1. 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

2. 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 N Engl J Med. 1997;337: AW
Fleming DT, et al. N Engl J Med. 1997;337:

3. 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

4. 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

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

6. 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

7. 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

8. 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)

9. 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.

11. 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

12. 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

13. Comparison Between HSV Culture and Quantitative PCR

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

15. % 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

16. 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

17. Reduction in Acquisition by condom use

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

20. 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

21. 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

22. Condom Efficacy in Women and Men for Studies Combined, > 25% vs
Adjusted HR* % CI
Women (0.26, 0.87)
Men (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.

23. Valaciclovir to reduce Transmisiion of Genital herpes
Corey et al NEJM Jan

24. Time to HSV-2 Infection in Susceptible Partners5
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

25. 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

26. 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

27. Condom use and acquisition of symptomatic genital herpes

28. Condom use and acquisition of HSV-2

30. 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

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

32. 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

33. 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