Issues in Genital Herpes Epidemic Spread Continues Most persons are undiagnosed Those who are diagnosed are largely untreated Subclinical Reactivation is common Transmission occurs from such reactivations

Trends in Herpes Simplex Virus 2 Seroprevalence in Persons Aged 12 Years and Older: 1976 vs 1994 Represents 1.6 million infections per year for seroprevalence by age 30% increase Prevalence by age (%) Trends in Herpes Simplex Virus 2 Seroprevalence in Persons Aged 12 Years and Older: 1976 vs 1994 Data from the National Health and Nutrition Examination Survey (NHANES) III showed a 30% increase in the seroprevalence of herpes simplex virus 2 (HSV-2) from 1976 to 1994 among persons 12 years and older. Seroprevalence of HSV-2 increased across all age, gender, and racial/ethnic groups studied More than 1 in 5 Americans (>45 million) 12 years and older in the noninstitutionalized civilian population are infected with HSV-2 Reference: Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med. 1997;337:1105-1111. AW-245 8-13-1996. Fleming DT, et al. N Engl J Med. 1997;337:1105-1111.

Like all other STI’s the Epidemiological and Clinical Morbidity of Genital herpes is similar among those with Infection and those with Disease: This fact applies to the synergism between HSV and HIV as well as the maternal fetal and sexual transmission risks

HSV and HIV HSV 2 seropositivity not clinical disease is the risk factor for increased acquisition . 2 fold increased risk of acquisition demontsrted in over 30 studies HSV-2 seropositivity and not clinical disease is the risk factor for the increased transmission risk HSV seropositivity and not clinical disease is the risk factor for HSV 2’s effects on HIV disease progression

Per Contact Probability of HIV Acquisition, Stratified by HIV RNA (HIV+ partner) and HSV Serostatus in the Susceptible Partner (Rakai,Uganda)

Facts about HSV-2 Infection Essentially all HSV seropositive persons ( 98%) reactivate subclinically (Wald NEJM 2000) 70% of those who are seropositive upon counselling ( college student or video) subsequently recognize they have clinical signs and symptoms which they and their health care providers have ascribed to other diagnoses.(Langenberg Ann.Int Med 1989: Wald STD 1999) Undiagnosed persons transmit infection more quickly to others than those with diagnosed infections; a fact true for maternal fetal as well as sexual partner transmission

Why HSV-2 seropositivity is a Relevant STI In the late 1970s we started to document subclinical (asymptomatic) shedding in symptomatic people (Rattray et al Brit J Ven Dis 1978:54) Initially in women -- cervical shedding Then men -- penile sweep Then women – vulvar sweeps Then men and women -- perianal shedding

The Development of HSV Detection by PCR a Decade ago brought Forth a New Reality Asymptomatic shedding was very very common it. (Krone CID:2000 ,Wald NEJM 2000;Wald JID 2002;Watts;Am J Ob Gyn 2003) it occurred in multiple anatomic sites including perirectal shedding All HSV-2 seropositives shed even low copies of HSV DNA are infectious i.e. have linear genomes and are inhibited by antivirals (Wald JCI 1999;Wald JID 2003)

Transmission of Genital HSV-2 Source Partner Virus in genital secretions: - + Itching: • Sexual Activity X X1 Exposed Partner Cultures: Genital lesions: HSV-2 serology: Date (March 2001): 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 29 HSV DNA/ml 108 107 106 105 104 Notes: 1. Source partner reports irritation during sexual intercourse.

Ratio of Positive PCR/Culture Comparison of Viral Isolation Rates and HSV DNA Detection from Simultaneously Obtained Swab Samples Mean No. of HSV DNA copies Positive Specimens Group Specimens Culture n % PCR n % Ratio of Positive PCR/Culture Total 36,471 1,087 3% 4,415 12% 4.1 4.6

Ratio of Positive PCR/Culture Comparison of Viral Isolation Rates and HSV DNA Detection from 36,471 Simultaneously Obtained Swab Samples Mean No. of HSV DNA copies Positive Specimens Culture n % PCR n % Ratio of Positive PCR/Culture 1,087 3% 4,415 12% 4.1 4.6

Comparison Between HSV Culture and Quantitative PCR

Frequency of HSV-2 Shedding by PCR in Men % of Days HSV DNA Detected # Days Sampled 2333 485 3648 1682

% of Days HSV DNA Detected Frequency of Genital HSV-2 Reactivation in Women HIV-n=188 HIV+n=23 % of Days HSV Isolated % of Days HSV DNA Detected # Days Sampled L. Corey & A. Wald

Interrupting the Transmission of Genital Herpes Vaccines: Hope springs eternal but we are years away Condoms we shall review the data but for persons with sequential monogamy the uptake is limited at best even with intense counselling Antivirals a new case management approach

Reduction in Acquisition by condom use

Results are stratified by sex and are based on reported lifetime condom use at study entry

HSV-2 transmission: STI Clinic Population Cohort of 1843 HSV-2-seronegative persons at risk for HSV-2 by virtue of either >4 partners in the prior 12 months, or one of 6 defined STIs Safer sex counseling at each visit

HSV-2 transmission: STI Clinic Study, Condom Use in Men, n=1275 0.035 0.57 (0.33, 0.96) 0.039 0.56 (0.33, 0.97) Condom use during study, > 65% vs. <65% of sex acts p-value Adjusted Hazard Rati0 Hazard Ratio (95% CI) * Adjusted for age, race, and frequency of sexual activity When used during the study for > 65% of sexual activity condoms were significantly protective for men

Condom Efficacy in Women and Men for Studies Combined, > 25% vs Adjusted HR* 95% CI Women 0.47 (0.26, 0.87) Men 0.63 (0.39, 1.02) *Adjusted for age, race, frequency of sex, and partners with genital herpes When we combined the data for both the serodiscordant monogamous couples and STD Clinic or “multiple partners” studies, we found that reported condom use on protocol in these 18 month studies was associated with relative protection from HSV-2 acquisition. These are the first data to document the protective effect of condom use against HSV-2 acquisition. Interestingly, although we had at the outset postulated that the HSV-2 exposure risk between the two populations would be different (frequent low dose exposure in the couples study vs infrequent higher dose exposure in the risk-taking group), the rates of hSV-2 acquisition did not differ significantly between the two populations.

Valaciclovir to reduce Transmisiion of Genital herpes Corey et al NEJM Jan 1 2004

Time to HSV-2 Infection in Susceptible Partners 5 P=0.039 HR = 0.52 (95% CI 0.27, 0.99) Placebo (n=741) 4 3 Percentage with HSV-2 Infection 2 Valaciclovir (n=743) 1 30 60 90 120 150 180 210 240 Time to HSV Infection(days) Number at Risk P V 741 743 689 693 663 667 627 647 604 623 581 599 562 589 546 572 387 388

Kaplan-Meier Estimates of Time to Overall Acquisition of Genital HSV-2 Infection in Susceptible Partners by Sex 10 Placebo: Female (n=244) 9 8 7 Percentage with HSV-2 Infection 6 5 4 Valaciclovir: Female (n=244) 3 2 Placebo: Male (n=497) 1 Valaciclovir: Male (n=499) 30 60 90 120 150 180 210 240 Time to HSV Infection(days) Number at Risk P V 244/497 244/499 227/462 226/467 219/445 215/452 206/422 209/438 199/407 200/423 192/392 187/412 187/378 186/403 182/367 182/390 135/255 121/267

Factors Influencing Transmission Number (%) of Susceptible Partners Acquiring HSV-2 Infection Valaciclovir, n=743 Placebo, n=741 4/127 (3.1%) 10/613 (1.6%) 10/401 (2.5%) 4/336 (1.2%) 8/137 (5.8%) 19/602 (3.2%) 21/409 (5.1%) 6/326 (1.8%) Duration of genital HSV-2 (source) < 2 yr > 2 yr Duration of relationship < 2.5 yr > 2.5 yr

Condom use and acquisition of symptomatic genital herpes

Condom use and acquisition of HSV-2

Who to treat? High Incidence Partnerships MSM HSV-2 seropositive partners of susceptible pregnant women HIV HSV-2 seropositive personswho are sexually active HSV-2 seropositive person who have recent infection HSV-2 seropositive persons with new sexual relationship

Needed to Treat Serodiscordant pregnant women Seronegative women Chiron Vaccine study Incid: need toRX 19% 11 11.4% 18 8.8% 23

Bottom Line There are “tools” to reduce transmission There is no excuse to keep ignoring genital herpes in STD clinics Screening for HSV-2 seropositivity should be offered to all persons attending an STD / STI clinic. This statement is made both from a case management and population/epidemiological perspective

Disclosure and Honesty If serologic screening is not done then all attendees should be informed that they have between a 30-50% of having an STD that the clinic is not going to assess that this STI increases their risk of HIV acquisition 2 fold and it can be reduced if they do not have it by the use of condoms If they do have HSV-2 infection they can reduce the risk of transmitting it to others by consistent condom use . there are antiviral drugs that can reduce transmission to others by 50%. The drugs need to be taken daily and they take 5 days to reduce shedding to levels associated with presumed efficacy. if you disclose all this it is perhaps ok to decide not to diagnose one of the most frequent STI’s that come through your door