Genital Herpes: Epidemiology and Public Health Perspectives H. Hunter Handsfield, M.D. Professor of Medicine University of Washington Director, STD Control Program Public Health - Seattle & King county

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) 20-50% of initial genital herpes HSV-2 Almost entirely genital; oral infection rare >90% of recurrent genital herpes

Genital Herpes: Initial Visits to Physician’s Offices, 1966-2000 Visits x 1,000 STD Surveillance 2000: National Disease and Therapeutic Index Year

Estimated Annual Incidence of STDs in the United States HIV 40,000 Syphilis 70,000 Hepatitis B 77,000 Gonorrhea 650,000 Genital herpes 1 million Chlamydia 3 million Trichomoniasis 5 million HPV 5.5 million Total annual incidence 15 million Kaiser Family Foundation and American Social Health Association. 1998.

Estimated Prevalences of Leading STDs HIV (560,000) Hepatitis B (750,000) Chlamydia (3 million) HPV (20 million) Herpes (45-60 million) Kaiser Family Foundation and American Social Health Association. 1998.

HSV-2 Seroprevalence in Men and Women NHANES II and III

Prevalence of Genital HSV Infection in Adults in the United States HSV-2, NHANES-II (1978) 16% HSV-2, NHANES-III (1991) 22% 45 million HSV-2 since 1991 5-15 million (?) Total HSV-2 50-60 million Genital HSV-1 infection 10 million (??) TOTAL 25-30% >60 million

Perceived Trauma of Contracting Genital Herpes I’m going to read you a list of items that people may or may not consider traumatic. For each one I read, please tell me how traumatic it would be for you personally: very traumatic, somewhat traumatic, not very traumatic, or not traumatic at all. Percent Saying “Very Traumatic” Acquiring AIDS Having genital herpes Breaking up with a significant other Getting fired from a job Failing a course in school

National STD Hotline Disease-Specific Calls, 1997 No. Calls Percent Genital herpes 63,484 47 HPV/warts 33,533 25 Chlamydia 17,341 13 Gonorrhea 11,300 8 Syphilis 8,753 7 Total 134,411

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 Subclinical infection Truly asymptomatic Unrecognized

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 rate much lower for genital HSV-1

Natural History of Genital HSV-1 Infection 83 pts (53 F, 30 M) with primary GH due to HSV-1 Followed >6 mo; median 2.7 yr Recurrences in 1st year 0 38% 1 35% >2 27% Days to first recurrence Median 223 d; CI95 170-335 d Mean recurrence rate Mean rate/yr (range) Yr 1 1.30 (0-8) Yr 2 0.70 (0-5) Yr 3 0.69 (0-4) Wald A et al, Abstract 442 IDSA 39 Oct 25-29, 2001

What Triggers Recurrent Outbreaks? Oral HSV-1 Other infections (“cold sore”, “fever blister”) Actinic/ultraviolet injury Other local trauma (e.g., surgery) Genital HSV-2 No clearly documented triggers No good data support stress, diet, menstruation, sex, etc, despite anecdotal reports and strongly held beliefs to the contrary

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

Association of HSV-2 Antibody with HIV Seroconversion in 9 Prospective Cohort and Nested Case-control Studies Wald A, Link K. J Infect Dis January 2002

Probability of HIV Transmission in 174 Monogamous Couples: Rakai, Uganda Wawer M, Gray R, Quinn TC, et al Int’l Retrovirus Meeting 2001

Genital Herpes and HIV Transmission Other things being equal, HSV-2 seropositive persons have twice the chance of acquiring HIV if sexually exposed On a population basis, HSV-2 infection may be most important STD in the U.S. and worldwide in enhancing HIV transmission efficiency Persons at high risk for HIV (MSM, IDU, and their sex partners) should routinely be offered HSV-2 serological testing and, if positive, counseled about the elevated HIV risk

Subclinical Viral Shedding in Genital Herpes Present 1-10% (PCR 5 - 30%) of asymptomatic days in persons with RGH due to HSV-2 Max frequency (5-10% of days, PCR 20-30%) in first year, then declines; but probably 2-3% of days (PCR 4-6%) for many years >95% of persons with HSV-2 have Asx shedding Similar frequency in persons with and without Sx Most episodes are symptomatic but unrecognized Accounts for most transmission Substantially reduced by suppressive antiviral therapy (frequency, viral titer) Uncommon in genital HSV-1 infection

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)

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Mean change from baseline Mean Change From Baseline Recurrent Genital Herpes Quality of Life Score 2 4 6 8 10 12 14 16 3 mo 6 mo 12 mo Mean Change and 95% CI Mean change from baseline Treatment group Valacyclovir 250 mg BID Acyclovir 400 mg BID Valacyclovir 250 mg QD Valacyclovir 500 mg QD Valacyclovir 1000 mg QD Placebo Patel et al. Sex Transm Infect. 1999;75:398

Transmission of Genital Herpes Langenberg AGM, et al Transmission of Genital Herpes Langenberg AGM, et al. NEJM 1999;341:1432-8 Chiron vaccine studies of HSV-2 seronegative persons Monogamous partners of persons with HSV-2 (N = 531) STD clinic patients with bacterial STD in past year or >4 partners in past year (N = 1,862) Follow-up: 11 visits at 2 wk to 3 mo intervals x 18 mo History, genital exam, HSV serology (Western blot), viral cultures of lesions Repeated safer sex counseling Outcome measures Primary: HSV-2 seroconversion Secondary: HSV-1 infection, clinical disease Vaccine and placebo recipients combined Acquisition rates similar in both studies, results combined

Transmission of Genital Herpes Langenberg AGM, et al Transmission of Genital Herpes Langenberg AGM, et al. NEJM 1999;341:1432-8 155 incident HSV-2 infections: 57 (37%) Sx, 98 (63%) Asx 19 incident HSV-1 infections Rate per 100 Person-Yr Infection Type Person-Yr Asx Sx Total Total HSV-2 3,015 3.2 1.9 5.1 Men 2,086 3.0 1.4 4.4 Women 929 3.8 3.0 6.8 HSV-1 pos 1,868 3.6 1.4 5.1 HSV-1 neg 1,147 2.6 2.6 5.2 Total HSV-1 1,170 0.6 1.0 1.6

Transmission of Genital Herpes Langenberg AGM, et al Transmission of Genital Herpes Langenberg AGM, et al. NEJM 1999;341:1432-8 Clinical misdiagnosis was common (20%) 13% of incident symptomatic infections were atypical (e.g., urethritis, cystitis, cervicitis, meningitis) 15% of asx seroconverters subsequently developed clinically evident disease (likely an underestimate) Half the HSV-1 infections were genital, half oral Incident infection was associated with young age (<30 yr) in women, but not men Incident infection was 2-3 times more common in nonwhites than whites Prior HSV-1 ameliorated incident HSV-2 (more asx infection) but did not influence acquisition rate Study design probably reduced infection rate

Other Factors in Genital Herpes Transmission Condom use Avoidance of sex when symptomatic Shorter duration of infection Shorter duration of relationship Sexual practices (vaginal, anal, orogenital; interaction with virus type) Circumcision status? Pregnancy? Immunodeficiency and/or HIV status?

Protection Against HSV-2 by Condoms Wald et al, JAMA 2001;3100-6 528 monogamous HSV-2-discordant couples 261 HSV-2-neg men, 267 HSV-2-neg women 18 mo. follow-up Relative transmission risk (hazard ratio) among couples with >25%condom use vs <25% use Male to female 0.085 (CI95 0.01-0.67) Female to male 2.02 (CI95 0.32-12.5)

Protection Against HSV-2 by Condoms Wald et al, National STD Prevention Conference, San Diego, CA, 2002: Abstract LB1 1,852 HSV-2-seronegative heterosexual M & F At risk for STD (>4 ptr or Hx of STD in past yr) 18 mo. follow-up Relative HSV-2 infection risk (hazard ratio) among persons with >65%condom use vs <65% use Men 0.58 (CI95 0.37-0.92) Women 0.66 (CI95 0.30-1.46)

Efficacy of Condoms in Preventing Genital Herpes: Summary Male Condom Partially effective; previous controversy notwithstanding, probably about equally effective for M F and F M Variable acceptability Probably most important in first 6-12 mo Female Condom Might be more effective (larger surface area covered) but no data available Low acceptability

Abstinence During Symptoms to Prevent Sexual Transmission of HSV Among HSV-2-discordant couples, transmission is less frequent in aware than in unaware couples Requires awareness of infection and recognition of symptoms Partially effective: Used successfully by many couples for several years Studied primarily for overt recurrent herpes in ongoing partnerships However, no data in serologically diagnosed persons counseled to recognize symptoms Likely less effective in new relationships or when infection is recent

Counseling Patients with Newly Diagnosed Genital Herpes Natural history of the disease Potential for recurrences Subclinical shedding Availability and efficacy of suppressive therapy Inform current and future sex partners Availability of type-specific serological testing to diagnose partner and assess risk of acquisition How to reduce transmission risk Avoid sex when symptomatic Condoms Antiviral therapy? Importance and avoidance of neonatal infection

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 Underutilization of type-specific serological testing Undertreatment Poor understanding of psychosocial impact Preventing neonatal herpes and maternal perinatal morbidity