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Genital Herpes: Framing the Problem, Diagnosing the Disease. Prevention and Management for Healthcare Providers. Genital Herpes: Epidemiology and Clinical Presentation. STDs are Sexist. Transmission efficiency greater male to female than the reverse

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genital herpes framing the problem diagnosing the disease
Genital Herpes: Framing the Problem, Diagnosing the Disease

Prevention and Management for Healthcare Providers


STDs are Sexist

  • Transmission efficiency greater male to female than the reverse
  • More women asymptomatic or with atypical, nonspecific symptoms; delayed care
  • Diagnosis more difficult in women
  • Complications more frequent in women, often severe or permanent

Herpes Simplex Virus

  • Mucocutaneous infection, retrograde infection of sensory nerves, continuous slow replication (with clinical latency) in cranial or spinal ganglia and peripheral nerve endings, mucocutaneous recurrences
  • HSV-1
    • Mostly orolabial (cold sores, fever blisters)
    • 20%-50% of initial genital herpes in North America and western Europe
  • HSV-2
    • Almost entirely genital; oral infection uncommon
    • >90% of recurrent genital herpes

Prevalence of Genital HSV Infection in Adults in the United States

  • HSV-2, NHANES-II (1978) 16% (15M age 15-49)
  • HSV-2, NHANES-III (1991) 22% (24M age 15-49)
  • HSV-2, NHANES 1999-2004 17% (27M age 15-49)
  • Genital HSV-1 infection 10 million (??)
  • TOTAL >20% >30 million





Xu F et al. JAMA. 2006;296:964-973.


Perceived Trauma of ContractingGenital Herpes

I'm going to read you a list of items that people may or may not consider traumatic. For each one I read, please tell me how traumatic it would be for you personally: very traumatic, somewhat traumatic, not very traumatic, or not traumatic at all.

Percent Saying "Very Traumatic"

Acquiring AIDS

Having genital herpes

Breaking up with a significant other

Getting fired from a job

Failing a course in school


Genital Herpes

and HIV Transmission

  • HSV-2 infection is the most important STD in enhancing HIV transmission efficiency; may account for up to half of all HIV infections
  • HSV-2 infected persons have 2–4x increased chance of acquiring HIV if sexually exposed
  • Persons with HIV and symptomatic genital herpes are more efficient HIV transmitters
  • HSV-2 serologic testing should be routine in persons with HIV or at high risk (men having sex with men, intravenous drug users, and their partners) [controversial]

Relative Risk of HIV Acquisition in HSV-2 Positive vs HSV-2 Negative Persons

Freeman EE et al. AIDS. 2006;20:73-83.


Clinical Spectrum of Genital Herpes

  • First episode infection
    • Primary: First infection with HSV-1 or -2 (~20%)
    • Nonprimary first episode: Prior infection with the opposite HSV type (~40%)
    • First recognized episode of longstanding infection (~40%)
  • Recurrent infection: Second or subsequent outbreak (HSV-2 >> HSV-1)
  • Subclinical infection: ~60%–90% of infections
    • Truly asymptomatic
    • Unrecognized

Clinical Manifestations of Genital Herpes

  • Initial infection
    • Vesiculopustular lesions (bilateral)
    • Cervicitis, urethritis
    • Lymphadenopathy
    • Neuropathic manifestations
    • Systemic inflammation (fever, etc)
    • Duration typically 2–4 weeks
  • Recurrent outbreaks
    • Unilateral lesions
    • Nonspecific symptoms (discharge, dysuria, etc)
    • Neuropathic prodrome
    • Duration 1–2 weeks
  • Common misdiagnoses
    • Vulvovaginal candidiasis and other vaginal infections
    • Syphilis, chancroid
    • Urinary tract infection
    • Genital trauma

Biomedical Complications

of HSV Infection

  • Localized neuropathies (eg, bladder paralysis)
  • Meningitis (isolated, recurrent)
  • Erythema multiforme, Stevens Johnson syndrome
  • Perinatal and maternal morbidity
    • Neonatal herpes
    • Cesarean section
  • Autoinoculation conjunctivitis, keratitis, whitlow
  • Chronic localized disease in immunodeficient patients (especially HIV/AIDS)
  • Enhanced HIV transmission
  • Rare disseminated infection, hepatic necrosis, death
recurrence rate after initial genital herpes
Mean recurrence rate in first year after initial genital HSV-2 infection (N = 457, median FU 391 days)

Men 5.2 episodes/yr

Women 4.0 episodes/yr

>6 recurrences in first year 38%

>10 recurrences in first year 20%

Rate gradually declines over several years

Recurrence after initial genital HSV-1 (N = 83)

Mean recurrences 1.3 yr 1, 0.7 yr 2, & beyond

38% had no recurrences

Recurrence Rate After Initial Genital Herpes

Diamond C, et al. Sex Transm Dis. 1999;26:221-225.

Engelberg R, et al. Sex Transm Dis. 2003;30:174-177.

what triggers recurrent outbreaks
Oral HSV-1

Other infections ('cold sore,' 'fever blister')

Actinic/ultraviolet injury

Other local trauma (eg, surgery)

Genital HSV-2

No clearly documented triggers

No good data support stress, diet, menstruation, sex, etc, despite anecdotal reports and strongly held beliefs to the contrary

What Triggers Recurrent Outbreaks?

Asymptomatic Viral Shedding in Transmission and Acquisition of HSV-2

Peter A. Leone, MD

Associate Professor of Medicine

University of North Carolina

Chapel Hill, North Carolina

Medical Director

North Carolina HIV/STD Prevention and Care Branch NCDHHS


Asymptomatic Viral Shedding

  • Asymptomatic viral shedding (AVS) is the presence of HSV on the surface of the skin/mucosa in the absence of signs and symptoms[1-3]

1. Corey L, Wald A. Sex Transm Dis. 1999;285-312.

2. Wald A, et al. N Engl J Med. 1995;333:770-775.

3. Mertz GJ, et al. Ann Intern Med. 1992;116:197-202.


Key Facts for Patients

  • Patients frequently spread GH between outbreaks[1]
  • Most patients shed virus asymptomatically*[2]
  • Patients cannot predict when AVS will occur[3]
  • All patients are at risk for AVS, regardless of outbreak frequency[3]
  • Recent data suggest shedding is a more continuous process than previously realized
  • Safer sex practices should be used
    • Even with safer sex , it is still possible to transmit HSV
    • Condoms cannot provide 100% protection against transmission, they do not cover all potential sites of HSV shedding

*Shedding in the absence of lesions

1. Corey L, Wald A. Sex Transm Dis. 1999:285-312.

2. Wald A, et al. N Engl J Med. 1995;333:770-775.

3. Mertz GJ, et al. Ann Intern Med. 1992;116:197-202.


Asymptomatic Viral Shedding Is Common and Can Occur Frequently

  • Most GH patients experience asymptomatic shedding*
  • PCR has a ~3-4 times higher detection rate than culture

PCR = polymerase chain reaction; *shedding in the absence of lesions; †shedding rates can vary based upon time since diagnosis, frequency of recurrences, method of detection, frequency/site of sampling

Gupta R, et al. J Infect Dis. 2004;190:1374-1381.

Wald A, et al. N Engl J Med. 1995;333:770-775.

Corey L, et al. N Engl J Med. 2004;350:11-20.


Viral Shedding Patterns Are Unpredictable and Influenced by Therapy

Wald A, et al. J Clin Invest. 1997;99:1092-1097.


Up to 70% of Transmission May Occur During Asymptomatic Viral Shedding

  • 9.7% of patients infected their partner (14/144)
  • Transmission frequently occurs between outbreaks

Transmission during asymptomatic

viral shedding

Up to






Transmission during symptomatic


Mertz GJ, et al. Ann Intern Med. 1992;116:197-202.

asymptomatic viral shedding can occur regardless of outbreak frequency
Asymptomatic Viral Shedding* Can Occur Regardless of Outbreak Frequency

Post-hoc analysis from a randomized, double-blind, placebo-controlled shedding substudy (n = 89) where 50 patients were given placebo once daily and followed for 60 days. Enrolled patients had a history of 0 to 9 recurrences/year and had been infected for a median of 6 years.

*Shedding in the absence of lesions.

*Shedding in the absence of lesions


Summary of Asymptomatic

Viral Shedding

  • Infection = Shedding
  • Asymptomatic viral shedding (AVS) is frequent and difficult to predict when and where
  • AVS does decrease with time but remains high over time
  • AVS driving force for transmission

Genital Herpes: Diagnosis

H. Hunter Handsfield, MD

University of Washington

etiology of genital ulcer disease
516 patients with genital ulcer disease from STD clinics in 10 of 11 US cities w/ highest syphilis rates

Excluded patients with typical herpes

PCR for HSV, Treponema pallidum, Haemophilus ducreyi

HSV 333 (64.5%)

Syphilis 64 (12.4%)

HSV + Syphilis 13 (2.5%)

Chancroid 16 (3.1%)

PCR negative 16 (22.4%)

Etiology of Genital Ulcer Disease

Mertz K, et al. J Infect Dis. 1998;178:1795-1798.

diagnosis of genital herpes
Test all genital ulcers for HSV, including clinically obvious genital herpes

Clinical diagnosis insensitive and nonspecific

Virus type determines clinical prognosis, transmission, and counseling

Virologic tests

PCR is test of choice; increasingly available

Culture: The primary test in most settings

Direct FA: Some don't provide virus type

Cytology (Tzanck prep): Insensitive, no virus type; do not use

Serologic testing: Use only glycoprotein G (gG)-based assays

Diagnosis of Genital Herpes
north carolina dx
Culture all genital lesions for HSV


HIV Test

Negative culture does not rule out HSV

May offer Type-specific serologic test

North Carolina Dx
type specific hsv serologic tests
Antibody to HSV-1 or -2 glycoprotein G (gG-1 or gG-2)

Western blot

The gold standard

Focus Technologies (now a subsidiary of Quest Diagnostics) HerpeSelect HSV-1 and HSV-2 ELISA

Sensitivity for HSV-2 ~90%, specificity ~98%

Focus Technologies HerpeSelect HSV-1 and HSV-2 Differentiation Immunoblot

Same antigen as ELISA, probably similar performance

Trinity Biotech Captia Type Specific HSV-1 nad HSV-2 ELISA

Biokit USA biokitHSV2

Point of care

HSV-2 only

Type-Specific HSV Serologic Tests
interpreting hsv 2 herpeselect
The numerical value is the ratio between the test optical density (OD) and control, not a titer

─ <0.9 Negative

─ 0.9–1.1 Equivocal

─ 1.1–3.5 Positive, but influenced by HSV-1

─ >3.5 Unequivocally positive


Varying values below 0.9 are meaningless

Some values 1.1–3.5 are false positive if HSV-1 antibody is present

Interpreting HSV-2 HerpeSelect
hsv igm testing is not clinically useful
Not type specific

Does not distinguish early from late infection

False-positive results common

There is no valid indication for use in adults

HSV IgM Testing is Not Clinically Useful
options for confirmatory testing of the focus hsv 2 elisa
Western blot

Focus immunoblot?

Focus ELISA avidity assay?

Commercial confirmatory tests (rumors)



Repeat/convalescent testing

Options for Confirmatory Testingof the Focus HSV-2 ELISA
time to hsv 2 seroconversion
Time to HSV-2 Seroconversion



Western Blot


Probability of Remaining Seronegative














Days From Primary Episode

uses of type specific hsv serology
Definite Indications

Diagnosis of GUD, recurrent symptoms, etc

Management of sex partners of persons with herpes

Persons with or at risk for HIV acquisition

Other Uses

Selected (all?) pregnant women and their partners

Patient request

Request to test for herpes

Comprehensive STD evaluation

Do Not Use Routinely to Screen All Sexually Active Persons (controversial)

Uses of Type-Specific HSV Serology

Prevention and Available and Emerging Treatments for HSV-2 Infection

Peter A. Leone, MD

University of North Carolina


Transmission Reduction:What Can Be Done?

  • Advise patients to avoid sexual contact during outbreaks

Transmission Reduction:What Can Be Done?

  • Advise patients to avoid sexual contact during outbreaks
  • Inform patients about transmission risk during periods of asymptomatic shedding

Transmission Reduction:What Can Be Done?

  • Advise patients to avoid sexual contact during outbreaks
  • Inform patients about transmission risk during periods of asymptomatic shedding
  • Offer suppressive therapy to patients as an option

Suppressive Antiviral Therapy

to ReduceTransmission Risk

proportion of susceptible partners with overall acquisition of hsv 2 infection
Proportion of Susceptible PartnersWith Overall Acquisition of HSV-2 Infection



48% reduction

P = .054

RR: 0.52 (95% CI: 0.27,0.97)

HR for Kaplan-Meyer Analysis

P = .039




% with HSV-2 Infection





Placebo Valacyclovir

500 mg once daily

Adapted from Corey L, et al. N Engl J Med. 2004;350:11-20.

proportion of susceptible partners with symptomatic genital herpes
Proportion of Susceptible PartnersWith Symptomatic Genital Herpes




75% reduction


P = .01

RR: 0.25 (95% CI: 0.08,0.74)


% with Symptomatic GH






Placebo Valacyclovir

500 mg once daily

Adapted from Corey L, et al. N Engl J Med. 2004;350:11-20.

cdc sexually transmitted diseases treatment guidelines and acog recommend daily therapy
CDC Sexually Transmitted Diseases Treatment Guidelines and ACOG Recommend Daily Therapy
  • CDC: Discordant couples should be encouraged to consider suppressive antiviral therapy as a part of a strategy to prevent transmission, in addition to consistent condom use and avoidance of sexual activity during recurrences
  • ACOG:For couples in which 1 partner has HSV-2 infection, suppressive* antiviral therapy should be recommended for the partner with HSV-2 to reduce the rate of transmission

Centers for Disease Control and Prevention. MMWR Recomm Rep. 2006;55(R-11):1-94.

*ACOG recommends valacyclovir 500-1000 mg daily for suppressive therapy.

ACOG Practice Bulletin. Obstet Gynecol. 2004;104:1111-1117.

interventions for hsv

oral antiviral therapy in first episodes

oral antiviral therapy at a start of recurrence

daily antiviral therapy to control disease and/or reduce risk of transmission

Interventions for HSV

Wald, Clinical Evidence ‘99

which patients should receive episodic antiviral therapy
First clinical episodes of genital herpes

All patients

Recurrent episodes

Clinically significant benefit (20 - 30%

decreased duration) from recurrent therapy

Prolonged episodes

Which Patients Should Receive Episodic Antiviral Therapy?
optimizing episodic hsv rx
Self -initiation of therapy important

Medication needs to be available to patient

Acyclovir can be dosed 3x/day - no clinical trials data, but plenty of experience

Optimizing episodic HSV Rx
initial episode

400 mg t.i.d. or 200 mg 5 times/d for 7 to 10 days


250 mg t.i.d. for 7 to 10 days


1 g b.i.d. for 7 to 10 days

Initial Episode
treatment options episodic therapy
Reduces the duration of recurrenceTreatment Options:Episodic Therapy

5-Day Shorter Regimens Regimens

Acyclovir 400 mg t.i.d. 800 mg t.i.d. for 2 days

800 mg b.i.d.

Famciclovir 125 mg b.i.d.1 g b.i.d. for 1 day

Valacyclovir 1 g q.d. 500 mg b.i.d. for 3 days

Centers for Disease Control and Prevention. MMWR Recomm Rep 2006;55(RR-11):1-93.

2006 cdc std treatment guidelines genital herpes suppressive therapy
Acyclovir 400 mg BID

Famciclovir 250 mg BID

Valacyclovir 0.5-1.0 g qd

North Carolina

Offer 4 months suppression with acyclovir to those with documented first episode HSV-2

2006 CDC STD Treatment GuidelinesGenital Herpes: Suppressive Therapy
treatment options suppressive therapy
Treatment Options:Suppressive Therapy
  • Possible dosing regimens¹:
  • Acyclovir
  • 400 mg b.i.d.
  • Famciclovir
  • 250 mg b.i.d.
  • Valacyclovir
  • 500 mg q.d. or (for >10 occurrences/year)
  • 1 g q.d.

Centers for Disease Control and Prevention. MMWR Recomm Rep 2002;51(RR-6):1-78.

transmission reduction what can be done
Advise patients to avoid sexual contact during outbreaks

Inform patients about transmission risk during periods of asymptomatic shedding

Offer suppressive therapy to patients as an option

Encourage patients to share their HSV status with their sexual partners

Promote condom use

Transmission Reduction:What Can Be Done?
transmission reduction disclosure to sexual partners
Transmission Reduction:Disclosure to Sexual Partners
  • A recent study found that a strong protective factor against genital HSV-2 acquisition was partner disclosure of genital herpes
  • Median time to transmission nondisclosers: 60 days
  • vs
  • disclosers: 270 days P = .03


Wald A, et al. J Infect Dis. 2006.

condom sense
Condoms appear ~ 50% protective against HSV-2 acquisition in men and in women.

Evidence for condoms' efficacy will always be measured indirectly

Condom Sense

Wald A, et al. Ann Intern Med 2005;143:707-713.

Wald A, et al. JAMA 2001;285:3100-3106.

Gottlieb SL, et al. J Infect Dis 2004;190:1059-1067.

what is on the horizon
Herpes Vaccine for Women

Enrollment completed Sept. 2007

Study to be completed 2010

Earlier studies showed a 75% reduction in HSV acquisition of genital herpes in vaccinated women

New Therapy

A new class of potent inhibitors of HSV that targets the virus helicase primase complex (BAY 57-1293). Entering clinical phase II trials

What Is on the Horizon?
Genital herpes is common and under-recognized

Shedding is the norm

Treat to control disease and/or transmission