Understanding Herpes Simplex Virus

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.²

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.

DIAGNOSIS

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.³

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.⁴

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.⁶

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.

Koutsky et al⁷ 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).⁷

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.

RECURRENCE

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.¹

TRANSMISSION

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.⁸ 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.⁸

The frequency of asymptomatic shedding was studied via daily self-culture in 27 women with recurrent genital herpes.⁹ 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.⁹

The risk of asymptomatic shedding is influenced by both the HSV serotype and the time elapsed since the outbreak. Koelle et al¹⁰ 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.¹⁰

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.¹¹

According to Wald et al¹², 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.¹²

TREATMENT

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.¹³ 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.³ 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.¹³

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.¹⁴ 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.¹⁴

Little research has been done to determine whether asymptomatic shedding is suppressed with antiviral therapy. Wald et al¹⁵ 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.¹⁵

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.

PREGNANCY

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.¹⁶

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.¹⁷

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.¹⁸ 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.¹⁷

Antiviral suppressive therapy may prove useful during pregnancy. Acyclovir suppression has been studied for efficacy in preventing the need for cesarean delivery.¹⁹ 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.¹⁹

CONCLUSION

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.

References:

REFERENCES

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.

7. Koutsky L, Stevens CE, Holmes KK, et al. Underdiagnosis of genital herpes by current clinical and viral-isolation procedures. NEJM. 1992;326:1533-1539.

8. Bryson Y, Dillon M, Bernstein D, et al. Risk of acquisition of genital herpes simplex virus type 2 in sex partners of persons with genital herpes: a prospective couple study. J Infect Dis. 1993;167:942-946.

9. Brock BV, Selke S, Benedetti J, et al. Frequency of asymptomatic shedding of herpes simplex virus in women with genital herpes. JAMA. 1990;263:418-420.

10. Koelle DM, Benedetti J, Langenberg A, Corey L. Asymptomatic reactivation of herpes simplex virus in women after the first episode of genital herpes. Ann Intern Med. 1992;116:433-437.

11. Mertz GJ, Benedetti J, Ashley R, et al. Risk factors for the sexual transmission of genital herpes. Ann Intern Med. 1992;116:197-202.

12. Wald A, Zeh J, Selke S, et al. Virologic characteristics of subclinical and symptomatic genital herpes infections. NEJM. 1995;333:770-775.

13. Whitley RJ, Gnann JW. Acyclovir: a decade later. NEJM. 1992;327:782-789.

14. Goldberg LH, Kaufman R, Kurtz TO, et al, and the Acyclovir Study Group. Long-term suppression of recurrent genital herpes with acyclovir. Arch Dermatol. 1993;129:582-587.

15. Wald A, Zeh J, Barnum G, et al. Suppression of subclinical shedding of herpes simplex virus type 2 with acyclovir. Ann Intern Med. 1996;124:8-15.

16. Reese EA, Hobbins JC, Mahoney MJ, Petrie RH. Medicine of the Fetus and Mother. Philadelphia: JB Lippincott; 1992:358-359.

17. American College of Obstetricians and Gynecologists. Perinatal herpes simplex virus infections. ACOG Technical Bulletin 122. Washington DC: ACOG; November 1988.

18. Brown ZA, Vontver LA, Benedetti J, et al. Genital herpes in pregnancy: risk factors associated with recurrences and asymptomatic viral shedding. Am J Obstet Gynecol. 1985;153:24-30.

19. Scott LL, Sanchez PJ, Jackson GL, et al. Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes. Obstet Gynecol. 1996;87:69-73.

Amy Solomon, MD, is a Chief Resident and Samuel Smith, MD, is the Director of Reproductive Endocrinology and Infertility in the Department of Obstetrics and Gynecology at Sinai Hospital in Baltimore.