1 Update: Genital Herpes Simplex Virus Infection Nick Van Wagoner, MD, PhDUniversity of Alabama at BirminghamWebinar
2 Nick Van Wagoner: Disclosures Will not discuss off-label use of commercial products and/or servicesNo 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-2Identify the clinical manifestations of HSV-2Choose appropriate test(s) for HSV-2 diagnosisDiscuss the management of HSV-2Introduce new research in HSV-2 prevention and treatment
4 HSV: Pearls Genital Herpes is the most prevalent STD in the U.S. Life-long infectionSexually transmittedMost people don’t know their infectedViral shedding occurs in the absence of symptomsTransmission usually occurs when symptoms are absent
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 atXu et al. JAMA : 296:Leone, Update on Epidemiology and Treatment Strategies for Genital Herpes
8 HSV Risk Factors Biology Gender Race Male Circumcision Age SociodemographicsIncomeLiving conditionsSexual NetworksBehaviorNo. of PartnersEarly Sexual DebutDrug UseXU et al., JAMA :Newman, STD : S4-S12
9 Unknown HSV-2 Infection Men Attending the JCHDHSV-2 PositiveKnow itHSV-2 PositiveDon’t know itHSV-2 Negative~80-90% of people that test positive for HSV-2 in the U.S are unaware that they are infectedXu et al. JAMA : 296: , MMWR (15):456
11 Virology: HSV-1 and HSV-2 Members of the human herpes virus family (herpetoviridae).Genome: ~154,000 bp DS DNAHSV-1 and HSV-2 50% IdenticalHSV-2 causes about ½ of genital ulcersThe other ½ are caused by HSV-1Todar. Ken Todar’s Microbial World. U of WisconsinDwyer and Cunningham. MJA (5):
13 HSV Genital/Anogenital Transmission SexualReceptive Vaginal--Insertive VaginalReceptive Anal--Insertive AnalReceptive Oral (HSV-1)Efficiency of sexual transmission: greater from men to womenLikelihood of transmission declines with duration of infection
14 Definitions of First Clinical Episodes Primary infectionFirst infection ever (HSV-1 or HSV-2)More severeNo antibody present when symptoms appearNon-primary infectionNew HSV-1 or HSV-2 in an individual previously seropositive to the other virusWill have antibody to the other HSV virus when symptoms appearSymptoms usually milder than primary infection
15 First Episode Primary Infection Characteristics of Lesions:Usually multiple and bilateralMore severe than recurrencesContain higher virus titers than in recurrenceLast days and shed virus for ~12 daysLocal symptoms include pain, itching, dysuria, vaginal or urethral discharge, and tender inguinal adenopathyCervicitis is commonSystemic SymptomsLast 2-4 weeksFever, headache, malaise, myalgiasWithout treatmentIncubation 2-12 days (average of 4 days)
16 Recurrent Symptomatic Infection Disease is milder and shorter in durationAntibody to HSV-2 presentProdromalLesions last 5-10 daysNo systemic symptomsHSV-2 is more prone to recur than HSV-1symptoms (localized tingling, irritation) in ~50% begin hours before lesions appear
17 HSV Lesion Progression A circumscribed elevated, sollid lesion, less than 1 cmPapuleVesicleA circumscribed, serous ,fluid filled elevation of the skin, less than 0.5 cmPustuleA small (< 1 cm in diameter), circumscribed superficial elevation of the skin that is filled with purulent material.UlcerA 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 skinCrustImages /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 TextbooksA circumscribed elevated, sollid lesion, less than 1 cmPapuleVesicleA circumscribed, serous ,fluid filled elevation of the skin, less than 0.5 cmPustuleA small (< 1 cm in diameter), circumscribed superficial elevation of the skin that is filled with purulent material.UlcerA 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 skinCrustLesions Can Have Many AppearancesImages /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 2007Gupta et al., Lancet 2007
20 Asymptomatic Viral Shedding No genital lesions presentBetween clinical outbreaksNo history of clinical outbreaksAntibody presentCommon sitesWomen: vulva and perianal regionMen: penile skin and perianal regionGreatest in the first 3 months but continuesAsymptomatic 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 time14 of 144 partners were infected(9.7%)Median 334 Days70% oftransmission occurred when the index case was asymptomaticMertz et al Risk Factors for the Sexual Transmission of Genital Herpes. Ann Intern Med. 116(3)
31 Clinical diagnosis is insensitive and nonspecific Clinical diagnosis should be confirmed by lab testingVirologicTwo typesSerologic
32 Virologic Tests Viral culture (gold standard) Preferred test for patients with genital ulcers or other mucocutaneous lesionsMost sensitive when lesions are in the vesicular-pustular stageSensitivity rapidly declines as lesions ulcerate and crustNucleic Acid AmplificationUser FriendlyMore Sensitive
33 Type-Specific Serologic Tests Type-specific and nonspecific antibodies to HSV develop during the first several weeks following infection and persist indefinitelyPresence of HSV-2 antibody indicates anogenital infectionPresence of HSV-1 does not distinguish anogenital from orolabial infection.
35 Type-specific antibody at time of presentation DiagnosisInfection TypeLesions/ SymptomsType-specific antibody at time of presentationHSV-1HSV-2First episode, Primary(Type 1 or 2)+/Severe, bilateral-First episode, Non-primaryType 2+/Moderate+First episode, Recurrence+/Mild+/-Symptomatic, Recurrence+/Mild,unilateralAsymptomatic, Infection
36 Candidate Patients for Type-Specific Genital Herpes Tests Testing RecommendedSwab Test (Viral Culture or PCR)Serological Test (Type Specific Ab)Typical Genital LesionXClinical dx with negative or no swab testAtypical Lesion (e.g, fissure, erythema)Recurrent lower genital tract inflammation with no lesions (e.g, dysuria, burning, itching)STI evaluation, no lesionsSexually active patient requests test, no lesionSex partner of patient with genital herpesExperts disagree on whether or not these patients should be testedHIV, no lesionSexual assault, no lesionPregnancy, no lesionsHigh risk populations (e.g. MSM), no lesionsFrom: The HERPES Testing Toolkit: A clinician’s guide to serologic testing for Herpes simlex virus (HSV). ASHA
38 Principles of Management of Genital Herpes Systemic antiviral chemotherapyPartially controls symptoms and signs of herpes episodesDoes not eradicate latent virusDoes not affect risk, frequency or severity of recurrences after drug is discontinuedCounselingNatural historySexual transmissionPerinatal transmissionMethods to reduce transmission
39 Antiviral Medications ManagementAntiviral MedicationsSystemic antiviral chemotherapy includes 3 oral medications:Acyclovir Valacyclovir FamciclovirTopical 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 symptomsPatients can be given prescriptions ahead of time
42 Suppressive Therapy for Recurrent Genital Herpes Reduces frequency of recurrencesReduces but does not eliminate subclinical viral sheddingPeriodically (e.g., once a year), reassess need for continued suppressive therapy.
44 HIV and HSV-2 coinfection is common Percent HVS-2 PositiveModifed from Russel et al. J of Clin Vir : 305; andWald 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-2Increased HSV-2 sheddingLarger, slower- healing lesions in persons with advanced HIVIncreased risk of HSV-2 acquisitionEffect of HSV-2 on HIVIncreases risk of HIV acquisition/ transmissionGenital Lesions provide a portal of entry for HIVIncreased number of activated CD4+ and CD8+ T cells in genital mucosa and skinIncreased HIV levels in plasma and genital tractHSVHIVLeone, 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 delivery1 in 3,000-20,000 live birthsAffects ~1,500-2,000 infants/yr in USGreater risk to infant if mother has primary genital lesionsPrimary genital lesions = 40-50% of infants affectedRecurrent genital lesions = 2-3%Risk of transmissionYoung maternal ageMaternal seronegativityPresence of vaginal lesions during deliveryInfant prematurityManifests during first 4 weeks after birth
49 Herpes in Pregnancy (Neonatal Herpes) Neonatal Herpes SyndromesSkin, 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 lesions40% of survivors may have neurological deficitsDisseminated (including liver, adrenal glands, lungs)Devastating50% mortalityPresent 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 PregnancyOral Acyclovir may be administered to pregnant women with first-episode genital herpes or recurrent herpesIV Acyclovir may be administered to pregnant women with severe HSV infectionNo increased risk of birth defects in women treated with acyclovir during 1st trimesterMore limited data for valacyclovir and famciclovirMany specialists recommend HSV suppression during third trimester in order to prevent C-section
54 Patient Counseling and Education GoalsHelp patients cope with the infectionPhysical and Psychological AspectsPrevent sexual and perinatal transmissionEducation is an ongoing processNature of the infectionTransmissionTreatment OptionsRisk-reductionPartner 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 TransmissionAbstain 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 episodesWhen and how to take antiretroviral medicationsRecognition of prodromal symptomsTreatment 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 partnersAsk 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 VaccineJohnston et al JCI. 121(12): 4600
63 Hope for a VaccineJohnston et al JCI. 121(12): 4600
69 Learning Objectives By the end of the Lecture: Reviewed HSV-2 epidemiology in the U.S.Understand the pathogenesis of HSV-2Identify the clinical manifestations of HSV-2Choose appropriate test(s) for HSV-2 diagnosisDiscuss the management of HSV-2Introduce new research in HSV-2 prevention and treatment