1. Genital Herpes: Framing the Problem, Diagnosing the Disease
Prevention and Management for Healthcare Providers

2. Genital Herpes: Epidemiology and Clinical Presentation

3. 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

4. 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

5. 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 % (27M age 15-49)
Genital HSV-1 infection 10 million (??)
TOTAL >20% >30 million
~30%
Total 18 17
Xu F et al. JAMA. 2006;296:

6. Perceived Trauma of Contracting Genital 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

7. 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]

8. Freeman EE et al. AIDS. 2006;20:73-83.
Relative Risk of HIV Acquisition in HSV-2 Positive vs HSV-2 Negative Persons
Freeman EE et al. AIDS. 2006;20:73-83.

9. 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

10. 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

11. 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

12. 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
Diamond C, et al. Sex Transm Dis. 1999;26:
Engelberg R, et al. Sex Transm Dis. 2003;30:

13. 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

14. 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

15. 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;
2. Wald A, et al. N Engl J Med. 1995;333:
3. Mertz GJ, et al. Ann Intern Med. 1992;116:

16. 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:
2. Wald A, et al. N Engl J Med. 1995;333:
3. Mertz GJ, et al. Ann Intern Med. 1992;116:

17. Asymptomatic Shedding
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
Asymptomatic Shedding
Via Culture†
Via PCR†
% of patients with ≥ 1 day
51%-61%
72%-88%
% of days
2.0%- 6.6%
7.8%- 27%
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:
Wald A, et al. N Engl J Med. 1995;333:
Corey L, et al. N Engl J Med. 2004;350:11-20.

18. Viral Shedding Patterns Are Unpredictable and Influenced by Therapy
Wald A, et al. J Clin Invest. 1997;99:

19. 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
70%
~30%
Total 18 17
Transmission during symptomatic
outbreaks
Mertz GJ, et al. Ann Intern Med. 1992;116:

20. 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 patiengts had a history of 0 to 9 recurrences/year and had been infected for a median of 6 years.
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

21. 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

22. Genital Herpes: Diagnosis
H. Hunter Handsfield, MD
University of Washington

23. 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 (64.5%)
Syphilis (12.4%)
HSV + Syphilis (2.5%)
Chancroid (3.1%)
PCR negative (22.4%)
Mertz K, et al. J Infect Dis. 1998;178:

24. 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

25. North Carolina Dx Culture all genital lesions for HSV
Obtain TRUST/RPR/EIA
HIV Test
Negative culture does not rule out HSV
May offer Type-specific serologic test

26. 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

27. 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
Notes
Varying values below 0.9 are meaningless
Some values 1.1–3.5 are false positive if HSV-1 antibody is present

28. 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

29. Options for Confirmatory Testing of the Focus HSV-2 ELISA
Western blot
Focus immunoblot?
Focus ELISA avidity assay?
Commercial confirmatory tests (rumors)
Focus
Others?
Repeat/convalescent testing

30. Time to HSV-2 Seroconversion
1.0
0.8
Western Blot
0.6
Probability of Remaining Seronegative
0.4
Focus
0.2
0.0 20 40 60 80
100
120
140
160
Days From Primary Episode

31. 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)

32. Prevention and Available and Emerging Treatments for HSV-2 Infection
Peter A. Leone, MD
University of North Carolina

33. Transmission Reduction: What Can Be Done?
Advise patients to avoid sexual contact during outbreaks

34. Transmission Reduction: What Can Be Done?
Advise patients to avoid sexual contact during outbreaks
Inform patients about transmission risk during periods of asymptomatic shedding

35. 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

36. Suppressive Antiviral Therapy to ReduceTransmission Risk

37. Proportion of Susceptible Partners With Overall Acquisition of HSV-2 Infection4
3.6%
48% reduction
P = .054
RR: 0.52 (95% CI: 0.27,0.97)
HR for Kaplan-Meyer Analysis
P = .039
(27/741) 3
1.9%
% with HSV-2 Infection 2
(14/743) 1
Placebo Valacyclovir
500 mg once daily
Adapted from Corey L, et al. N Engl J Med. 2004;350:11-20.

38. Proportion of Susceptible Partners With Symptomatic Genital Herpes
2.5
2.2%
(16/741)
75% reduction 2
P = .01
RR: 0.25 (95% CI: 0.08,0.74)
1.5
% with Symptomatic GH 1
0.5%
(4/743)
0.5
Placebo Valacyclovir
500 mg once daily
Adapted from Corey L, et al. N Engl J Med. 2004;350:11-20.

39. 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 ;55(R-11):1-94.
*ACOG recommends valacyclovir mg daily for suppressive therapy.
ACOG Practice Bulletin. Obstet Gynecol ;104:

40. Interventions for HSV Beneficial
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
Wald, Clinical Evidence ‘99

41. Which Patients Should Receive Episodic Antiviral Therapy?
First clinical episodes of genital herpes
All patients
Recurrent episodes
Clinically significant benefit ( %
decreased duration) from recurrent therapy
Prolonged episodes

42. 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

43. Initial Episode Acyclovir
400 mg t.i.d. or 200 mg 5 times/d for 7 to 10 days
Famciclovir
250 mg t.i.d. for 7 to 10 days
Valacyclovir
1 g b.i.d. for 7 to 10 days

44. Treatment Options: Episodic Therapy
Reduces the duration of recurrence
5-Day Shorter Regimens Regimens
Acyclovir mg t.i.d 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 mg b.i.d. for 3 days
Centers for Disease Control and Prevention. MMWR Recomm Rep 2006;55(RR-11):1-93.

45. 2006 CDC STD Treatment Guidelines Genital Herpes: Suppressive Therapy
Acyclovir 400 mg BID
Famciclovir 250 mg BID
Valacyclovir g qd
North Carolina
Offer 4 months suppression with acyclovir to those with documented first episode HSV-2

46. Candidates for Antiviral Suppressive Therapy
In HSV 2-Infected Patients
Use Antiviral Suppressive Therapy Primarily to
Control Disease
Reduce Transmission
With new infection √
With bothersome outbreaks
Who are immunocompromised
Who are in late pregnancy
Who are distressed by the diagnosis
With a sexual partner who is uninfected or has an unknown HSV status
With multiple sexual partners

47. 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.

48. 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

49. 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
SHARING
Wald A, et al. J Infect Dis

50. Condom Sense
Condoms appear ~ 50% protective against HSV-2 acquisition in men and in women.
Evidence for condoms' efficacy will always be measured indirectly
Wald A, et al. Ann Intern Med 2005;143:
Wald A, et al. JAMA 2001;285:
Gottlieb SL, et al. J Infect Dis 2004;190:

51. What Is on the Horizon? Herpes Vaccine for Women New Therapy
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 ). Entering clinical phase II trials

52. Conclusions Genital herpes is common and under-recognized
Shedding is the norm
Treat to control disease and/or transmission