# Presentation: 534161

## Genital and Perirectal Herpes Simplex Virus Infection

- Herpes Simplex Virus (HSV) Type 2

## Learning Objectives

- Upon completion of this content, the learner will be able to:
- Describe the epidemiology of genital HSV in the U.S.
- Describe the pathogenesis of genital HSV.
- Discuss the clinical manifestations of genital HSV.
- Identify the common methods used in the diagnosis of genital HSV.
- Describe patient management for genital HSV.
- Summarize appropriate prevention counseling messages for genital HSV.
- Describe public health measures for the prevention of genital HSV.

## Lessons

- Epidemiology: Disease in the U.S.
- Pathogenesis
- Clinical manifestations
- Diagnosis
- Patient management
- Prevention

## Lesson I: Epidemiology: Disease in the U.S.

## Incidence and Prevalence

- Genital herpes is a recurrent, lifelong viral infection.
- Two HSV serotypes – HSV-1 & HSV-2
- HSV-2 causes the majority of genital and perirectal herpetic outbreaks in the U.S.
- Approximately 1 million new cases occur each year.

- Epidemiology

## Incidence and Prevalence (continued)

- 50% or more of new cases are asymptomatic or unrecognized.
- In the U.S., 22% of adults over age 12 have HSV-2 antibodies.
- HSV-2 antibodies are not routinely detected until puberty.
- HSV-2 seroprevalence increases with age up to 40 years then levels off.

- Epidemiology

## Seroprevalence of HSV-2 in NHANES, 1988-1994, by Gender and Race, U.S.

*Source*: Fleming DT et al. NEJM, 337(16):1105-1111, 1997.

- Epidemiology

## Transmission

- HSV-2 is transmitted sexually and perinatally.
- Most sexual transmission occurs while source case is asymptomatic.
- Efficiency of sexual transmission is greater from men to women than from women to men.

- Epidemiology

## Transmission (continued)

- Likelihood of transmission to others declines with increased duration of infection.
- Incubation period after acquisition is 2-12 days (average is 4 days).
- Genital HSV-2 infection facilitates both acquisition and transmission of HIV infection.

- Epidemiology

## Lesson II: Pathogenesis

## Virology

- HSV-1 and HSV-2 are members of the human herpes viruses (herpetoviridae).
- All members of this species establish latent infection in specific target cells.
- Infection persists despite the host immune response, often with recurrent disease.

- Pathogenesis

## Transmission electron micrograph of Herpes Simplex Virus

*Source*: CDC Public Health Image Library/Dr. Erskine Palmer

- Pathogenesis

## Pathology

- The virus remains latent indefinitely.
- Reactivation, precipitated by multiple known and unknown factors, induces viral replication.
- The re-activated virus may cause a cutaneous outbreak of herpetic lesions.
- Up to 90% of persons seropositive for HSV-2 antibody have no clinical history of anogenital herpes outbreaks.

- Pathogenesis

## Lesson III: Clinical Manifestations

## Definitions of Infection Types

- _First Clinical Episode_
- Primary infection
- First infection **ever** with either HSV-1 or HSV-2
- Disease is more severe than recurrent disease
- No antibody present when symptoms appear
- Non-primary infection
- Newly acquired HSV-1 or HSV-2 infection in an individual **previously seropositive to the other virus**
- Symptoms usually milder than primary infection
- Antibody present when symptoms appear

- Clinical Manifestations

## Definitions of Infection Types

- _Recurrent symptomatic infection_
- Disease usually mild and short in duration
- Antibody present when symptoms appear
- _Asymptomatic infection_
- No known history of clinical outbreaks
- Serum antibody is present

- Clinical Manifestations

## Types of Infection

| Infection Type | Lesions/ Symptoms | Type-specific antibody at time of presentation |  |
| --- | --- | --- | --- |
|  |  | HSV-1 | HSV-2 |
| First episode, Primary
(Type 1 or 2) | +/Severe, bilateral | - | - |
| First episode, Non-primary
Type 2 | +/Moderate | + | - |
| First episode, Recurrence
Type 2 | +/Mild | +/- | + |
| Symptomatic, Recurrence
Type 2 | +/Mild, 
unilateral | +/- | + |
| Asymptomatic, Infection
Type 2 | - | +/- | + |

- Clinical Manifestations

## First Episode Primary Infection without Treatment

- Characterized by multiple lesions that are more severe, last longer, and have higher titers of virus than recurrent infections
- Lesion progression:
- papules  vesicles  pustules  ulcers  crusts  healed
- Illness lasts 2-4 weeks
- Often associated with systemic symptoms including fever, headache, malaise, and myalgia

- Clinical Manifestations

## First Episode Primary Infection without Treatment (continued)

- Local symptoms include pain, itching, dysuria, vaginal or urethral discharge, and tender inguinal adenopathy
- Numerous, bilateral painful genital lesions; last an average of 11-12 days
- Median duration of viral shedding (from the onset of lesions to the last positive culture) is ~12 days
- HSV cervicitis occurs in most primary HSV-2 (~90%) and  primary HSV-1 (~70%) infections

- Clinical Manifestations

## Herpes: Primary Complex

*Source*: Cincinnati STD/HIV Prevention Training Center

- Clinical Manifestations

## Herpes: Genitalis Multiple Ulcer

*Source*: Cincinnati STD/HIV Prevention Training Center

- Clinical Manifestations

## Herpes: Genitalis External-Labia Minor

*Source*: Cincinnati STD/HIV Prevention Training Center

- Clinical Manifestations

## Herpes: Genitalis Clinical Periurethal Lesions on Vestibule

*Source*: Cincinnati STD/HIV Prevention Training Center

- Clinical Manifestations

## Herpes: Cervicitis

*Source*: Cincinnati STD/HIV Prevention Training Center

- Clinical Manifestations

## Herpes on the Buttock

*Source*: Cincinnati STD/HIV Prevention Training Center

- Clinical Manifestations

## Herpes: Possible Oralis Soft Palate

*Source*: Cincinnati STD/HIV Prevention Training Center

- Clinical Manifestations

## Recurrent Infection Without Treatment

- Prodromal symptoms (localized tingling, irritation) in ~50% begin 12-24 hours before lesions
- Illness lasts 5-10 days
- Symptoms tend to be milder, less severe than in primary infection
- Usually there are no systemic symptoms
- HSV-2 primary infection more prone to recur than HSV-1 primary infection

- Clinical Manifestations

## Asymptomatic Viral Shedding

- Rates of asymptomatic shedding are greater with HSV-2 than HSV-1.
- Most HSV-2 is transmitted during asymptomatic shedding.
- Shedding rates are greatest in the first 3 months after infection.
- Asymptomatic shedding is of briefer duration than during clinical recurrences.

- Clinical Manifestations

## Asymptomatic Viral Shedding (continued)

- Acyclovir chemosuppression dramatically reduces shedding.
- Most common sites of asymptomatic shedding are vulva and perianal areas in women and penile skin and perianal area in men.

- Clinical Manifestations

## Complications of Genital Infection

- Aseptic meningitis
- More common in primary than recurrent infection
- Generally no neurological sequelae
- Rare complications include:
- Stomatitis and pharyngitis
- Radicular pain, sacral parathesias
- Transverse myelitis
- Autonomic dysfunction

- Clinical Manifestations

## Lesson IV: HSV Diagnosis 

## HSV Diagnosis

- Clinical diagnosis is insensitive and nonspecific.
- Clinical diagnosis should be confirmed by lab testing:
- Virologic tests
- Type-specific serologic tests

- Diagnosis

## Virologic Tests 

- Viral culture (gold standard)
- Preferred test for patients with genital ulcers or other mucocutaneous lesions
- Antigen detection (DFA or EIA)
- Better than culture for detecting HSV in healing lesions
- Cytology (Tzanck or Pap)
- Insensitive and nonspecific and should not be relied on for HSV diagnosis
- PCR
- Preferred test for detecting HSV in spinal fluid

- Diagnosis

## Comparison of Virologic Tests

|  | Viral culture | Antigen detection (DFA or EIA) | Cytology (Tzanck or Pap) | PCR |
| --- | --- | --- | --- | --- |
| Sensitivity
(no false-negatives) | 80%-90% (primary episode) | >85% (in symptomatic shedders) | 50% |  |
| Specificity
(no false-positives) | 99% |  | Non-specific |  |
| Test notes | Positive in 80%-90% of primary infection and 30% of recurrent infection; allows for easiest typing; most are positive in 1-3 days, but held 5-7 days | May be better than culture for healing lesions; rapid (2-12 hours) | Identifies typical HSV-infected cells in exfoliated cells or biopsies | Clinical significance of positive result being established |

- Diagnosis

## Type-specific Serologic Tests

- Type-specific and nonspecific antibodies to HSV develop during the first several weeks following infection and persist indefinitely.
- Presence of HSV-2 antibody indicates anogenital infection.
- Presence of HSV-1 does not distinguish anogenital from orolabial infection.

- Diagnosis

## Uses of Type-specific Serologic Tests

- To confirm clinical diagnosis
- To diagnose unrecognized infection
- To manage sex partners of persons with genital herpes

- Diagnosis

## Special Diagnostic Considerations 

- Establish the etiology of atypical genital ulcer(s) to include mixed infections (e.g., syphilis and chancroid), unusual infections (e.g., LGV, HIV, CMV), and other causes (e.g., cancer).
- Evaluate for acyclovir resistance in patients with persistent genital herpes despite antiviral suppressive therapy.

- Diagnosis

## Lesson V: Patient Management

## Principles of Management of Genital Herpes

- Systemic antiviral chemotherapy
- Partially controls symptoms and signs of herpes episodes
- Does not eradicate latent virus
- Does not affect risk, frequency or severity of recurrences after drug is discontinued
- Counseling should include natural history, sexual and perinatal transmission, and methods to reduce transmission.

- Management

## Antiviral Medications

- Systemic antiviral chemotherapy includes 3 oral medications:
- Acyclovir
- Valacyclovir
- Famciclovir
- Topical antiviral treatment has minimal clinical benefit and is not recommended.

- Management

## Management of First Clinical Episode of Genital Herpes

- Many patients with first episode present with mild clinical manifestations but later develop severe or prolonged symptoms.
- Antiviral therapy has dramatic effect, especially if symptoms <7 days and no history of oral HSV.

- Management

## CDC-Recommended Regimens for First Clinical Episode

- Acyclovir 400 mg orally 3 times a day for 7-10 days, or
- Acyclovir 200 mg orally 5 times a day for 7-10 days, or
- Famciclovir 250 mg orally 3 times a day for 7-10 days, or
- Valacyclovir 1 g orally twice a day for 7-10 days

- Management

## Recurrent Episodes of Genital Herpes

- Most patients with symptomatic, first-episode genital HSV-2 experience recurrent outbreaks.
- Episodic and suppressive treatment regimens are available.
- Treatment options should be discussed with ALL patients.

- Management

## Episodic Treatment for Recurrent Genital Herpes

- Ameliorates or shortens duration of lesions
- Requires initiation of therapy within 1 day of lesion onset
- Provide patient with a supply of drug or a prescription and instructions to self-initiate treatment immediately when symptoms begin.

- Management

## CDC-Recommended Regimens for Episodic Therapy

- Acyclovir 400 mg orally 3 times a day for 5 days, or
- Acyclovir 200 mg orally 5 times a day for 5 days, or
- Acyclovir 800 mg orally twice a day for 5 days, or
- Famciclovir 125 mg orally twice a day for 5 days, or
- Valacyclovir 500 mg orally twice a day for 3-5 days, or
- Valacyclovir 1 g orally once a day for 5 days

- Management

## Suppressive Therapy for Recurrent Genital Herpes

- Reduces frequency of recurrences
- Reduces but does not eliminate subclinical viral shedding
- Periodically (e.g., once a year), reassess need for continued suppressive therapy.

- Management

## CDC-Recommended Regimens for Suppressive Therapy

- 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

- Management

## Severe Disease

- IV acyclovir should be provided for patients with severe disease or complications requiring hospitalization.
**CDC-Recommended Regimen**:
- Acyclovir 5-10 mg/kg IV every 8 hours for 2-7 days or until clinical improvement
- Follow with oral antiviral therapy to complete at least 10 days total therapy

- Management

## Allergy, Intolerance, and Adverse Reactions

- Allergic and other adverse reactions to acyclovir, valacyclovir, and famciclovir are rare.
- Desensitization to acyclovir is described by Henry RE, et al., Successful oral acyclovir desensitization.  Ann Allergy 1993; 70:386-8.

- Management

## Herpes and HIV Infection	

- HIV-infected patients may have prolonged, severe, or atypical episodes of genital, perianal, or oral herpes.
- Genital ulcers increase the risk of HIV transmission and acquisition.

- Management

## CDC-Recommended Regimens for Episodic Infection in HIV-Infected Persons

- Acyclovir 400 mg orally 3 times a day for 5-10 days, or
- Acyclovir 200 mg orally  5 times a day for 5-10 days, or
- Famciclovir 500 mg orally twice a day for 5-10 days, or
- Valacyclovir 1 g orally twice a day for 5-10 days

- Management

## CDC-Recommended Regimens for Daily Suppressive Therapy in HIV-Infected Persons

- Acyclovir 400-800 mg orally twice a day or 3 times a day, or
- Famciclovir 500 mg orally twice a day, or
- Valacyclovir 500 mg orally twice a day

- Management

## Herpes in Pregnancy 

- Risk for transmission to neonate from infected mother is high (30%-50%) among women who acquire genital herpes near the time of delivery and low (<1%) in women with histories of recurrent herpes at term or who acquire genital HSV during the first half of pregnancy.

- Management

## Herpes in Pregnancy (continued) 

- Prevention of neonatal herpes depends on avoiding acquisition of HSV during late pregnancy and avoiding exposure of the infant to herpetic lesions during delivery.

- Management

## Herpes in Pregnancy (continued) 

- Ask all pregnant women if they have a history of genital herpes.
- At the onset of labor:
- Question all women about symptoms of genital herpes, including prodrome.
- Examine all women for herpetic lesions.
- Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally.

- Management

## Herpes in Pregnancy (continued) 

- Acyclovir may be administered orally to pregnant women with first-episode genital herpes or severe recurrent herpes and should be administered IV to pregnant women with severe HSV infection.
- The safety of systemic acyclovir, valacyclovir, and famciclovir therapy in pregnant women has _not_ been established.

- Management

## Lesson VI: Prevention

## Patient Counseling and Education

- Goals
- Help patients cope with the infection
- Prevent sexual and perinatal transmission
- Psychological impact of infection is often substantial.
- Counsel initially at first visit.
- Education on chronic aspects may be beneficial after acute illness subsides.

- Prevention

## Patient Counseling and Education

- Counseling should include:
- Nature of the infection
- Transmission
- Treatment issues
- Risk-reduction strategies
- Emphasize potential for recurrent episodes, asymptomatic viral shedding, and sexual transmission.

- Prevention

## Nature of the Infection

- Sexual transmission of HSV can occur during asymptomatic periods.
- Stressful events may trigger recurrences.
- Prodromal symptoms may precede outbreaks.

- Prevention

## Transmission

- Abstain from sexual activity with uninfected partners when lesions or prodromal symptoms are present.
- Inform current sex partners.
- Inform future sex partners before initiating sex.

- Prevention

## Treatment Options

- Discuss:
- Effectiveness of suppressive and episodic therapy to prevent or shorten the duration of recurrent episodes
- When and how to take antiretroviral medications
- Recognition of prodromal symptoms

- Prevention

## Risk Reduction

- Assess client's behavior-change potential.
- Discuss prevention strategies (abstinence, mutual monogamy with an uninfected partner, condoms, limiting number of sex partners, etc.).
- Work with patient to develop individualized risk-reduction plans.

- Prevention

## Counseling for Asymptomatic Persons 

- Give asymptomatic persons diagnosed with HSV-2 infection by type-specific serologic testing the same counseling messages as symptomatic persons.
- Teach the common manifestations of genital herpes, as many patients will become aware of them with time.

- Prevention

## Partner Management 

- Symptomatic sex partners
- Evaluate and treat in the same manner as patients who have genital lesions.
- Asymptomatic sex partners
- Ask about history of genital lesions.
- Educate to recognize symptoms of herpes.
- Offer type-specific serologic testing.

- Prevention

## Case Study

## Roberta Patterson: History

- 26-year-old woman, presents for her first prenatal visit
- Concerned for her baby because of her husband’s history of genital herpes
- States that she is 6 weeks pregnant
- Has never had symptoms of vaginal or oral herpes
- Diagnosed and treated for chlamydia 7 years ago (age 19); no other STD diagnoses reported
- Her 26-year-old husband had his first episode of genital herpes 8 years ago; no other STD diagnoses reported. No visible HSV lesions since they’ve been sexually active.  Reports having had no prodromal symptoms or symptoms of active disease.
- No other sex partners for the last 16 months

- Case Study

## Physical Exam

- Vital signs: blood pressure 112/68, pulse 58, respiration 13, temperature 38.5° C
- Cooperative, good historian
- Chest, heart, musculoskeletal, and abdominal exams within normal limits
- Uterus consistent with a 6-week pregnancy
- Normal vaginal exam without signs of lesions or discharge
- No lymphadenopathy

- Case Study

## Questions

- Which HSV general education messages should be discussed with Roberta?
- Given that Roberta’s husband Franklin has a history of genital herpes, would it be appropriate to test Roberta for genital herpes using a type-specific serologic test?
- What other STD screening should be considered for Roberta?

- Case Study

## Roberta’s Laboratory Results

- HSV gG-based type-specific serologies: HSV-1 negative; HSV-2 positive
- DNA probe for *Chlamydia trachomatis*: negative
- Culture for *Neisseria gonorrhoeae*: negative
- RPR: nonreactive
- HIV antibody test: negative
- Pregnancy test: positive
- What would you tell Roberta about her HSV infection, based on clinical manifestations and test results?
- Would routine viral cultures during Roberta's pregnancy be recommended?

- Case Study

## Partner Management

- _Sex Partner and Exposure Information_
- Franklin Patterson
- First sexual exposure: 16 months agoLast sexual exposure: 1 month ago
- History of genital herpes infection; first episode 8 years ago. No HSV testing or treatment at time of first episode or with subsequent episodes.
- No history of other STDs.
- 6.  Franklin reports genital lesions during Roberta's sixth month of pregnancy. Which laboratory tests should be performed on him?

- Case Study

## Franklin’s Laboratory Results

- HSV cultures: HSV-1 negative; HSV-2 positive
- DNA probe for *Chlamydia trachomatis*: negative
- Culture for *Neisseria gonorrhoeae*: negative
- RPR: nonreactive
- DFA: negative for *Treponema pallidum*
- HIV antibody test: negative
- 7.  What is an appropriate episodic treatment for Franklin?

- Case Study

## Follow-Up

- Roberta had no HSV symptoms during her pregnancy.
- She opted to take the acyclovir treatment in late pregnancy after a discussion with her nurse-midwife that included the following points:
- The safety of systemic acyclovir therapy in pregnant women has not been established.
- Preliminary data suggest that acyclovir treatment late in pregnancy might diminish the frequency of HSV occurrence at term that would necessitate an abdominal delivery.
- At onset of labor, she reported no prodromal or other HSV symptoms and no lesions were found on examination.
- After a 14-hour labor, she vaginally delivered a healthy 7.2 lb baby girl.

- Case Study

## Questions

- What questions should ALL women beginning labor be asked?
- If Roberta has genital herpetic lesions at the onset of labor, should she deliver vaginally or abdominally?   What is the risk to the infant?

- Case Study

## Questions

- 10. Roberta is asymptomatic at the time of delivery. Is it medically appropriate for her to deliver vaginally?
- 11. If Roberta had acquired genital herpes around the time of delivery, would she be more or less likely to transmit genital herpes to her baby during a vaginal delivery than if she had a history of recurrent genital herpes?

- Case Study