# Presentation: 114224

## 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.**

## 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)**** **

## 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?**

## 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**

**Diagnosis of Genital Ulcer Disease**

## 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**

## 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** 	**	**

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## 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**

**Serological Testing for HSV Infection**

## 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 **

## 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 detected****	****	****168 (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**

## 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**

## 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**

## Slide 24

## 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)**

**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**

## 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**

## 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**

## OD Index <3.0 

**Western blot done**** **

**44 HSV-1 neg by Western blot**

**58 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**

## HSV-2 ELISA Testing Algorithm

**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**

## HSV-2 ELISA Testing Algorithm No. 2

**HSV-2 pos, HSV-1 neg**

**HSV-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**

## Sensitivity and specificity of Focus ELISA vsWB and Focus inhibition assays

**Sensitivity and specificity of Focus ELISA vs****WB and Focus inhibition assays**

**a ****ELISA Index value above which the sample is considered positive.**

## 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**

## 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 <25%), not for diagnostic testing (prior probability typically **_**>**_**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**

## 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**

## Costs of HSV Serological Tests

**Focus ELISA**
**HSV-2**
**HSV-1 **
**Focus immunoblot**
**Western blot**

**Cost**
**$5**
**$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**

## 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**

## 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**

## 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**

## 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**
**	****	**

## 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**** **

## 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**

## Slide 43

## 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**

## 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)**

## 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**

## 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**
**	**

## 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)**

## 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?**

**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**

## 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)**

## 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**

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

## Slide 54

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

## 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)**

## 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 1.01-3.49****	****	****	****13/26  (50)**
**	****OD **_**>**_**3.50****	****	****	****	****80/84  (95) ****	****	****	****	****      ****	**

***  ~1000 men tested, prevalence ~11%**

**Golden MR, Handsfield HH, Wald A, Ashley Morrow R:  Unpublished**

## 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?**

## 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)**

## 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**