (27%). However, practical serologic diagnosis will be a necessary component of prevention with this predominantly subclinical STD. I therefore recommend interviewing patients every 12 to 18 months to determine the extent of therapeutic benefit, consider the individual's risk of future outbreaks, and decide whether continuation is warranted. In addition to loss of self-esteem, patients may experience unresolved anger at themselves and the source partner, become obsessed with implications of the diagnosis, or lapse into depression with each outbreak. With each new sexual relationship, a woman's odds of acquiring HSV infection rise another 5% (risk is slightly lower in men because of reduced transmission efficiency). Consequently, until an effective vaccine or cure for HSV infection is found, episodic or suppressive antiviral therapy accompanied by patient counseling will remain the standard of care.
Moreover, the distribution of lesions in women generally extends over areas (labia majora, perineum, perianal area) not protected by condoms. When these occur in the absence of genital lesions, the diagnosis is likely to be missed even if the patient presents for care. However, it lacks the scope of Western blots, having been designed to test for antibodies to HSV glycoprotein G-2 (gG-2) rather than for the entire fingerprint of HSV glycoprotein responses. In contrast, those with HSV-1 infection rarely experience more than one or two episodes a year. However, it is not clear whether a positive PCR assay in patients with a negative culture reflects a true risk of transmission. All three drugs have been shown to reduce time to cessation of viral shedding and duration of pain.
In addition to reduced asymptomatic shedding, it prevents most symptomatic episodes and reduces the severity of those that do occur. The drug was well-tolerated, with an adverse outcome profile comparable to that of placebo. A patient who has remained partially symptomatic or has experienced prodromes (but not actual recurrences) while taking the drug is likely to become highly symptomatic once antiviral treatment is discontinued.
And because few people regard oral-genital contact as risky, the incidence of HSV-1 infection has expanded even faster than that of HSV-2 infection. In both women and men--especially if they practice receptive anal intercourse--viral transverse myelitis or autonomic dysfunction may produce urinary hesitancy and retention, leading to the mislabeling of an entire class of patients as having idiopathic urinary retention. As a result, the test is likely to read as positive an atypical response that includes a gG-2 band but no corroborating evidence--a situation that occurs with a low but significant frequency in the general population, especially among children. In some studies, men had approximately 20% more recurrences than did women, with the most common sites being the shaft of the penis and the glans. Since some patients may find one agent more effective than others or complain of headache with one agent but not others, I typically encourage patients to try each for different episodes and then select the one that seems to be most convenient, best tolerated, and most effective. On the other hand, a patient who has remained completely asymptomatic may be able to terminate therapy without ill effects, provided that safer sex practices are maintained. It also should be emphasized that this is a condition in which appearances can be deceiving, and that the source partner may or may not be the one with symptoms. Although condoms probably offer an advantage, there are no data demonstrating their protection. Bowel dysfunction and impotence are other presentations that are unlikely to suggest herpes to anyone but a virologist. Patients with a primary episode may present with large and painful lesions in these areas and no genital lesions or only a scattering of small vesicles a millimeter or two in diameter on the genitalia.
In women, recurrences tended to affect the labia majora, labia minora, clitoral hood, perineum, or perianal area. Assuming some degree of prior sexual activity in both cases, unless both are tested via Western blot (a good idea, if feasible), there is no way of determining whether the couple is truly discordant or whether one partner is merely asymptomatic. And despite women's higher risk, routine gynecologic examination rarely includes careful inspection of the vulva and perineum, areas where herpes lesions are often found. In patients of both sexes, HSV lesions of the rectal mucosa may cause proctitis associated with anorectal pain, discharge, tenesmus, and constipation. Prior to the appearance of lesions, patients typically experience a localized prodrome such as tingling or itching, although remote symptoms (e.
But because most HSV-1 infections are transmitted through oral-genital contact, genital herpes can occur in a monogamous relationship with a partner who is seronegative for HSV-2.
More important, most people with either HSV-1 or HSV-2 infection are unaware of it, and a negative history provides no protection at all.

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