1. The Public Health Response to Genital Herpes: Where Do We Stand? H. Hunter Handsfield, M.D. Connie L. Celum, M.D., M.P.H. Lawrence Corey, M.D. Gail Bolan, M.D., M.P.H. Peter A. Leone, M.D., M.P.H.

2. The Public Health Response to Genital Herpes: Where Do We Stand?  Diagnosis: Test Performance and Practical Issues in Implementation (Handsfield; 20 min)  HIV/HSV-2 Interactions: Implications for Prevention (Celum; 20 min)  Prevention: Effective Strategies Old and New (Corey; 20 min)  A Real-World Model (Straw Man?) for Genital Herpes Clinical Care and Prevention in Public Health Settings (Handsfield; 5 min)  Comment and Critique (Bolan, Leone, Panel; 10 min)  Discussion (Audience and Panel; 30 min)

3. Diagnosis of Genital Herpes: Test Performance and Practical Issues in Implementation H. Hunter Handsfield, M.D. University of Washington Public Health - Seattle & King County Seattle, Washington The Public Health Response to Genital Herpes: Where Do We Stand?

4. Public Health Issues in Genital Herpes Public Health Issues in Genital Herpes The Six Biggies  Preventing sexual transmission of HSV  Relationship of HSV-2 infection to HIV transmission and its prevention  Underdiagnosis of genital ulcer disease  The roles of type-specific serological testing  Under-treatment  Preventing neonatal herpes

5. Diagnosis of Genital Ulcer Disease

6. Clinical Diagnosis of Genital Ulcer Disease  N = 446; microbiologic or virologic diagnosis made in 220 (49%)  Sensitivity of classical clinical appearance was poor (31-35%) for herpes, syphilis, and chancroid  Specificity was good for syphilis (98%), high PPV  Specificity only 94%for HSV and chancroid, low PPV  Conclusion: Classic chancre reliably indicates syphilis, but is insensitive; otherwise, clinical diagnosis is unreliable lab tests essential DiCarlo RP, Martin DH. CID 1997;25:299-300

7. Etiology of Genital Ulcer Disease  516 GUD patients from STD Clinics in 10 of 11 U.S. cities w/ highest syphilis rates  Excluded patients with typical herpes  PCR for HSV, T. pallidum, H. ducreyi HSV 333(64.5%) Syphilis 64(12.4%) HSV + Syphilis 13 (2.5%) Chancroid 16 (3.1%) PCR negative 116(22.4%) Mertz K et al, JID 1998;178:1795-8

18. Diagnosis of Genital Herpes  Test all genital ulcers for HSV  Also test all cases of classical 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, little or no use  Serological testing: Use only glycoprotein G (gG) based assays

19. Serological Testing for HSV Infection

20. Type-Specific HSV Serological Tests Antibody to HSV-1 or -2 glycoprotein G (gG-1 or gG-2)  Western blot –The gold standard  Focus Technologies (formerly MRL) HerpeSelect TM HSV-1 and HSV-2 ELISA –Sensitivity for HSV-2 ~90, specificity ~98%  Focus Technologies HerpeSelect TM HSV-1 and HSV-2 Differentiation Immunoblot –Same antigen as ELISA, probably similar performance

21. Proficiency Testing for HSV-1 and HSV-2 Antibody Tests American College of Clinical Pathologists  HSV-1 positive, HSV-2 negative (Western blot) serum sent to 172 participating laboratories - HSV-1 antibody detected168 (98%) - HSV-2 reported positive EIA(N = 153) 73 (48%) Non-EIA (N = 26) 23 (89%) gG based EIA (Focus) (N = 44) 0  Tests to be avoided: Wampole, Zeus, DiaSorin Ashley-Morrow R, Friedrich R: Am J Clin Path December 2003

22. Barriers to HSV-2 Serological Testing Barriers to HSV-2 Serological Testing (And to Genital Herpes Prevention in General)  Disbelief that HSV-2 infection matters  Test performance  Cost  Counseling barriers  Benefits vs Risks

23. Barriers to HSV-2 Serological Testing Barriers to HSV-2 Serological Testing (And to Genital Herpes Prevention in General)  Disbelief that HSV-2 infection matters  Test performance  Cost  Counseling barriers  Benefits vs Risks

25. Persons at Risk Desire HSV Testing  Leeds, UK, 200 consecutive STD patients: 92% for themselves, 91% for their partners (Fairley & Monteiro, Genitourin Med 1997;73:259-62)  Seattle, Washington, USA, STD clinic patients ( Wald et al, unpublished) - Cost-free testing: 756/1477 (51%) - At $15.00: 558/3099 (18%)  Studies also indicate that many persons say they a positive test result would be put to use to protect partners from transmission (Stoner; Douglas; others)

26.  A decision to not even offer serological testing to persons at risk for genital herpes is, at its core, paternalistic: - “I know what is best for you... -...and I’m not even going to give you the option”  A decision to not offer testing essentially prioritizes provider issues over patient needs and prevention - Counseling uncertainties - Time - Costs Testing for Genital Herpes

27. Barriers to HSV-2 Serological Testing Barriers to HSV-2 Serological Testing (And to Genital Herpes Prevention in General)  Disbelief that HSV-2 infection matters  Test performance  Cost  Counseling barriers  Benefits vs Risks

28. Positive Predictive Value Sensitivity 90 %, Specificity 98% Prevalence PPV FP Rate  10% 83% 1 in 6  25% 94% 1 in 20  50% 98% 1 in 50

29. 102 Men HSV-2 pos ELISA Western blot done 44 HSV-1 neg by Western blot58 HSV-1 pos by Western blot 44 HSV-2 pos by Western blot (PPV=100%) 41 HSV-2 pos by Western blot (PPV=71%) 33/34 HSV-2 pos by Western blot (PPV=97%) OD Index >3.0 8/24 HSV-2 pos by Western blot (PPV=33%) OD Index <3.0 PPV of HSV-2 ELISA Based on HSV-1 Serostatus and ELISA Optical Density Index

30. HSV-2 serology Run HSV-1 serology HSV-2 true positive HSV-2 OD Index <3.0 HSV-2 indeterminate Repeat testing 3 months or Western Blot HSV-2 OD Index >3.0 HSV-2 ELISA Testing Algorithm HSV-1 negative HSV-1 positive

31. Routine HSV-1 and -2 Serology HSV-2 pos, HSV-1 negHSV-2 pos, HSV-1 pos HSV-2 true positive HSV-2 OD Index <3.0 Indeterminate F/u testing 3 months or Western Blot HSV-2 OD Index >3.0 HSV-2 ELISA Testing Algorithm No. 2

32. Sensitivity and specificity of Focus ELISA vs WB and Focus inhibition assays a ELISA Index value above which the sample is considered positive.

33. Options for Confirmatory Testing of the Focus HSV-2 ELISA  Western blot  HSV-1/OD index testing algorithm  Focus immunoblot?  Focus ELISA avidity assay?  Commercial confirmatory tests (rumors) - Focus - Others?  Repeat/convalescent testing

34. A Perspective on Confirmatory Testing  Confirmation of Focus HSV-2 ELISA is an issue only in populations at low or modest risk (e.g., prevalence 50%) - Clinical suspicion of herpes - Sex partners of HSV-2-infected persons - Most (all?) populations at risk for HIV  In lower risk settings, follow the OD index/HSV-1 algorithm if/when confirmed in larger studies  “Sell” HSV serological testing as test for diagnosis and for other patently high-risk settings - Screening in other settings will follow naturally as providers gain comfort with high-risk testing

35. Barriers to HSV-2 Serological Testing Barriers to HSV-2 Serological Testing (And to Genital Herpes Prevention in General)  Disbelief that HSV-2 infection matters  Test performance  Cost  Counseling barriers  Benefits vs Risks

36. Costs of HSV Serological Tests  Focus ELISA - HSV-2 - HSV-1  Focus immunoblot  Western blot Cost $5 $25 $50 Lab Fee* $15 # $10 # $40 $120-150 Medicaid Reimb $22 $15 $40 Variable * PHSKC Laboratory # HSV-1 stand alone $15, HSV-1 & 2 $25; STD Clinic pays $5 each

37. Barriers to HSV-2 Serological Testing Barriers to HSV-2 Serological Testing (And to Genital Herpes Prevention in General)  Disbelief that HSV-2 infection matters  Test performance  Cost  Counseling barriers  Benefits vs Risks

38. Elements of Herpes Education and Counseling  Natural course of disease  Subclinical shedding  Options to reduce transmission risk - Symptom recognition abstinence - Condoms - Antiviral therapy  Increased risk of HIV conferred by HSV-2  Neonatal herpes risks and prevention  Minimal pre-test counseling: Counseling should not be a barrier to testing

39. Barriers to HSV-2 Serological Testing Barriers to HSV-2 Serological Testing (And to Genital Herpes Prevention in General)  Disbelief that HSV-2 infection matters  Test performance  Cost  Counseling barriers  Benefits vs Risks

40. Benefits and Risks of Genital Herpes Diagnosis and Prevention Efforts  It is extremely unlikely that confirming a suspected diagnosis, revealing subclinical infection, or confirming susceptibility (negative result) will increase risks of transmission or acquisition of either HSV-2 or HIV –The one-sided bell curve  Thus, the burden of proof is on those who say such efforts would not reduce transmission

41. Public Health Approaches to Genital Herpes Prevention  Test all genital ulcers for HSV  Liberal use of type-specific serologic tests - Sex partners of infected persons - Suggestive symptoms - Patient request to R/O genital herpes - Selected pregnant women and partners - Persons with or at risk for HIV infection  Assure that patients’ sex partners are evaluated

42. Public Health Approaches to Genital Herpes Prevention  Counsel infected persons and partners - Subclinical shedding - Symptom recognition - Personal prevention strategies (condoms, abstinence during symptoms)  Consider antiviral therapy to prevent Cesarean section (may help prevent some cases of neonatal herpes)  Antiviral therapy of selected infected persons to prevent transmission

44. Clinical Spectrum of Genital Herpes  First episode infection –Primary infection (~20%) –Nonprimary first-episode infection (~40%) –First clinical episode of chronic infection (~40%)  Recurrent infection (HSV-2 > HSV-1)  Subclinical infection –Truly asymptomatic –Unrecognized

45. Psychosocial Impact of Genital Herpes  Every study of psychosocial impact and every survey of patients with genital herpes has found fear of transmission to sex partners to be among the top 3 (usually no. 1 or 2) sources of concern, anxiety and stress  Cited by 37% to 89% of patients - - Luby & Klinge (1985) - - Silver et al (1986) - - Catotti/ASHA (1991) - - Keller et al (1991) - - Carney et al (1993) - - Mindel et al (1993) - - Carney et al (1994) - - Mindel et al (1996) - - IHMF/IHA (2000) - - IHMF/IHA (2002)

46. Recurrence Rate After Initial Genital Herpes  Mean recurrence rate in first year after initial genital HSV-2 infection (N = 457, median FU 391 days) - Men5.2 episodes/yr - Women4.0 episodes/yr  >6 recurrences in first year38%  >10 recurrences in first year20%  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

47. Biomedical Complications of HSV-2 Genital Infection  Localized neuropathic manifestations  Meningitis (isolated, recurrent)  Erythema multiforme, Stevens Johnson syndrome  Perinatal and maternal morbidity - Neonatal herpes - Cesarean section  Nongenital autoinoculation syndromes (conjunctivitis, keratitis, whitlow)  Chronic localized disease in immunodeficient patients (especially HIV/AIDS)  Enhanced HIV transmission

48. Uses of Type-Specific HSV Serology Definite Indications  Diagnosis of GUD, recurrent Sx, etc  Management of sex partners of persons with herpes  Persons with or at risk for sexual acquisition of HIV 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)

49. HSV-2 Serological Testing in Pregnancy  Pregnant woman with husband/partner suspected to have genital herpes - HSV-2 positive: Reassure; examine for lesions at term and avoid invasive obstetrical procedures - HSV-2 negative: Test partner and/or avoid exposure in third trimester  Husband/partner with past STD or at risk  All pregnant women? All husbands / partners?

50.  A decision to not even offer serological testing to persons at risk for genital herpes is, at its core, paternalistic: - “I know what is best for you... -...and I’m not even going to give you the option”  A decision not to offer testing essentially prioritizes provider issues over patient needs and prevention - Counseling uncertainties - Time - Costs Screening for Genital Herpes

51. Persons at Risk Desire HSV Testing  Leeds, UK, 200 consecutive STD patients: 92% for themselves, 91% for their partners (Fairley & Monteiro, Genitourin Med 1997;73:259-62)  Seattle, Washington, USA, STD clinic patients ( Wald et al, unpublished) - Cost-free testing: 756/1477 (51%) - At $15.00: 558/3099 (18%)  Studies also indicate that many persons say they a positive test result would be put to use to protect partners from transmission (Stoner; Douglas; others)

52. Herpes Simplex Virus  Mucocutaneous infection, retrograde infection along sensory nerves, latent infection in cranial nerve or dorsal spinal ganglia, mucocutaneous recurrences  HSV-1 –Mostly orolabial (cold sores, fever blisters) –20-30% of initial genital herpes  HSV-2 –Almost entirely genital; oral infection rare –>90% of recurrent genital herpes

53. How is Genital Herpes Viewed by Newly Diagnosed Patients and Persons At Risk?

55. How is Genital Herpes Viewed by Most Clinicians and the Public Health Establishment?

56. Older HSV Serological Tests  Several technologies available - Indirect immunofluorescence (IFA) - Neutralization - Complement fixation - EIA/ELISA  Interpretation - Positive/negative is valid: i.e., tests accurately determine presence or absence of antibody to HSV - No distinction between HSV-1 and HSV-2 (despite manufacturers’ claims to the contrary!) - Differentiation between IgG and IgM not useful; IgM antibody often present in recurrent herpes  Do not use to diagnose suspected genital herpes; specifically request a gG-based type- specific test (Focus HerpeSelect  or WB)

57. Experience with HSV-2 ELISA (Focus) Public Health/Harborview STD Clinic 110 asx males with + ELISA (OD >1.0)* Western blot confirmed, No. (%) Total 93/110 (85) OD 1.01-3.4913/26 (50) OD >3.5080/84 (95) * ~1000 men tested, prevalence ~11% Golden MR, Handsfield HH, Wald A, Ashley Morrow R: Unpublished

58. Uses of Type-Specific HSV Serological Tests in Pregnancy  Husband/partner suspected to have genital herpes - If she is HSV-2-positive, reassure her (and keep a lookout for HSV lesions at term) - If she is HSV-2-negative, test partner; if he is positive (or if not tested), assertively counsel to avoid sex in last trimester  Husband/partner with past STD or at risk  Diagnostic testing: All pregnant women with apparent initial genital herpes (culture and serology)  All pregnant women and their partners?

59. Psychological Impact of Genital Herpes Diagnosis  Significant impact (Carney et al, Genitourin Med 1994;70:40-5) - Depression, isolation, fear of rejection: 55-82%of patients with initial GH - Less frequent with repeat outbreaks (28-58%)  Or not so significant: No impairment on standard psych testing of patients with RGH (median 6 yr) (Brookes et al, Genitourin Med 1993;69:384-7)  Responds to suppressive treatment (Patel et al, Sex Transm Infect 1999;75:398)  Anecdotal experience reassuring with frequent testing - Public Health - Seattle King Co. STD Clinic - Prenatal patients <5% (Brown et al)

60. Psychological Impact of Genital Herpes Diagnosis  So, the psychological impact is or isn’t very large; variable results, undoubtedly related to differences between populations and study design  Whatever impact there is appears to be largely transient, likely responsive to counseling, and reduced by antiviral therapy  Thus, either it is not a serious problem...OR  It is a serious problem, making it all the more important to prevent continued transmission - which requires serologic diagnosis