**Note: Hospital Practice suspended publication as of September, 2001. This article was saved from their site in order not to lose the valuable information in it. **

Most patients with herpes simplex virus infection have mild or sub clinical disease and fail to seek medical attention or are misdiagnosed. But inexpensive and accurate new serologies are being developed. Chronic suppressive therapy in patients with frequent recurrences reduces viral shedding and may reduce transmission.

About 48 million people in the United States have genital herpes. 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). 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). Serum samples collected during the National Health and Nutrition Examination Surveys (NHANES) II and III showed a 30% nationwide increase in HSV-2 prevalence from the late 1970s to the mid-1990s (Table 1). Seroprevalence was considerably higher among women than among men, and higher among African Americans than among other ethnic or racial groups.

Fifteen years ago, it was unusual to diagnose HSV-2 infection among 20-year-olds. 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. White adolescents are nearly five times more likely to have herpes today than they were in the 1970s.

Ironically, one culprit may be widespread misunderstanding of health promotion messages. Many teenagers have grown up thinking that they can change partners indiscriminately as long as they use a condom. 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. 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. Moreover, the distribution of lesions in women generally extends over areas (labia majora, perineum, perianal area) not protected by condoms. 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. Although condoms probably offer an advantage, there are no data demonstrating their protection. Total protection is obtainable only through monogamous sex with an uninfected partner. 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.

A Diagnostic Challenge

The incidence of herpes infection has risen so rapidly largely because this is a silent pandemic. Most patients have mild or sub clinical disease and either do not seek medical attention or are misdiagnosed when they do seek it. In the NHANES III study, nine of 10 HSV-positive subjects did not know that they were infected. Atypical clinical presentations are common in primary infection. They range from a generalized flu-like illness to neurologic manifestations such as aseptic meningitis, lymphadenopathy, skin edema, and transient autonomic neuropathy. When these occur in the absence of genital lesions, the diagnosis is likely to be missed even if the patient presents for care. 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. Bowel dysfunction and impotence are other presentations that are unlikely to suggest herpes to anyone but a virologist. 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.

New Diagnostic Techniques. Even if the physician decides to order a culture, the results may be misleading. 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. 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.

Unfortunately, the gold standard of laboratory diagnosis--the Western blot--is expensive and may be difficult to obtain. (Physicians can obtain the Western blot from the University of Washington Diagnostic Virology Section or Viridae Clinical Sciences [604-689-9404; www.viridae.com]). 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. 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.

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. S. Food and Drug Administration (FDA)--have an accuracy of less than 70% for HSV-2. A more reliable ELISA with a sensitivity of about 95% and specificity of 96% to 98% has been developed and is awaiting release. 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. 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. Sensitivity is also an issue, especially for a test designed to rule out genital herpes. The Western blot remains the gold standard for this purpose. Similar problems plague a new point-of-case gG-2 test.

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. Their role in STD clinics and other settings of high HSV prevalence, however, remains to be determined. 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, 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.

Primary or Recurrence?

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. 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. 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. Indeed, a significant proportion of first episodes are really recurrences that are reflected in mild symptoms and minimal systemic sequelae.

For the majority of patients with genital herpes, recurrences represent only a nuisance, and episodic antiviral treatment is satisfactory. 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. 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. 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. Suppressive therapy clearly is preferred in this group.

Asymptomatic shedding--an important contributor to HSV spread--is common in both sexes, particularly in the period immediately surrounding a symptomatic episode. Studies employing viral culture suggest that patients with genital herpes experience viral shedding on 1% to 5% of asymptomatic days. 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. 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. However, it is not clear whether a positive PCR assay in patients with a negative culture reflects a true risk of transmission.

Medical Management

While there is no cure for genital herpes at this time, we are fortunate in having a number of selective antiviral agents--acyclovir, famciclovir. and valacyclovir--that have been shown to be safe and effective for both acute and chronic suppressive treatment (Table 2). 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). 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. All three drugs have been shown to reduce time to cessation of viral shedding and duration of pain. 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.

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. 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. 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.

Continuous use of either acyclovir or famciclovir has been shown to suppress both symptomatic and asymptomatic HSV shedding by 80% to 90%. In two placebo-controlled Canadian studies of famciclovir (125 and 250 mg tid in women and 250 mg bid in men), the antiviral agent reduced days of asymptomatic shedding from 3.09% to 0.52% or less in women and from 1.09% to 0.08% in men (Figure 5). 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. 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%). The drug was well-tolerated, with an adverse outcome profile comparable to that of placebo.

It is important for physicians to emphasize that use of antivirals should not become an excuse to abandon safer sex practices. Condom use should remain consistent, and couples should be abstinent (even from oral-genital sex) during periods of active infection. Promotion of condom use may lead to greater patient selectivity in choosing sexual partners and increased dialogue with physicians concerning STDs in general. However, practical serologic diagnosis will be a necessary component of prevention with this predominantly subclinical STD.

Duration of Chronic Treatment. The optimal duration of suppressive antiviral treatment is unknown. 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. 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. 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. 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.

There also are emotional and lifestyle factors to consider. For example, a patient whose primary relationship has just ended may want to suspend antiviral therapy until sex is contemplated with another partner. 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.

Supportive Counseling

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. 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.

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. Since news of a definitive diagnosis is nearly always upsetting, the physician should arrange one or more follow-up counseling sessions as well as provide printed material for home reference (available at www.viridae.com). 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.

For most patients, the greatest concern is fear of transmission to sexual partners. 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. Others will turn to anonymous sex in order to avoid the issue. 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. In extreme cases, suicide may be contemplated. Referral to a psychotherapist or couple counselor may be indicated.

Patients in committed relationships generally find that their partners are understanding. There are exceptions, however, and it is unwise to assume that all is well simply because the patient is in a long-term relationship. 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. 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). Thus, a diagnosis of genital herpes is simply a matter of bad luck--not promiscuity. 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. 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.

Future Interventions

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. Regimens combining older agents that target viral DNA polymerase with immunomodulators or ribonucleotide reductase inhibitors are also in development.

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. A 1994 trial noted a decreased recurrence in patients who received a glycoprotein gD candidate vaccine; however, later follow-up trials using a gD/gB glycoprotein combination had unconvincing results for both treatment and prevention. A DNA-based vaccine is in phase 1 clinical trials.

In summary, there is no evidence that an established latent HSV infection can be reversed or diminished with any of the existing antiviral agents. 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. 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. 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.

Selected Reading

Diaz-Mitoma F et al: Oral famciclovir for the suppression of recurrent genital herpes. JAMA 280:887, 1998

Fleming DT et al: Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 337:1105, 1997

Reitano M et al: Valacyclovir for the suppression of recurrent genital herpes simplex virus infection: A large-scale, dose range-finding study. J Infect Dis 178:603, 1998

Sacks SL et al: Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. JAMA 276:44, 1996

Spruance S et al: A large-scale, placebo-controlled, dose-ranging trial of peroral valacyclovir for episodic treatment of recurrent herpes genitalis. Arch Intern Med 156;1729, 1996

Tyring SK et al: A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. Arch Dermatol 134:185, 1988

Wald A et al: Frequent genital HSV-2 shedding in immunocompetent women. J Clin Invest 99:1092, 1997