Amy Solomon, MD

Genital herpes simplex virus is epidemic among sexually active women. Patients 	must be educated about their infection and the potential for transmission to a partner or newborn--including the 	role of asymptomatic shedding. This review provides current information on the diagnosis, recurrence, transmission, 	treatment, and pregnancy risks of genital herpes.
Amy Solomon, MD, Samuel Smith, MD

Genital herpes simplex virus (HSV) infection is a growing epidemic, with 21.7% of the US population seropositive 	for HSV-2 antibodies. This represents a 31% increase in HSV prevalence over the last 10 years.1 The 1600 cases 	of neonatal herpes infection occurring annually in the United States make this more than just a gynecologic problem.

When a woman presents to her physician with genital lesions, she expects information, counseling, and treatment 	options. If the lesions are herpetic, she should be informed about modes of con-traction, ways to prevent transmission, 	treatments available, and implications for future pregnancies. Today, every physician who provides primary care 	for women must be well-informed about HSV epidemiology, diagnosis, transmission and shedding, and management of 	flares and future pregnancies.

Painful or pruritic vesicles clustered on the labia and/or buttocks are the classic clinical signs of a genital 	HSV outbreak in a female patient (Figure). These vesicles may also manifest as pustular lesions on an erythematous 	base. Other common signs and symptoms include dysuria, tender inguinal lymph nodes, and cervical ulcerations (Table 	1). Often, there is a 1- to 2-day prodromal period of tingling or pruritus in the genital region, generalized malaise, 	and low-grade fever that precedes the appearance of vesicles. The primary HSV attack can last up to several weeks. 	The vesicles eventually develop scabs and disappear, but may recur during the initial outbreak. Herpes recurrences 	do not usually last as long as the initial occurrence.

The diagnosis of herpes is usually based on symptoms and clinical findings. When the diagnosis is questionable, 	a number of tests may be used for confirmation. Viral culture is reliably sensitive and widely used, but requires 	several days to yield results. HSV recovery for culture decreases with the increasing stage of the lesion; for 	example, vesicular lesions result in positive cultures about 90% of the time, compared with only 25% to 30% recovery 	in crusted lesions.

The Tzanck smear, a rapid and inexpensive test, is performed by opening a vesicle, scraping the exposed base 	with a scalpel, and placing the debris on a slide. Giemsa, Sedi, or Wright's stain is applied, and the specimen 	is examined microscopically for characteristic cytopathology such as multinucleated giant cells, atypical keratinocytes, 	and "ground-glass" cytoplasm. However, as the value of the Tzanck smear is severely limited by variable 	interpretation and it only has a sensitivity of about 50%, the diagnosis should always be confirmed by culture.

More rapid results can be obtained using immunofluorescent assay, but this study is less specific. Polymerase 	chain reaction for viral DNA has been found to be as effective as viral culture, but may not be readily available.5 	Type-specific serologic assays such as the Western blot have the potential to distinguish between HSV-1 and HSV-2, 	but these tests are not yet available for widespread commercial use.

The major limitation of all of these tests is sampling error. If a lesion is swabbed after a scab has formed 	or is not scraped sufficiently, any diagnostic test may fail to confirm the clinical suspicion. This contributes 	to patient anxiety and confusion, so it is important to discuss the possibility of false-negative results. Many 	cases of HSV are undiagnosed or miscommunicated to the patient. A patient should not be told that she does not 	have HSV based on a negative test result if she appears to have the virus clinically; she should instead be in- 	formed that herpes is still suspected despite the findings. She should be instructed to take precautions to limit 	spread and transmission, and to return for retesting at the earliest sign of a vesicular or pustular recurrence.

 evaluated the underdiagnosis of genital herpes by different 	techniques using 779 women with clinical signs and symptoms of HSV selected from the patient population of a sexually 	transmitted disease (STD) clinic. After performing both cultures and serologic testing, they found that culture 	was the most effective test for confirming a clinical diagnosis of a primary herpes episode. To increase sensitivity, 	the cultures had to be obtained from multiple anatomic sites, including the anus. HSV was isolated from one or 	more urogenital or anorectal specimens in 77% of women with a primary herpes episode. By contrast, HSV-2 antibodies 	were detected using Western blot assay in only 34% of women with a primary episode. HSV-1 antibodies alone were 	detected in 23% of patients with initial episodes.

Recurrent episodes were best confirmed by serologic testing, however, with HSV-2 antibodies detected by Western 	blot in 37 of 38 women with recurrences; only 34% of women with a recurrent episode yielded a positive culture 	from an external genital lesion. The researchers hypothesized that antibodies take longer to develop, and so are 	not as readily detectable in a primary episode as they are in a recurrent episode (Table 2).

A patient with genital lesions suspicious for HSV should also undergo serologic testing for syphilis, and testing 	for HIV should be discussed as well. A complete gynecologic examination should include cultures (or DNA probes) 	for gonorrhea and chlamydia, plus a vaginal pH test, a "whiff" test, and a saline-mount slide for bacterial 	vaginosis and trich-omoniasis. Patient education regarding hygiene and care of the lesions is essential to prevent 	spread of infection to the eyes or other parts of her body. She should also be warned about spreading infection 	to other family members by bathing together or sharing towels, soap, or underwear.

Condoms must be used to reduce the risk of transmission to the patient's partner, but cannot guarantee protection 	against spread during intercourse. As there is always a potential risk of asymptomatic viral shedding, condoms 	should always be employed even in the absence of lesions. More importantly, whether the episode is primary or recurrent, 	testing of the patient's partner for HSV is strongly advised. The diagnosis of herpes is considered a harsh "life 	sentence" by many patients, carrying a social stigma of uncleanliness and promiscuity. The patient may be 	forced to question the stability of her relationship, or worry about being blamed for unfaithfulness or previous 	liaisons. She may feel sexually undesirable or even ruined, and must decide between risking rejection by telling 	partners about her infection or dealing with guilt if she keeps it a secret.

The physician must be aware of the physical and emotional consequences conferred by a diagnosis of genital HSV. 	Patients are often stunned during the initial discussion, and may fail to remember simple information. They need 	time to process the data, so it is wise to schedule a follow-up visit for review and questions. Literature should 	be given to the patient to take home so she can absorb the facts at her own pace. It is helpful to encourage the 	patient to focus on a treatment plan and allow her to make some decisions about her therapy.

Herpes infections are especially disturbing because of the  possibility of frequent recurrences. The virus ascends 	to the dorsal-root ganglia and becomes latent, remaining sequestered  until an outbreak is triggered. Then the virus 	replicates and returns down the axons, innervating the genitalia.  Menstruation, physical or emotional stress, immunosuppression, 	sexual intercourse, and pregnancy can all trigger herpes recurrences.  From 80% to 85% of women who experience a 	primary episode of HSV infection will have at least one recurrence  during their lifetime.1 A study of recurrence 	rates by Benedetti et al1 demonstrated that more than 35% of patients  with initial symptomatic infection will have 	six or more recurrences in a year. A prolonged primary outbreak  increases the likelihood of frequent recurrences. 	Men with HSV-2 experience 20% more herpes recurrences than do women.

Perhaps the least understood aspects of HSV are transmission and viral shedding. Physicians routinely urge abstinence 	or use of condoms during outbreaks, but abstinence is sometimes not realistic and condoms cannot ensure complete 	protection from contact with lesions. Furthermore, recent studies reveal that a large percentage of transmission 	occurs from asymptomatic viral shedding in the absence of lesions. These studies have important implications for 	patients and their partners in preventing HSV transmission.

The risk of acquiring HSV-2 among sexual partners was prospectively analyzed in a study by Bryson et al.

 After 16 months of observation, 14% of initially HSV-2 sero- negative partners seroconverted. 	All seroconverters were women, suggesting that women are at greater risk for acquiring HSV than are men. None of 	the couples in which seroconversion occurred used condoms or spermicides during asymptomatic periods. There was 	an annual 10% acquisition rate of HSV-2 among couples.

The frequency of asymptomatic shedding was studied via daily self-culture in 27 women with recurrent genital 	herpes.

 All subjects who performed the test for more than 100 consecutive days 	and 80% of women who obtained cultures for 50 days were able to document asymptomatic viral shedding. The shedding 	was not temporally related to menstruation or contraceptive use.

The risk of asymptomatic shedding is influenced by both the HSV serotype and the time elapsed since the outbreak. 	Koelle et al

 studied 306 women with initial herpes episodes, performing vulvar 	and cervical cultures every 4 to 6 weeks during symptom-free periods. Asymptomatic shedding was documented in 11.9% 	of women after primary HSV-1 compared with 18.3% after primary HSV-2, and in 22.1% after recurrent HSV-2 episodes. 	Asymptomatic cervical shedding was more frequently detected soon after resolution of the initial episode of HSV-2 	infection. HSV was detected in the cervix on 3.1% of the days sampled in the first year, compared with 1.3% of 	days sampled after the first year.

Asymptomatic shedding was documented in 17% of women within 3 months of resolution of the primary HSV episode. 	The frequency of asymptomatic shedding dropped to 7% in the intervals 4 to 6 months and 7 to 9 months after resolution 	of the primary episode. Patients should be informed that asymptomatic shedding is greatest soon after the primary 	outbreak resolves.

Mertz et al11 characterized specific risk factors for the transmission of genital HSV, and found that most horizontal 	transmission occurs in the absence of recognized lesions. They also found that prior exposure to HSV-1 may protect 	against acquisition of HSV-2. Among the couples studied, an annual HSV-2 acquisition rate of 31.8% was noted in 	female partners lacking HSV-1 or HSV-2 antibodies. By contrast, women with HSV-1 antibodies had a 9.1% annual HSV-2 	acquisition rate. Thirteen of the 14 subjects who contracted HSV-2 during the study were able to provide detailed 	histories. In 9 subjects, transmission occurred when the source partner was clinically asymptomatic. The researchers 	concluded that in 70% of subjects who acquired HSV, transmission occurred during periods of asymptomatic shedding. 	Also, they noted that the risk of acquisition was higher in women than in men.

, women with frequent symptomatic recurrences have 	been shown to have more subclinical shedding, and may be at increased risk for transmitting HSV. In a study that 	followed the course of genital herpes in 110 women, the researchers defined viral shedding without a visible lesion 	as subclinical. Subclinical shedding was documented in 55% of women with HSV-2 and in 52% of women with both HSV-1 	and HSV-2. It occurred on a mean of 2% of the days monitored, and on more than 5% of monitored days in 11% of women 	with HSV-2. Subclinical shedding episodes lasted a mean of 1.5 days. Women with more than 12 clinically apparent 	outbreaks per year had more frequent viral shedding, and half the episodes of shedding occurred within 7 days of 	an outbreak.

Like HIV, human papillomavirus, and hepatitis B, HSV essentially has no cure. Patients with infrequent recurrences 	may need only reassurance and topical anesthetic ointment. Sitz baths, warm compresses, and a nonnarcotic analgesic 	provide local relief during the initial episode, as well as recurrences. Patients with more frequent recurrences 	may benefit from using oral antiviral medications such as acyclovir. Oral acyclovir therapy, 200 mg, 5 times a 	day for 10 days, shortens the duration of viral shedding and decreases healing time in initial outbreaks.

 For recurrent herpes, acyclovir can be given at 400 mg tid for 7 to 10 days, although 	the labeling recommendations and guidelines from the US Centers for Disease Control and Prevention suggest 200 	mg, 5 times a day for 5 days. Valacyclovir, a prodrug of acyclovir, has recently been approved by the US Food and 	Drug Administration for the treatment of both primary and recurrent HSV. It has the benefit of greater absorption 	and bioavailability than acyclovir, and so has a more convenient dosing schedule of 1 g bid for 10 days for initial 	outbreaks, and 500 mg bid for 5 days for a recurrence.

Famciclovir has also received FDA approval for recurrent herpes, and is given at 125 mg bid for 5 days. Severe 	local disease or systemic complications may require treatment with IV acyclovir. Patients who have six or more 	episodes per year or those who feel psychologically disabled by their condition are good candidates for suppressive 	therapy with acyclovir.

 Suppressive dosing of acyclovir may reduce the frequency 	of recurrences by up to 80%; indeed, approximately 25% to 30% of patients will have no further recurrences while 	taking suppressive acyclovir.

Herpes outbreaks may be suppressed for long periods of time. A multicenter trial involving more than 1100 patients 	with a history of frequent recurrences (at least 12 episodes per year) evaluated acyclovir, 400 mg bid, for chronic 	suppression.

 Patients were followed prospectively for 5 years. More than 20% 	of patients who received suppressive therapy with acyclovir were recurrence-free for the full 5 years. From 86% 	to 90% of patients remained recurrence-free for 3-month intervals during their fifth year of treatment. No serious 	side effects or drug toxicities were reported.

Little research has been done to determine whether asymptomatic shedding is suppressed with antiviral therapy. 	Wald et al

 performed a randomized, double-blind study to evaluate this, assigning 	34 women with HSV-2 to receive either acyclovir, 400 mg bid for 70 days followed by a washout period and then 70 	days of placebo, or the reverse order. The women collected daily genital swabs for HSV culture and kept a diary 	of symptoms. Acyclovir use was associated with a 94% reduction in subclinical shedding when compared with placebo. 	Additional research to evaluate the role of chronic acyclovir in preventing transmission of HSV-2 is clearly warranted.

Many patients feel that they are no longer sexually desirable, or refrain from sex for fear of transmitting 	the disease. Some are too embarrassed to reveal their condition to their partners and risk exposing others. Herpes 	suppression therapy may provide hope for these patients. Formulating a treatment plan with the patient that includes 	suppression therapy gives her a positive focus and a sense of autonomy.

HSV may be acquired in utero, intrapartum, or postpartum. About 5% of babies with neonatal herpes acquire the 	virus prior to labor. Direct contact with the maternal genitalia or secretions during delivery accounts for about 	85% of neonatal herpes. Intrauterine infection occurs in about 5% of cases. Postnatal acquisition occurs by direct 	contact with an infected caretaker, and accounts for the other 10% of neonatal herpes.2 Perinatal HSV infection 	may be manifested by vesicular lesions on the skin, with or without conjunctivitis, in 15% of cases. It involves 	the central nervous system in 15% of cases, sometimes resulting in convulsions. Systemic disease is seen in 70% 	of neonatal cases, and is characterized by such findings as hepatitis, hemolytic anemia, pulmonary disease, petechiae, 	and thrombocytopenia.

The overall incidence of neonatal infection is 0.01% to 0.4% of deliveries. Primary maternal HSV infection poses 	a greater risk to the baby than do recurrences. Neonates born vaginally to mothers with a primary herpes outbreak 	have a 50% infection rate. By contrast, neonates delivered vaginally during a recurrent HSV episode have an infection 	risk of only 1% to 4%. These findings suggest that maternal antibodies confer some protection to the fetus.

One study on risk factors associated with HSV recurrences and asymptomatic shedding during pregnancy looked 	at 147 pregnant women with recurrent HSV acquired prior to pregnancy and 15 women who experienced primary HSV infection 	during pregnancy.

 A higher number of clinical recurrences were noted during 	gestation, possibly owing to the mild immunosuppression of pregnancy. The mean number of recurrences per trimester 	rose significantly from 0.97 to 1.26 to 1.63 as pregnancy progressed. The 15 patients with primary herpes in pregnancy 	had fewer recurrences than did those who acquired HSV prior to conception. The median number of symptomatic recurrences 	of HSV during gestation was four in the recurrent HSV group and two in the primary HSV group (p <.01). However, 	asymptomatic shedding was seen in 33% of the primary HSV group, compared with only 12.9% of the recurrent HSV group. 	Young age and recent acquisition of genital herpes were identified as risk factors for asymptomatic shedding of 	HSV during pregnancy.18 The role of asymptomatic shedding in transmission of HSV to the baby is still unclear.

The American College of Obstetricians and Gynecologists recommends performing cultures when a woman has active 	lesions during pregnancy to confirm the diagnosis. If there are no lesions during labor, vaginal delivery is not 	contraindicated. Similarly, amniocentesis to rule out intrauterine HSV infection is not recommended. Pregnant patients 	at term with visible HSV lesions or prodromal symptoms who are in labor or who have ruptured membranes should undergo 	cesarean section.

Antiviral suppressive therapy may prove useful during pregnancy. Acyclovir suppression has been studied for 	efficacy in preventing the need for cesarean delivery.

 Women with primary genital 	herpes during pregnancy were randomly assigned to receive acyclovir, 400 mg tid, or placebo from 36 weeks of gestation 	until delivery. None of the women treated with acyclovir had clinical evidence of active herpes at the time of 	delivery, as compared with 36% of those treated with placebo. None of the women treated with acyclovir underwent 	cesarean section, in contrast to 36% of those treated with placebo. No neonates from the acyclovir group had evidence 	of HSV infection or suffered adverse drug effects.

Herpes infections continue to spread despite campaigns for safe sex and increased use of antiviral medications. 	The physician must be armed with the latest information so that patients can be educated about transmission, shedding, 	and treatment options. Cultures should be taken from more than one anatomic site to improve the accuracy and sensitivity 	of diagnosis, which should include adjunctive testing for other STDs. Counseling should encompass recurrences, 	triggers, and what can be expected of the virus and its course. There is an annual 10% acquisition rate of HSV-2 	between sexual partners, but women with HSV-1 antibodies are less likely to acquire HSV-2. Asymptomatic shedding 	may be responsible for transmission in 70% of cases, is more common in women with frequent recurrences, and is 	greater right after the primary episode.

Uncomplicated HSV infection is most effectively treated with oral acyclovir, valacyclovir, or famciclovir. The 	risk of transmission to the neonate during vaginal delivery is up to 50% during a primary episode, compared with 	less than 4% with active recurrent infection. Suppression therapy has a major role in decreasing transmission to 	partners and to the neonate during pregnancy. Research is ongoing to develop a safe vaccine for HSV but, for the 	present, herpes remains one of our most prevalent and devastating STDs.

1.    Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann Intern Med. 1994;121:847-854.

2.    Whitley RJ. Herpes simplex virus infections of women and their offspring: implications for a developed society. Proc Natl Acad Sci USA. 1994;91:2441-2447.

3.    Woolley P. Management of genital herpes. The Practitioner. 1994;238:406-410.

4.    Hensleigh P. Herpes in pregnancy--it's especially serious for the neonate. Contemp Ob/Gyn. 1994;10:25-35.

5.    Nahass GT, Goldstein BA, Zhu WY, Serfling U, et al. Comparison of Tzanck smear, viral culture, and DNA diagnostic methods in detection of herpes simplex and varicella-zoster infection. JAMA. 1992;268:2541-2544.

6.    Mertz G. Epidemiology of genital herpes infections. Infect Dis Clin North Am. 1993;4:825-839.

Amy Solomon, MD

Articles

Understanding Herpes Simplex Virus