1. Update: Genital Herpes Simplex Virus Infection
Nick Van Wagoner, MD, PhD
University of Alabama at Birmingham
Webinar

2. Nick Van Wagoner: Disclosures
Will not discuss off-label use of commercial products and/or services
No commercial interest or affiliations

3. Learning Objectives By the end of the Lecture:
Reviewed HSV-2 epidemiology in the U.S.
Understand the pathogenesis of HSV-2
Identify the clinical manifestations of HSV-2
Choose appropriate test(s) for HSV-2 diagnosis
Discuss the management of HSV-2
Introduce new research in HSV-2 prevention and treatment

4. HSV: Pearls Genital Herpes is the most prevalent STD in the U.S.
Life-long infection
Sexually transmitted
Most people don’t know their infected
Viral shedding occurs in the absence of symptoms
Transmission usually occurs when symptoms are absent

5. Epidemiology Genital HSV in the U.S.

6. HSV is the Most Prevalent STD in the US
Over 1 million new genital herpes infections occur each year.
Centers for Disease Control and Prevention: available at
Xu et al. JAMA : 296:
Leone, Update on Epidemiology and Treatment Strategies for Genital Herpes

7. Seroprevalence of HSV-2, NHANES, 2005-2008
Overall Seroprevalence: 16.2%
Women: 20.9%
Men: 11.9%
MMWR (15):456

8. HSV Risk Factors Biology Gender Race Male Circumcision Age
Sociodemographics
Income
Living conditions
Sexual Networks
Behavior
No. of Partners
Early Sexual Debut
Drug Use
XU et al., JAMA :
Newman, STD : S4-S12

9. Unknown HSV-2 Infection
Men Attending the JCHD
HSV-2 Positive
Know it
HSV-2 Positive
Don’t know it
HSV-2 Negative
~80-90% of people that test positive for HSV-2 in the U.S are unaware that they are infected
Xu et al. JAMA : 296: , MMWR (15):456

10. Pathogenesis

11. Virology: HSV-1 and HSV-2
Members of the human herpes virus family (herpetoviridae).
Genome: ~154,000 bp DS DNA
HSV-1 and HSV-2 50% Identical
HSV-2 causes about ½ of genital ulcers
The other ½ are caused by HSV-1
Todar. Ken Todar’s Microbial World. U of Wisconsin
Dwyer and Cunningham. MJA (5):

12. Asymptomatic
Infection
Gupta et al., Lancet 2007

13. HSV Genital/Anogenital Transmission
Sexual
Receptive Vaginal--Insertive Vaginal
Receptive Anal--Insertive Anal
Receptive Oral (HSV-1)
Efficiency of sexual transmission: greater from men to women
Likelihood of transmission declines with duration of infection

14. Definitions of First Clinical Episodes
Primary infection
First infection ever (HSV-1 or HSV-2)
More severe
No antibody present when symptoms appear
Non-primary infection
New HSV-1 or HSV-2 in an individual previously seropositive to the other virus
Will have antibody to the other HSV virus when symptoms appear
Symptoms usually milder than primary infection

15. First Episode Primary Infection
Characteristics of Lesions:
Usually multiple and bilateral
More severe than recurrences
Contain higher virus titers than in recurrence
Last days and shed virus for ~12 days
Local symptoms include pain, itching, dysuria, vaginal or urethral discharge, and tender inguinal adenopathy
Cervicitis is common
Systemic Symptoms
Last 2-4 weeks
Fever, headache, malaise, myalgias
Without treatment
Incubation 2-12 days (average of 4 days)

16. Recurrent Symptomatic Infection
Disease is milder and shorter in duration
Antibody to HSV-2 present
Prodromal
Lesions last 5-10 days
No systemic symptoms
HSV-2 is more prone to recur than HSV-1
symptoms (localized tingling, irritation) in ~50% begin hours before lesions appear

17. HSV Lesion Progression
A circumscribed elevated, sollid lesion, less than 1 cm
Papule
Vesicle
A circumscribed, serous ,fluid filled elevation of the skin, less than 0.5 cm
Pustule
A small (< 1 cm in diameter), circumscribed superficial elevation of the skin that is filled with purulent material.
Ulcer
A localized defect in the skin of irregular size and shape where epidermis and some dermis have been lost.
Varying colors of liquid debris (serum or pus) that has dried on the surface of the skin
Crust
Images /Definitions from: missinglink.ucsf.edu/ (2009)
living with herpes.net (2009)
Cincinnati STD/HIV Prevention Training Center

18. HSV Lesion Progression
Herpes Doesn’t Read Textbooks
A circumscribed elevated, sollid lesion, less than 1 cm
Papule
Vesicle
A circumscribed, serous ,fluid filled elevation of the skin, less than 0.5 cm
Pustule
A small (< 1 cm in diameter), circumscribed superficial elevation of the skin that is filled with purulent material.
Ulcer
A localized defect in the skin of irregular size and shape where epidermis and some dermis have been lost.
Varying colors of liquid debris (serum or pus) that has dried on the surface of the skin
Crust
Lesions Can Have Many Appearances
Images /Definitions from: missinglink.ucsf.edu/ (2009)
living with herpes.net (2009)
Cincinnati STD/HIV Prevention Training Center

19. Asymptomatic Infection Asymptomatic But Shedding HSV-2
Gupta et al., Lancet 2007
Gupta et al., Lancet 2007

20. Asymptomatic Viral Shedding
No genital lesions present
Between clinical outbreaks
No history of clinical outbreaks
Antibody present
Common sites
Women: vulva and perianal region
Men: penile skin and perianal region
Greatest in the first 3 months but continues
Asymptomatic shedding is of briefer than during clinical recurrences

21. Viral Shedding occurs in the absence of symptoms
Featured are patterns of asymptomatic shedding seen in 2 women from a 1995 study by Wald and colleagues. As shown, shedding was identified at multiple sites and was either clustered around lesion periods or occurred in a random pattern.
Patient A intermittently shed virus during the period when lesions were visible and also shed virus from the perianal area 2 days after the lesions had healed.
Patient B shed virus on multiple days in the absence of lesions.
Mark et al, JID 198:

22. Transmission usually occurs when symptoms are absent
144 discordant couples followed over time
14 of 144 partners were infected
(9.7%)
Median 334 Days
70% of
transmission occurred when the index case was asymptomatic
Mertz et al Risk Factors for the Sexual Transmission of Genital Herpes. Ann Intern Med. 116(3)

23. Clinical Manifestations

24. Herpes: Primary Complex
Clinical Manifestations
Herpes: Primary Complex
papules  vesicles  pustules  ulcers  crusts  healed
Source: Cincinnati STD/HIV Prevention Training Center

25. Herpes: Genitalis Multiple Ulcer
Clinical Manifestations
Herpes: Genitalis Multiple Ulcer
papules  vesicles  pustules  ulcers  crusts  healed
Source: Cincinnati STD/HIV Prevention Training Center

26. Herpes: Genitalis External- Labia Minor
Clinical Manifestations
Herpes: Genitalis External- Labia Minor
papules  vesicles  pustules  ulcers  crusts  healed
Source: Cincinnati STD/HIV Prevention Training Center

27. Herpes: Genitalis Clinical Periurethal Lesions on Vestibule
Clinical Manifestations
Herpes: Genitalis Clinical Periurethal Lesions on Vestibule
papules  vesicles  pustules  ulcers  crusts  healed
Source: Cincinnati STD/HIV Prevention Training Center

28. Clinical Manifestations
Herpes: Cervicitis
papules  vesicles  pustules  ulcers  crusts  healed
Source: Cincinnati STD/HIV Prevention Training Center

29. Clinical Manifestations
Herpes on the Buttock
papules  vesicles  pustules  ulcers  crusts  healed
Source: Cincinnati STD/HIV Prevention Training Center

30. HSV Diagnosis

31. Clinical diagnosis is insensitive and nonspecific
Clinical diagnosis should be confirmed by lab testing
Virologic
Two types
Serologic

32. Virologic Tests Viral culture (gold standard)
Preferred test for patients with genital ulcers or other mucocutaneous lesions
Most sensitive when lesions are in the vesicular-pustular stage
Sensitivity rapidly declines as lesions ulcerate and crust
Nucleic Acid Amplification
User Friendly
More Sensitive

33. 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.

34. Lab-Based Serology Tests
% Sensitivity (95% CI)
% Specificity (95% CI)
HerpesSelect HSV-1 ELISA
91 (85-95)
92 (85-97)
HerpeSelect HSV-2 ELISA
96 (89-99)
97 (93-99)
HerpeSelect HSV-1 Immunoblot IgG
99 (96-100)
95 (89-98)
HerpeSelect HSV-2 Immunoblot IgG
97 (91-100)
98 (95-100)
Captia HSV-1 ELISA
88 (82-94)
100 (96-100)
Captia HSV-2 ELISA
97 (89-100)
90 (84-95)
Point-of-Care Serology
HerpeSelect Express Rapid HSV-2 IgG
98 (95-99) (Capillary whole blood)
99 (97-100) (Capillary whole blood)
Biokit HSV-2 Rapid Test
Sure-Vue HSV-2 Rapid Tests
92 (91-94) (Capillary whole blood)
87 (85-89) (Capillary whole blood)
From: The HERPES Testing Toolkit: A clinician’s guide to serologic testing for Herpes simlex virus (HSV). ASHA

35. Type-specific antibody at time of presentation
Diagnosis
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
+/Mild
+/-
Symptomatic, Recurrence
+/Mild,
unilateral
Asymptomatic, Infection

36. Candidate Patients for Type-Specific Genital Herpes Tests
Testing Recommended
Swab Test (Viral Culture or PCR)
Serological Test (Type Specific Ab)
Typical Genital Lesion X
Clinical dx with negative or no swab test
Atypical Lesion (e.g, fissure, erythema)
Recurrent lower genital tract inflammation with no lesions (e.g, dysuria, burning, itching)
STI evaluation, no lesions
Sexually active patient requests test, no lesion
Sex partner of patient with genital herpes
Experts disagree on whether or not these patients should be tested
HIV, no lesion
Sexual assault, no lesion
Pregnancy, no lesions
High risk populations (e.g. MSM), no lesions
From: The HERPES Testing Toolkit: A clinician’s guide to serologic testing for Herpes simlex virus (HSV). ASHA

37. Patient Management

38. 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
Natural history
Sexual transmission
Perinatal transmission
Methods to reduce transmission

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

40. First Clinical Episode Start Early and Treat Longer
2010 STD Treatment Guideline 2010

41. Episodic Treatment for Recurrent Genital Herpes
Therapy should be initiated within one day of symptoms
Patients can be given prescriptions ahead of time

42. 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.

43. Special Populations

44. HIV and HSV-2 coinfection is common
Percent HVS-2 Positive
Modifed from Russel et al. J of Clin Vir : 305; and
Wald and Celum. Medscape CE course 2005:

45. HSV HIV HSV and HIV are linked Effect of HIV on HSV- 2
Alters the clinical presentation of HSV-2
Increased HSV-2 shedding
Larger, slower- healing lesions in persons with advanced HIV
Increased risk of HSV-2 acquisition
Effect of HSV-2 on HIV
Increases risk of HIV acquisition/ transmission
Genital Lesions provide a portal of entry for HIV
Increased number of activated CD4+ and CD8+ T cells in genital mucosa and skin
Increased HIV levels in plasma and genital tract
HSV
HIV
Leone, Update on Epidemiology and Treatment Strategies for Genital Herpes

46. CDC-Recommended Regimens for Episodic Infection in HIV-Infected Persons Treat Longer

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

48. Herpes in Pregnancy (Neonatal Herpes)
Most commonly transmitted during delivery
1 in 3,000-20,000 live births
Affects ~1,500-2,000 infants/yr in US
Greater risk to infant if mother has primary genital lesions
Primary genital lesions = 40-50% of infants affected
Recurrent genital lesions = 2-3%
Risk of transmission
Young maternal age
Maternal seronegativity
Presence of vaginal lesions during delivery
Infant prematurity
Manifests during first 4 weeks after birth

49. Herpes in Pregnancy (Neonatal Herpes)
Neonatal Herpes Syndromes
Skin, eye and mouth (SEM)
Typically lesions are on the scalp, mouth, nose, and eye (where the skin comes in contact with the mother’s genital lesions)
CNS (Seizures, lethargy, and hypotonia)
Accounts for ~60% of cases.
May have skin lesions
40% of survivors may have neurological deficits
Disseminated (including liver, adrenal glands, lungs)
Devastating
50% mortality
Present with shock (multi-organ system failure)

50. 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.

51. 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.

52. Herpes in Pregnancy (continued)
Treatment in Pregnancy
Oral Acyclovir may be administered to pregnant women with first-episode genital herpes or recurrent herpes
IV Acyclovir may be administered to pregnant women with severe HSV infection
No increased risk of birth defects in women treated with acyclovir during 1st trimester
More limited data for valacyclovir and famciclovir
Many specialists recommend HSV suppression during third trimester in order to prevent C-section

53. Lesson VI: Prevention

54. Patient Counseling and Education
Goals
Help patients cope with the infection
Physical and Psychological Aspects
Prevent sexual and perinatal transmission
Education is an ongoing process
Nature of the infection
Transmission
Treatment Options
Risk-reduction
Partner Management

55. Nature of the Infection
Sexual transmission of HSV can occur during asymptomatic periods.
Stressful events may trigger recurrences.
Prodromal symptoms may precede outbreaks.

56. 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.

57. 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
Treatment is not curative

58. 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.

59. Counseling for Asymptomatic Persons
Asymptomatic HSV-2 infected persons should receive the same counseling messages as symptomatic persons.
Teach the common manifestations of genital herpes

60. Partner Management Symptomatic sex partners Asymptomatic 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.

61. The Future of HSV-2 (vaccination and microbicides)

62. Hope for a Vaccine
Johnston et al JCI. 121(12): 4600

63. Hope for a Vaccine
Johnston et al JCI. 121(12): 4600

64. Belshe et al NEJM

65. Johnston et al JCI. 121(12): 4600

66. Therapeutic Vaccines for HSV-2
Johnston et al JCI. 121(12): 4600

67. Tenofovir Microbidice: HIV and HSV-2 Prevention
51% Reduction in HSV-2 Acquisition in women using the Tenofovir Gel
HIV
Karim et al Science. 329:1168

68. New Therapeutics
Still Searching…

69. Learning Objectives By the end of the Lecture:
Reviewed HSV-2 epidemiology in the U.S.
Understand the pathogenesis of HSV-2
Identify the clinical manifestations of HSV-2
Choose appropriate test(s) for HSV-2 diagnosis
Discuss the management of HSV-2
Introduce new research in HSV-2 prevention and treatment