1. HSV Prevention for STD Programs Where do we go from here? Pete Leone, MD Associate Professor of Medicine University of North Carolina Medical Director North Carolina HIV/STD Prevention and Care Branch NCDHHS

2. Genital Herpes is the Most Prevalent STD in the United States Centers for Disease Control and Prevention. Available at: http://www.cdc.gov. Accessed November 14, 2006. Xu F, et al. JAMA. 2006;296:964-973. US Census Bureau. Available at: http://www.census.gov. Accessed December 12, 2006. Chlamydia 3 Million 1 Hepatitis B 1.25 Million 1 Human Papillomavirus 20 Million 1 HIV/AIDS 1.2 Million 1 Genital HSV-2 50 Million 2,3 Over 1 Million New Genital Herpes Infections per Year in the US 1

3. Age-Adjusted HSV-2 Seroprevalence According to the Lifetime Number of Sex Partners, by Race/Ethnicity and Sex NHANES in 1999-2004 Xu et al. JAMA. 2006;296:964-973.

4. Why Diagnose Genital Herpes? Ongoing Epidemic - Most HSV-2 seropositive persons are symptomatic (disease) and virtually all will have viral shedding (infectious) but undiagnosed/unrecognized Transmission of herpes to newborn during pregnancy or delivery Transmission of herpes to newborn during pregnancy or delivery – Occurs in 1 per 3,200 live births – May lead to serious complications such as seizures, blindness, psychomotor retardation, spasticity, learning disabilities, and death Brown Z et al. JAMA. 2003;289:203-209 HSV transmission occurs in setting of undiagnosed/unrecognized infection Mertz GJ, et al. Ann Intern Med. 1992;116:197-202 HSV-2 increases risk of HIV acquisition and transmission Wald A, Link K. J Infect Dis. 2002;185:45-52

5. The Majority of HIV + Patients are Infected With HSV-2 60%-70% of HIV + patients in the US are also infected with HSV-2 2,3 –coinfection with HSV-2 is most common in: 3  women (76%)  heterosexuals (75%)  African Americans (78%) 1. Centers for Disease Control and Prevention. Available at: http://www.cdc.gov. Accessed November 14, 2006. 2. Meyer JL, et al. Sex Transm Infect. 2005;81:309-315. 3. Ramaswamy M, et al. Sex Transm Dis. 2006;33:96-101. HIV and HSV-2 HIV only HIV + Population >1 Million Patients 1

6. A Significant Proportion of HIV Infections in the US Can be Attributed to HSV-2 Wald A and Link K. J Infect Dis. 2002;185:45-52. 35% 19% MSM = men who have sex with men. Among HSV-2 seropositive persons, an estimated 52% of sexually transmitted HIV-1 infections may be attributed to HSV-2 infections

7. HSV We didn’t abandon bacterial STI control after Rakai HSV control is still important but almost non- existent Prevention largely dependent on Diagnosis Prevention for those with HSV on: - Reducing HSV transmission - Reducing HIV acquisition and transmission

8. Prevalence of HSV-2 Infection 17% US Adult Population 22-26% General Medical Clinics 20-35% Prenatal Clinics 40-60% STD Clinics 50-90% HIV Infected Individuals Corey JID 186(suppl) 2002; Weis Herpes11(suppl) 2004; McClelland JID 2005; Xu JAMA 2006 Leone STD 2004; Wald STD 1997; Cherpes STD 2003 Nahmias Scand J Infect Dis 1990; Crosby J Pediatr Adolesc Gynecol 2003 Gottleib JID 2002; Austin STD 1999

9. Let’s Start with GUD Evaluation: 2006 CDC STD Treatment Guidelines All patients who have genital ulcers should be evaluated with a serologic test for syphilis and a diagnostic evaluation for genital herpes;…. Specific tests for evaluation of genital ulcers include 1) syphilis serology and either darkfield examination or direct immunofluorescence test for T. pallidum; 2) culture or antigen test for HSV; and 3) culture for H. ducreyi. Both virologic and type-specific serologic tests for HSV should be available in clinical settings that provide care for patients with STDs or those at risk for STDs. MMWR Recomm Rep. 2006;55 (R-11) 1-94.

10. Challenges With Clinical Diagnosis: No “Ulcers” on Physical Exam Classic Common

11. Etiology of Genital Ulcer Disease 516 patients with genital ulcer disease from STD clinics in 10 of 11 US cities with highest syphilis rates PCR for HSV, T pallidum, H ducreyi HSV320(62%) Syphilis51(10%) HSV + syphilis13(3%) Chancroid16(3%) PCR negative116(22%) Mertz K et al. JID. 1998;178:1795-1798.

12. Diagnostic Approaches to Screening and Testing Lesion Evaluation With Viral Culture – Typing can be performed – Yields a high rate of false negatives With PCR – Typing can be performed – 3-4 times more sensitive than viral culture – More expensive Serologic Evaluation Use only glycoprotein G–based, type- specific antibody tests Order test by name (listed alphabetically) – FDA-cleared assays HerpeSelect ™ -1 ELISA HerpeSelect ™ -2 ELISA HerpeSelect ™ 1 and 2 Immunoblot IgG HSV-2 ELISA (Trinity) – Other assays (point-of-care tests) Biokit HSV-2 SureVue HSV-2

13. Public Health Laboratories and Type-specific Serology Public Health Laboratories and Type-specific Serology 2004 Survey of 144 members of the Association of Public Health Laboratories (ASHTO) Type of test# of labs %# of Tests Any Test5447.4 Culture5043.942,707 Direct Detection 1815.89,956 Serology1714.9 Type- specific76.113,263 WB10.9913 Non type- specific 108.82505 Dicker et al; STD 2007

14. HerpeSelect Serologic Tests for HSV-2 2007 Total number of tests performed : ~2.5 million. Total number sold to public health: ~25,000

15. Arguments concerning serologic screening Time - can be minimal with use of tools - Dx no more complicated then HIV or Syphilis tests results Cost - charge for test - selected screening ( we already do this for Ct ) - cost saving by reducing visits / misdiagnosis/ transmission of HSV HIV - need program science to measure impact and set priority Psychological - the impact of a new HSV-2 serologic diagnosis usually small and transient and requires minimal education and counseling - revised tool kits with access to internet based education - maybe the trauma is to the staff? Smith Int J STD AIDS 2000 Narouz Sex Transm Infect 2003 Miyai Sex Transm Dis 2004 Rosenthal Sex Transm Infect 2006 Richards Sex Transm Dis 2007

16. Case for Serologic Screening in STD Clinics We continue to do almost nothing for the most prevalent STI and the 3 rd most costly STI Our approach for testing only GUD will miss majority of individuals with GH since lesions present for only ~12-15 days/yr We already collect risk factors /sexual history which would allow us to selectively screen Need screen criteria based on outcomes….. HIV risk, transmission potential, peak incidence population, etc. Consideration must also be given to overall prevalence in local population as a screening criteria – GC model Majority of STD clients want or expect to be tested High prevalence in STD clinics translates into high PPV Wald et al, NEJM 1995 Fairly et al, Genitourin Med 1998 Brugha et al Sex Transm Infect 1999

17. Starting Point : Current CDC Recommendations for HSV Serologic Testing Patients – With recurrent genital symptoms or with atypical symptoms and negative HSV cultures 1 – With a clinical diagnosis only (i.e., without laboratory confirmation) 1 – With a partner with genital herpes Some specialists believe….. – Who present for a comprehensive STD evaluation 1 With HIV infection Having had multiple sex partners Who are MSM, at increased risk of HIV acquisition – Who are pregnant? (not in CDC or ACOG guidelines) Centers for Disease Control and Prevention. MMWR Recomm Rep 2006;55(RR-11):1-93.

18. 4 Low Cost Steps for Reducing Risk of HSV Sexual Transmission Condom Use Antiviral Suppressive Therapy Avoid sexual contact during outbreaks Disclosure to Sexual partners

19. Patients Are at Risk for Asymptomatic Viral Shedding Regardless of How Long Diagnosed Post-hoc analysis from a randomized, double-blind, placebo-controlled shedding substudy (N=89) when 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. Mean % of Days of Asymptomatic Viral Shedding Years Since Patient Was Diagnosed With Genital Herpes Data on file, GlaxoSmithKline. (N=7) (N=18)(N=11) (N=14)

20. HIV Acquisition Risk is Particularly Increased With Incident HSV-2: Pune, India Adjusted Hazard Ratio Reynolds SJ, et al. J Infect Dis. 2003:187;1513-1521.

21. Adjusted Hazard Ratio Relationship between HSV-2 and HIV acquisition studied in 4295 high-risk HIV − MSM in EXPLORE study (conducted in US) Intensive behavioral interventions did not reduce HIV acquisition Brown EL, et al. Am J Epidemiol. 2006;164:733-741. Risk of HIV Acquisition is Particularly Increased With Incident HSV-2: MSM HSV-2 Status

22. Impact of Suppressive Therapy on HSV Incidence The impact of suppressive therapy is modest at current coverage levels but could be substantially increased with higher rates of diagnosis and a focus on coverage soon after infection Williams Sex Transm Dis 2007 Blower JID 2004 Virological core group (11% of infected individuals) can cause a disproportionately large percentage (44%) of new infections

23. Priority for Suppression Therapy in STD Clinics INCIDENT CASES to Reduce HSV Transmission Highest rates of HSV shedding during the first year Transmission potential greatest during first few months of a discordant relationship Targeted Cost Covering for Suppression STD clinics could focus on suppression for incident/newly Dx cases (4-6 mo’s) Suppression for those starting new relationships Suppression should, however, be offered to all

24. Cost of Antiviral Suppression Acyclovir - U.S. <$1/day North Carolina - $9.60/ 120 day supply. Famciclovir - ~U.S. $8/day Valacyclovir - U.S.$ 4-8/day North Carolina - ~$30/mo. The Red Book :Pharmacy’s Fundamental Reference 2004

25. HSV Intervention YES WE CAN!