Adolescent Health Care: A Practical Guide

Chapter 65

Herpes Genitalis

Gale R. Burstein

Kimberly A. Workowski

Genital herpes is a chronic lifelong viral disease. Herpes genitalis lesions are caused by a large DNA virus, herpes simplex virus (HSV), with two serotypes, herpes simplex type 1 (HSV-1) and herpes simplex type 2 (HSV-2). Although HSV-1 is becoming more prominent as a cause of first-episode genital herpes, most cases of recurrent genital herpes are caused by HSV-2. These viruses have the ability to become latent and recur. Although the herpes genitalis prevalence has increased dramatically over the last 30 years, over the last decade the HSV-2 infection has declined. On the basis of serological studies, genital HSV-2 infection has affected at least 50 million persons in the United States. Most persons infected with HSV-2 have not been diagnosed. Many such persons have mild or unrecognized infections but shed virus intermittently in the genital tract. Most genital herpes infections are transmitted by persons unaware that they have the infection or who are asymptomatic when transmission occurs.

Epidemiology

Incidence and Prevalence

1. HSV infections are the most common cause of genital ulcerative disease in the United States and one of the most common sexually transmitted diseases (STDs). However, most people who have serological evidence of infection are asymptomatic. The National Health and Nutrition Examination Survey III (NHANES III) conducted between 1988 and 1994 estimated that 22% of the U.S. population older than 12 years is seropositive for HSV-2, yet only 9% of those testing HSV-2-positive reported a history of genital ulcerative disease (Fleming et al., 1997).
2. The incidence of new HSV-2 infections among the seronegative population increased sharply during the 1970s and 1980s. From 1970 to 1985, the annual incidence of HSV-2 infection increased by 82% (Armstrong et al., 2001). However, the U.S. age-adjusted HSV-2 prevalence has decreased from 21.0% (95% CI, 19.1–23.1) in the NHANES III conducted between 1988 and 1994 to 17.0% (95% CI: 15.8–18.3) in the NHANES conducted between 1999 and 2004 (Xu et al., 2006). This represents a 19% decrease in prevalence.
3. HSV-2 prevalence varies by age, gender, and race.
4. Age: The prevalence of infection increases rapidly after puberty, reaching a peak in the third decade of life. Approximately 1.6% (95% CI, 1.3–2.0) of adolescents aged 14 to 19 years are infected with HSV-2 (a 72% decrease observed from the 1999 to 2004 NHANES compared to NHANES III data) and 10.6% (95% CI, 8.9–12.5) of 20- to 29-year-olds are HSV-2 seropositive (a 38% decrease observed from the 1999–2004 NHANES compared to NHANES III data) (Xu et al., 2006).
5. Ethnicity: NHANES in 1999 to 2004 estimated overall HSV-2 seroprevalence rates to be higher among blacks (41.7%; 95% CI, 38.5–45.1) than whites (13%; 95% CI, 21.0–14.1) (Xu et al., 2006).
6. Gender: NHANES in 1999 to 2004 estimated overall HSV-2 seroprevalence rates to be higher among females (22.8%; 95% CI, 21.2–24.4) than among males (11.2%; 95% CI, 9.9–12.6). Differences in HSV-2 prevalence rates by gender may reflect that females are more than 5 to 6 times susceptible to acquire an incident HSV-2 infection following exposure as compared to males (Wald et al., 2001).
7. Up to 50% of first-episode cases of genital herpes are caused by HSV-1. However, an estimated 96% of recurrent symptomatic genital infections are caused by HSV-2 and 4% by HSV-1 (Solomon et al., 2003).

Recurrent Episodes

1. Symptomatic recurrent episodes are more likely following primary HSV-2 infection as compared to HSV-1. In a cohort study, 180 days following a primary genital herpes episode, only 40% of HSV-1 infected patients but 90% of 123 HSV-2 infected patients experienced a symptomatic recurrence (Reeves et al., 1981). Identification of the type of infecting strain may have some prognostic importance to the individual and may be useful in counseling.
2. Asymptomatic viral shedding is more frequent following initial infection with HSV-2 than for HSV-1. In a cohort study of 110 HSV-infected females followed up with daily genital specimens for a median of 105 days, subclinical viral shedding was detected in 29% of 14 HSV-1 infected females, in 55% of HSV-2 infected females, and in 52% of females coinfected with HSV-1 and HSV-2 (Wald et al., 1995). Shedding occurred for a longer duration

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in HSV-2 infected females (2% of days) compared to HSV-1 infected females (0.7% of days).

Transmission

1. Mode of transmission: Transmission is through sexual contact, either genital–genital or oral–genital, and by mucosal contact with infected secretions.
2. Reservoir: Humans are the sole known reservoir of infection.
3. Risk of transmission
4. Gender: Females are at greater risk of HSV acquisition compared to men. Among 528 monogamous couples discordant for HSV-2 infection (261 male and 267 female susceptible to HSV-2 infection), 9.7% of females versus 1.5% of males acquired HSV-2, at a rate of 8.9/10,000 episodes of sex in females and 1.5/10,000 episodes of sex in males (Wald et al., 2001).
5. Asymptomatic versus symptomatic: Although viral shedding is highest while genital lesions are present, most sexual transmission of HSV-2 occurs on days without genital lesions in the source partner. In a 7-week study of 69 immunocompetent persons with genital HSV-2 infection who provided daily genital mucosal swabs for HSV detection, HSV-2 was detected by polymerase chain reaction (PCR) on 27% of asymptomatic days and 87% of symptomatic days (Gupta et al., 2004).
6. Age and sexual activity: Younger age and more frequent sexual activity were associated with higher risk of human immunodeficiency virus 2 (HIV-2) acquisition (Wald et al., 2001).
7. HIV status: HSV-2 viral shedding rates among human immunodeficiency virus (HIV)-seropositive women was four times greater compared to HSV-2 viral shedding in HIV-seronegative women (13.2% versus 3.6%) (Augenbraun et al., 1995). HSV-2 shedding can occur in 3% of infected adults and is more likely during a first or recurrent genital HSV-2 episode (Wald et al., 2004).

Health care providers have an obligation to inform their patients about the natural history of disease with potential recurrent episodes and the risk of transmitting HSV during asymptomatic periods. Persons with genital HSV infection should be encouraged to inform their current or prospective sexual partners that they have genital herpes.

Infections by Serological Type

1. HSV-1: Infection typically manifests as oral-labial lesions, but the frequency of HSV-1 genital infections is increasing. Recurrences and subclinical shedding are much less frequent than with genital HSV-2 infection.
2. HSV-2: Infection typically manifests as anogenital lesions. Antibodies are not routinely detected until puberty, when antibody levels correlate with past sexual activity.

Pathogenesis

Virus particles can be shed in salivary, cervical, and seminal secretions of infected individuals. The virus gains entry into the body through mucosal surfaces or abraded skin and replicates in the epidermal and dermal cells of a susceptible host. After replication, the virus spreads through contiguous cells to mucocutaneous projections of sensory nerves.

In oral herpes, the virus lodges in the trigeminal ganglion; in genital herpes, the sacral dorsal root (S2 to S4) ganglion is the target site. Centrifugal spread can then occur through peripheral sensory nerves back to the skin surface, so that large areas may be involved.

After resolution of the primary disease, the virus becomes latent. Latency appears to be life long but is interrupted by periods of viral reactivation, leading to silent viral shedding or clinically apparent recurrence. Reactivation of latent virus leads to transport of viral genomes to the skin surface, where replication occurs in the dermis and epidermis. Reactivation can be triggered by a variety of stimuli, such as ultraviolet light, immunosuppression, fever, pneumococcal pneumonia, stress, and local trauma. Frequency and clinical severity of reactivation depend on factors such as the host immunological status and the severity and viral type of the primary infection.

Clinical Manifestations

Definition of Terms

1. Primary infection: Genital herpes in a patient seronegative for antibody to HSV-1 or HSV-2.
2. First clinical episode: First episode of clinical manifestations due to HSV-1 or HSV-2 infection. This term includes both nonprimary first episodes, (i.e., positive serology), and primary infections.
3. Recurrent clinical episode: Recurrence of genital HSV lesions in a patient with a previously documented symptomatic genital herpes episode.
4. Atypical clinical episode: Episode of clinical manifestations due to HSV-1 or HSV-2 infection that do not include classicgenital lesions.

Classic Primary Infection

1. Primary genital HSV infection involves both systemic and local symptoms.
2. Incubation: Clinical manifestations begin approximately a week following initial infection.
3. Systemic symptoms occur over the first week of illness in more than half of infected individuals, which may include fever, headache, malaise, and myalgias.
4. Local symptoms include painful lesions (99% of females and 95% of males), dysuria (83% of females and 44% of males), pruritus, vaginal or urethral discharge, and tender inguinal adenopathy.
5. One third of males develop urethritis whereas 70% to 90% of females develop cervicitis with first episode of infection.
6. Herpetic lesions can be extensive and can involve the vulva, perineum, vagina, and cervix or, in males, large areas of the penis. Lesions usually begin as small papules or vesicles on an erythematous base that rapidly spread over the genital area. Multiple small pustular lesions coalesce into large areas of ulceration. Pain and irritation from lesions usually peak between days 7 and 11 of disease and heal

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over the second week. Crusting and reepithelization occurs in the penile and mons area, but crusting does not occur on mucosal surfaces. Scarring is uncommon. New crops of lesions can form in more than 75% of primary infections. Lesions typically heal by the end of the third week of disease.

5. Central nervous system complaints, such as headache, stiff neck, and mild photophobia, may occur in the first week of illness in almost 70% of females and 40% of males with primary HSV-2 disease.
6. Pharyngeal infection is commonly seen in association with primary genital infection with both HSV-1 and HSV-2.
7. Median duration of viral shedding is 12 days.
8. Complications can include aseptic meningitis and other neurological complications, such as autonomic nervous system dysfunction and transverse myelitis, extragenital lesions located in the buttock, groin, or thighs areas, and disseminated disease.

First Clinical Episode

1. First episodes of genital herpes are more often associated with systemic symptoms, a prolonged duration of lesions and viral shedding, and likely to involve multiple genital and extragenital sites compared to recurrent episodes.
2. Approximately 50% of persons with their first clinical episode of symptomatic genital herpes have serological evidence of prior HSV infection, that is, the first clinical episode is not a result of the primary infection.
3. Prior HSV-1 infection diminishes the severity of first genital herpes episodes.

Recurrent Episodes

1. Clinical manifestations are localized to the genital region and are mild to moderate compared to primary infection.
2. Duration: The duration of the episode usually ranges from 6 to 12 days.
3. Prodromal symptoms: Prodromal symptoms occur in approximately 60% of episodes. Prodromal symptoms vary and can range from mild paresthesias to shooting pains in the buttocks, legs, or hips.
4. Lesions in recurrent episodes are often:
5. Unilateralwith a much smaller area of involvement
6. Associated with fewer lesionscompared to the primary infection
7. Occur in predominantly nonmucosalskin
8. Clinical episodes can vary considerably in the severity and duration of disease between episodes in the same individual and among different individuals.
9. Symptoms are typically more severe among females.
10. Duration: Lesions typically heal by the second week of disease.
11. Shedding: In untreated patients, the average duration of viral shedding is 4 days.
12. After the first year, recurrences tend to decrease in frequency. Among 59 HSV-1–infected and 191 HSV-2–infected persons, the median annual recurrence rate in the first year following primary infection was one for HSV-1 infection and five for HSV-2 (Benedetti et al., 1999). In the second year, the median was zero recurrences for HSV-1 infection and four recurrences for HSV-2. The annual recurrence rate continued to decline in subsequent years, even for patients observed for >8 years. However, one third of patients experienced no decrease in recurrences over a 5-year period, and 25% of patients had more recurrences in year 5 than in year 1 (Benedetti et al., 1999).

Atypical Episodes

1. Atypical episodes may have manifestations of either a primary infection or a recurrent episode.
2. Episodes may present with genital pruritus, papules, or fissures, dysuria, urethritis, or cervicitis.

Differential Diagnosis

Herpes genitalis lesions must be differentiated from early syphilis, chancroid, lymphogranuloma venereum, granuloma inguinale, excoriations, allergic and irritant contact dermatitis, and genital lesions of Behçet syndrome.

Diagnosis

Genital herpes is the most prevalent cause of genital ulcers in the United States. Patients with genital ulcer disease can also be infected with syphilis and/or chancroid. The clinical diagnosis of genital herpes is both insensitive and nonspecific. The classical painful multiple vesicular or ulcerative lesions are absent in many infected persons. Up to 50% of first-episode cases of genital herpes are caused by HSV-1, but recurrences and subclinical shedding are much less frequent for genital HSV-1 infection than genital HSV-2 infection. As the distinction between HSV-1 and HSV-2 influences prognosis and counseling, the clinical diagnosis of genital herpes should be confirmed by laboratory testing.

Laboratory Evaluation

1. Virological tests: Isolation of HSV in cell culture is the preferred virological test in patients who present with genital ulcers or other mucocutaneous lesions. However, sensitivity of culture may be low in recurrent lesions and declines rapidly as lesions begin to heal.
2. Culture technique: Obtaining the proper specimen and using the appropriate transport medium and conditions is essential for culturing a viable organism.

• Intact vesicles: If intact vesicles are present, aspirate the vesicle fluid using a fine-gauge needle or, if vesicles are too small to aspirate, gently unroof the vesicle and swab the debris at the vesicle base. Use cotton or Dacron swabs (without a wooden stick) rather than calcium alginate, which inactivates the virus, and place the specimen in viral transport medium.
• Pustules: If pustules are present, unroof the pustule and wash away purulent material with sterile saline; then swab the base of the lesion.
• Ruptured vesicle: To culture a ruptured vesicle or ulcer, swab the base of the lesion.
• Crusted lesion: If a lesion is crusted, wash away necrotic debris with sterile saline, then swab the lesion base. When swabbing the base of a lesion, remember that friction must be used to obtain cells. Avoid contaminating the specimen with alcohol, soap, blood, or stool.

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If viral transport medium is not available, substitute sterile distilled water. Leave the swab in the transport medium if transport time is <8 hours. If transport time is longer, swirl the swab vigorously in the medium and remove. If a laboratory courier is used, refrigerate the specimen before pickup.

1. Polymerase chain reaction (PCR) assays: PCR assays for HSV DNA are more sensitive and may be used instead of viral culture; however, PCR tests are not Food and Drug Administration (FDA)-cleared for testing of genital specimens. As with culture, lack of HSV detection does not indicate lack of HSV infection, as viral shedding is intermittent. Both PCR and viral culture should be typed to determine if HSV-1 or HSV-2 is the cause of the infection.
2. Cytological detection: Cytological detection of cellular changes of herpes virus infection is insensitive and nonspecific, both in genital lesions (Tzanck preparation) and cervical Pap smears, and should not be used.
3. Type-specific serological tests: Both type-specific and non–type-specific antibodies to HSV develop during the first several weeks following infection and persist indefinitely. Accurate type-specific assays for HSV antibodies must be based on the HSV-specific glycoprotein G2 for the diagnosis of HSV-2 infection and glycoprotein G1 for diagnosis of HSV-1 infection. Such assays first became commercially available in 1999, but older assays that do not accurately distinguish HSV-1 from HSV-2 antibody, despite claims to the contrary, remain commercially available. Therefore, the type-specific gG-based assays should be specifically requested when serology is performed.
4. Available tests: Currently, the FDA-approved gG-based type-specific assays are moderate complexity, laboratory-based tests, and point-of-care tests that provide results for HSV-2 antibodies from capillary blood or serum. The laboratory gG-based type-specific tests include HerpeSelect 1 ELISA IgG, HerpeSelect 2 ELISA IgG, and HerpeSelect1 and 2 Immunoblot IgG (Focus Diagnostics Inc., Cypress, CA); and CAPTIA HSV-1 IgG Type Specific EIA and CAPTIA HSV-2 IgG Type Specific EIA (Trinity Biotech, Bray, Ireland). The point-of-care tests include the Biokit HSV-2 Rapid Test (Biokit USA, Lexington, MA) and Sure Vue HSV-2 Rapid Test (Fisher Health Care, Houston, TX).
5. Sensitivity and specificity: The sensitivities of these tests for detection of HSV-2 antibody vary from 80% to 98%, and false-negative results may occur, especially at early stages of infection. The specificities of these assays are ≥96%. False-positive results can occur, especially in patients with low likelihood of HSV infection. Repeat or confirmatory testing may be indicated in some settings, especially if recent acquisition of genital herpes is suspected.
6. Meaning of positive test: Most people with HSV-2 antibody by type-specific testing have anogenital HSV infection acquired during adolescence or adulthood, which may be asymptomatic. Most people with HSV-1 antibody have oral HSV infection acquired in childhood, which also may be asymptomatic. However, acquisition of genital HSV-1 appears to be increasing, and genital infection may be asymptomatic. Lack of symptoms in an HSV-1 seropositive person does not distinguish anogenital from orolabial or cutaneous infection. Persons with HSV-1 infection remain at risk for HSV-2 acquisition.
7. Potential uses of type-specific test: Type-specific HSV serological assays may be useful in the following clinical situations:

• Recurrent or atypical genital symptoms with negative HSV cultures
• A clinical diagnosis of genital herpes without laboratory confirmation
• A sex partner with genital herpes

Some experts believe that HSV serological testing should be included in a comprehensive evaluation for STDs in persons with multiple sexual partners, in persons with HIV infection, and in men who have sex with men (who have a higher risk of HIV acquisition). Screening for HSV-1 or HSV-2 in the general population is not indicated.

3. Additional laboratory work-up: Additional evaluation of a genital ulcer should include a serological test for syphilis. In settings where chancroid is prevalent, a Haemophilus ducreyiculture should also be performed. Because STD coinfection is frequent among adolescents, evaluation for gonorrhea, chlamydia, trichomonas, and an HIV test should also be performed.

Therapy

Principles of Genital Herpes Management

Antiviral chemotherapy offers clinical benefits to most symptomatic patients and is the mainstay of management. In addition, counseling regarding the natural history of genital herpes, sexual and perinatal transmission, and methods to reduce transmission is integral to clinical management.

Systemic antiviral drugs partially control the symptoms and signs of herpes episodes when used to treat first clinical episodes and recurrent episodes or when used as daily suppressive therapy. However, these drugs neither eradicate latent virus nor affect the risk, frequency, or severity of recurrences after the drug is discontinued. Randomized trials indicate that three antiviral medications provide clinical benefit for genital herpes—acyclovir, valacyclovir, and famciclovir. Valacyclovir is the valine ester of acyclovir and has enhanced absorption on oral administration. Famciclovir, a prodrug of penciclovir, also has high oral bioavailability. Topical therapy with antiviral drugs for genital HSV offers minimal clinical benefit, and is not recommended (Centers for Disease Control and Prevention, 2006).

First Clinical Episode of Genital Herpes

Many patients with first-episode herpes present with mild clinical manifestations but later develop severe or prolonged symptoms. The Centers for Disease Control and Prevention (CDC) (Centers for Disease Control and Prevention, 2006) recommend that patients with initial genital herpes should receive antiviral therapy.

CDC recommended regimens:

• Acyclovir 400 mg orally three times a day for 7 to 10 days,
• OR
• Acyclovir 200 mg orally five times a day for 7 to 10 days,
• OR
• Famciclovir 250 mg orally three times a day for 7 to 10 days,

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• OR
• Valacyclovir 1 g orally twice a day for 7 to 10 days.
• Treatment may be extended if healing is incomplete after 10 days of therapy.

Established Herpes Simplex Virus -2 Infection

Most patients with symptomatic, first-episode genital HSV-2 infection subsequently experience recurrent episodes of genital lesions; recurrences are much less frequent following initial genital HSV-1 infection. Intermittent asymptomatic shedding occurs in all patients with genital HSV-2 infection, even in those with long-standing or clinically silent infection. Treatment options should be discussed with all patients, regardless of severity or frequency of recurrent outbreaks. Antiviral therapy for recurrent genital herpes can be administered either episodically to diminish or shorten the duration of lesions, or continuously as suppressive therapy to reduce the frequency of recurrences and possibly decrease the risk of transmission to susceptible partners.

Suppressive Therapy for Recurrent Genital Herpes

Suppressive therapy reduces the frequency of genital herpes recurrences by 70% to 80% among patients who have frequent recurrences (i.e., ≥6 recurrences/year), and many patients report no symptomatic outbreaks. Treatment is also effective in patients with less frequent recurrences. Safety and efficacy have been documented among patients receiving daily therapy with acyclovir for as long as 6 years, and with valacyclovir or famciclovir for 1 year. Quality of life is often improved in patients with frequent recurrences who receive suppressive compared with episodic treatment. The frequency of recurrent outbreaks diminishes over time in many patients, and the patient's psychological adjustment to the disease may change. Therefore, the need to continue therapy should be discussed periodically during suppressive treatment (e.g., once a year).

CDC recommended regimens:

• Acyclovir 400 mg orally twice a day,
• OR
• Famciclovir 250 mg orally twice a day,
• OR
• Valacyclovir 500 mg orally once a day^*,
• OR
• Valacyclovir 1 g orally once a day.
• ^*Valacyclovir 500 mg once a day might be less effective than other valacyclovir or acyclovir dosing regimens in patients who have very frequent recurrences (i.e., ≥10 episodes/year).

Overall, valacyclovir and famciclovir are most likely comparable to acyclovir in clinical outcome. Ease of administration and cost also are important considerations for prolonged treatment.

Episodic Therapy for Recurrent Genital Herpes

Effective episodic treatment of recurrent herpes requires initiation of therapy within 1 day of lesion onset, or during the prodrome that precedes some outbreaks. In those with known genital infection, a supply of drug or a prescription can be provided with instructions to self-initiate treatment immediately when symptoms begin.

CDC recommended regimens:

• Acyclovir 400 mg orally three times a day for 5 days,
• OR
• Acyclovir 800 mg orally twice a day for 5 days,
• OR
• Acyclovir 800 mg orally three times a day for 2 days
• OR
• Famciclovir 125 mg orally twice a day for 5 days,
• OR
• Famciclovir 1,000 mg orally twice daily for 1 day,
• OR
• Valacyclovir 500 mg orally twice a day for 3 days,
• OR
• Valacyclovir 1 g orally once a day for 5 days.

Severe Disease

Intravenous acyclovir therapy should be provided for patients who have severe disease or complications that necessitate hospitalization, such as disseminated infection, pneumonitis, hepatitis, or complications of the central nervous system (e.g., meningitis or encephalitis). The recommended regimen is acyclovir 5 to 10 mg/kg body weight IV every 8 hours for 2 to 7 days or until clinical improvement is observed, followed by oral antiviral therapy to complete at least 10 days of total therapy (Centers for Disease Control and Prevention, 2006).

Human Immunodeficiency Virus Infection

Immunocompromised patients may have prolonged or severe episodes of genital, perianal, or oral herpes. Lesions caused by HSV are common among HIV-infected patients and may be severe, painful, and atypical. HSV shedding is increased in HIV-infected persons. Although antiretroviral therapy reduces the severity and frequency of symptomatic genital herpes, frequent subclinical shedding still occurs. Subclinical mucosal HSV is associated with higher loads of mucosal HIV. Suppressive or episodic therapy with oral antiviral agents is effective in decreasing the clinical manifestations of HSV among HIV-seropositive persons. HIV-infected persons are likely to be more contagious for HSV; the extent to which suppressive antiviral therapy will decrease HSV transmission from this population is unknown. As HIV-infected persons are evaluated for a variety of chronic infections that may become problematic with increasing immunosuppression, some experts suggest that type-specific serologies should be offered to HIV-infected persons during their initial evaluation, and suppressive antiviral therapy considered.

CDC recommended regimens for daily suppressive therapy in persons infected with HIV:

• Acyclovir 400 to 800 mg orally two to three times a day,
• OR
• Famciclovir 500 mg orally twice a day,
• OR
• Valacyclovir 500 mg orally twice a day.

Recommended regimens for episodic infection in persons infected with HIV:

• Acyclovir 400 mg orally three times a day for 5 to 10 days,
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• OR
• Famciclovir 500 mg orally twice a day for 5 to 10 days,
• OR
• Valacyclovir 1 g orally twice a day for 5 to 10 days.

In the doses recommended for treatment of genital herpes, acyclovir, valacyclovir, and famciclovir are safe for use in immunocompromised patients. For severe cases, initiating therapy with acyclovir 5 to 10 mg/kg body weight IV every 8 hours may be necessary.

If lesions persist or recur in a patient receiving antiviral treatment, HSV resistance should be suspected and a viral isolate obtained for sensitivity testing. Such patients should be managed in consultation with a specialist, and alternate therapy, such as foscarnet or topical cidofovir gel 1%, should be considered.

Management of Sex Partners

The sex partners of patients who have genital herpes likely benefit from evaluation and counseling. Symptomatic sex partners should be evaluated and treated in the same manner as patients who have genital lesions. Asymptomatic sex partners of patients who have genital herpes should be questioned concerning histories of genital lesions, and offered type-specific serological testing for HSV infection.

Prevention

1. Avoidance of intercourse: Sexual transmission of HSV can occur during asymptomatic periods. Persons with active lesions or prodromal symptoms should abstain from intercourse with uninfected partners until the lesions are clearly healed.
2. Condom use: Because viral shedding can occur in the absence of lesions, providers should recommend consistent and correct condoms use to any patient who has had an episode of genital herpes. Male latex condoms may reduce the risk of HSV acquisition and infection. Among 1,843 HSV-2–negative men and women with four or more sexual partners or an STD in the last year, persons reporting more frequent condom use were at lower risk for acquiring HSV-2 than persons who used condoms less frequently (Wald et al., 2005). In a study following 528 monogamous couples discordant for HSV-2 infection, condom use during ≥25% of sex acts was associated with protection against HSV-2 acquisition in for women, but not for men (Wald et al., 2001). Wald also found that the HSV-2 acquisition rate decreased with decreasing sexual activity. Having sex when genital lesions were present increased the risk of HSV-2 acquisition, but the increase did not reach statistical significance (Wald et al., 2001).
3. Use of suppressive therapy: Treatment with valacyclovir 500 mg daily decreases the rate of HSV-2 transmission in discordant, heterosexual couples in which the source partner has a history of genital HSV-2 infection (Corey et al., 2004). HSV-2 discordant couples should be encouraged to consider suppressive antiviral therapy as part of a strategy to prevent transmission, in addition to avoidance of sexual activity during recurrences and consistent condom use. These findings are also likely to apply to persons who have multiple partners, to those who are HSV-2 seropositive without a history of genital herpes, and to men who have sex with men, because the effect of antiviral therapy on viral shedding is unlikely to be related to the behavior of the infected persons.
4. Vaccination: No effective vaccine is yet available for HS However, research is continuing in the development of an effective vaccine.

Complications

1. Significant psychological distress: Initially, denial, shock, fear, guilt, feelings of social isolation, and anger are common. Anxiety and depression also occur and may persist in some patients.
2. Local complications: Secondary bacterial infection of lesions, phimosis (males) or labial adhesions (females), urinary retention, constipation, and impotence. Sacral radiculopathy can also occur, causing paresthesias in the lower extremities.
3. Proctitis: Occurs predominately in persons who participate in receptive anal intercourse. Presenting complaints may include rectal bleeding, mucoid discharge, constipation, tenesmus, fever, and, occasionally, impotence.
4. Herpes keratitis: This is predominantly associated with HSV-1 infection.
5. Encephalitis and meningitis: Encephalitis is typically associated with oral HSV-1 infection and aseptic meningitis is typically associated with genital HSV-2 infection.
6. Neonatal herpes: Most mothers of infants who acquire neonatal herpes lack histories of clinically evident genital herpes. The risk for transmission to the neonate from an infected mother is high (30%–50%) among women who acquire genital herpes near the time of delivery and is low (<1%) among women with histories of recurrent herpes at term or who acquire genital HSV during the first half of pregnancy. However, because recurrent genital herpes is much more common than initial HSV infection during pregnancy, the proportion of neonatal HSV infections acquired from mothers with recurrent herpes remains high. Prevention of neonatal herpes depends both on preventing acquisition of genital HSV infection during late pregnancy and avoiding exposure of the infant to herpetic lesions during delivery. Infants exposed to HSV during birth, as documented by virological testing or presumed by observation of lesions, should be followed up carefully in consultation with a specialist.

Web Sites

For Teenagers and Parents

http://www.ashastd.org". The Herpes Resource Center (HRC, supported by the American Social Health Association [ASHA]) focuses on increasing education, public awareness, and support to anyone concerned about herpes. The HRC provides accurate information about herpes with informational Web sites, brochures and books, a hotline, a chat room, e-mail responses to questions, and referrals to local Support Groups. Accessed May 7, 2007.

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National Herpes Hotline (supported by ASHA).Provides accurate information and appropriate referrals to anyone concerned about herpes. Telephone:1-800-277-8922.

http://www.cdc.gov/std/Herpes/default.htm. Centers for Disease Control and Prevention. Provides patient HSV information. Accessed May 7, 2007.

http://www.herpeshelp.com/(Supported by Glaxo Wellcome). Herpes help informational Web site. Accessed May 7, 2007.

http://www.iwannaknow.org/(Supported by ASHA). Provides information to teens and parents about teen sexual health and STDs. Accessed May 7, 2007.

http://www.plannedparenthood.org/. Planned Parenthood HSV informational Web site. Accessed May 7, 2007.

For Health Professionals

http://www.cdc.gov/STD/treatment. Sexually Transmitted Diseases Treatment Guidelines, 2006. Accessed May 7, 2007.

References and Additional Readings

Armstrong GL, Schillinger J, Markowitz L, et al. Incidence of herpes simplex virus type 2 infection in the United States. Am J Epidemiol 2001;153:912.

Augenbraun M, Feldman J, Chirgwin K, et al. Increased genital shedding of herpes simplex virus type 2 in HIV-seropositive women. Ann Intern Med 1995;123:845.

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

Benedetti JK, Zeh J, Selke S, et al. Frequency and reactivation of nongenital lesions among patients with genital herpes simplex virus. Am J Med 1995;98:237.

Benedetti JK, Zeh J, Corey L. Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time. Ann Intern Med 1999;131:14.

Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2006. MMWR 2006;55 (RR11):16–20.

Chosidow O, Drouault Y, Leconte-Veyriac F, et al. Famciclovir vs. acyclovir in immunocompetent patients with recurrent genital herpes infections: a parallel-groups, randomized, double-blind clinical trial. Br J Dermatol 2001;144:818.

Conant MA, Schacker TW, Murphy RL, et al. Valacyclovir versus acyclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials. Int J STD AIDS2002;13:12.

Corey L, Handsfield HH. Genital herpes and public health: addressing a global problem. JAMA 2000;283:791.

Corey L, Wald A. Genital herpes. In: Holmes KK, Sparling PF, Mardh PA, et al., eds. Sexually transmitted diseases, 4th ed. New York: McGraw-Hill; 2007.

Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004;350:11.

Cowan FM. Testing for type-specific antibody to herpes simplex virus–implications for clinical practice. J Antimicrob Chemother 2000;45(Suppl T3):9.

DeJesus E, Wald A, Warren T, et al. Valacyclovir for the suppression of recurrent genital herpes in human. J Infect Dis 2003;188:1009.

Druce J, Catton M, Chibo D, et al. Utility of a multiplex PCR assay for detecting herpesvirus DNA in clinical samples. J Clin Microbiol 2002;40:1728.

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

Gottlieb SL, Douglas JM Jr, Foster M, et al. Incidence of herpes simplex virus type 2 infection in 5 Sexually Transmitted Disease (STD) clinics and the effect of HIV/STD risk-reduction counseling. J Infect Dis 2004;190:1059.

Gupta R, Wald A, Krantz E, et al. Valacyclovir and acyclovir for suppression of shedding of herpes simplex virus in the genital tract. J Infect Dis 2004;190:1374.

Haddow LJ, Mindel A. Genital herpes vaccines–cause for cautious optimism. Sex Health 2006;3:1.

Laffery WE, Downey L, Celum C, et al. Herpes simplex virus type 1 as a cause of genital herpes: impact on surveillance and prevention. J Infect Dis 2000;181:1454.

Langenberg AGM, Corey L, Ashley RL, et al. A prospective study of new infections with herpes simplex virus type 1 and type 2. N Engl J Med 1999;341:1432.

Leone PA, Trottier S, Miller JM. Valacyclovir for episodic treatment of genital herpes: a shorter 3-day treatment course compared with 5-day treatment. Clin Infect Dis2002;34:958.

McCormack O, Carboy J, Nguyen L, et al. Clinical inquiries. What is the role of herpes virus serology in sexually transmitted disease screening? J Fam Pract 2006;55:451.

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

Mertz GJ, Schmidt O, Jourden JL, et al. Frequency of acquisition of first-episode genital infection with herpes simplex virus from symptomatic and asymptomatic source contact.Sex Transm Dis 1985;12:33.

Miyai T, Turner KR, Kent CK, et al. The psychosocial impact of testing individuals with no history of genital herpes for herpes simplex virus type 2. Sex Transm Dis 2004;31:517.

Posavad CM, Wald A, Kuntz S, et al. Frequent reactivation of herpes simplex virus among HIV-1-infected patients treated with highly active antiretroviral therapy. J Infect Dis2004;190:693.

Reeves WC, Corey L, Adams HG, et al. Risk of recurrences after first episodes of genital herpes. Relations to HSV type and antibody response. N Engl J Med 1981;305:315.

Romanowski B, Aoki FY, Martel AY, et al., Collaborative Famciclovir HIV Study Group. Efficacy and safety of famciclovir for treating mucocutaneous herpes simplex infection in HIV-infected individuals. AIDS 2000;14:1211.

Romanowski B, Marina RB, Roberts JN. Valtrex HS230017 Study Group. Patients' preference of valacyclovir once-daily suppressive therapy versus twice-daily episodic therapy for recurrent genital herpes: a randomized study. Sex Transm Dis 2003;30:226.

Sacks SL. Famciclovir suppression of asymptomatic and symptomatic recurrent anogenital herpes simplex virus shedding in women: a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, single-center trial. J Infect Dis 2004;189:1341.

Scoular A. Using the evidence base on genital herpes: optimising the use of diagnostic tests and information provision. Sex Transm Infect 2002;78:160.

Scoular A, Gillespie G, Carman WF. Polymerase chain reaction for diagnosis of genital herpes in a genitourinary medicine clinic. Sex Transm Infect 2002;78:21.

Solomon L, Cannon MJ, Reyes M, et al. Epidemiology of recurrent genital herpes simplex virus types 1 and 2. Sex Transm Infect 2003;79:456.

P.841

Song B, Dwyer DE, Mindel A. HSV type specific serology in sexual health clinics: use, benefits, and who gets tested. Sex Transm Infect 2004;80:113.

Turner KR, Wong EH, Kent CK, et al. Serologic herpes testing in the real world: validation of new type-specific serologic herpes simplex virus tests in a public health laboratory.Sex Transm Dis 2002;29:422.

Wald A, Carrell D, Remington M, et al. Two-day regimen of acyclovir for treatment of recurrent genital herpes simplex virus type 2 infection. Clin Infect Dis 2002;34:944.

Wald A, Ericsson M, Krantz E, et al. Oral shedding of herpes simples virus type 2. Sex Transm Infect 2004;80:272.

Wald A, Huang ML, Carrell D, et al. Polymerase chain reaction for detection of Herpes Simplex Virus (HSV) DNA on mucosal surfaces: comparison with HSV isolation in cell culture.J Infect Dis 2003;188:1345.

Wald A, Langenberg AGM, Krantz E, et al. The relationship between condom use and herpes simplex virus acquisition. Ann Intern Med 2005;143:707.

Wald A, Langenberg AGM, Link K, et al. Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women. JAMA 2001;285:3100.

Wald A, Zeh J, Selke S, et al. Virological characteristics of subclinical and symptomatic genital herpes infection. N Engl J Med 1995;333:770.

Whittington WL, Celum CL, Cent A, et al. Use of a glycoprotein G-based type-specific assay to detect antibodies to herpes simplex virus type 2 among persons attending sexually transmitted disease clinics. Sex Transm Dis 2001;28:99.

Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA 2006;296:964.

Zimet GD, Rosenthal SL, Fortenberry JD, et al. Factors predicting the acceptance of herpes simplex virus type 2 antibody testing among adolescents and young adults. Sex Transm Dis 2004;31:665.