# Presentation: 552817

## 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

- Prevalenceby age (%)

**30% increase**

**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**

- Fleming DT, et al. *N Engl J Med*. 1997;337:1105-1111.

**Notes:**
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.

## 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 |  | 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 |  |

- Notes: 1. Source partner reports irritation during sexual intercourse.

| HSV DNA/ml |  |  |
| --- | --- | --- |
|  | 108 |  |
|  | 107 |  |
|  | 106 |  |
|  | 105 |  |
|  | 104 |  |
|  |  |  |

## Slide 10

## Comparison of Viral Isolation Rates and         HSV DNA Detection from Simultaneously Obtained Swab Samples 

**Total**

**36,471**

**1,087**

**3%**

**4,415**

**12%**

**4.1**

**4.6**

**Group**

**Specimens**

**Culture**
**n         %**

**PCR**
**n           %**

**Ratio of Positive PCR/Culture**

**Mean No.**
**of HSV DNA copies**

_**Positive Specimens**_

## Comparison of Viral Isolation Rates and         HSV DNA Detection from  36,471 Simultaneously Obtained Swab Samples 

**1,087**

**3%**

**4,415**

**12%**

**4.1**

**4.6**

**Culture**
**n         %**

**PCR**
**n           %**

**Ratio of Positive PCR/Culture**

**Mean No.**
**of HSV DNA copies**

_**Positive Specimens**_

## Comparison Between HSV Culture and Quantitative PCR

## Frequency of HSV-2 Shedding by PCR in Men

**% of Days HSV DNA Detected**

**2333**

**485**

**3648**

**1682**

**# Days Sampled**

## Frequency of Genital HSV-2 Reactivation in Women

**% of Days HSV Isolated**

**# Days Sampled**

**% of Days HSV DNA Detected**

- HIV-n=188
- HIV+n=23

- 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 

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

## Slide 19

## 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

- When used during the study for > 65% of sexual activity condoms were significantly protective for men

- * Adjusted for age, race, and frequency of sexual activity

## Condom Efficacy in Women and Menfor Studies Combined, > 25% vs. <25%

- <date/time>

- Condom Efficacy in Women and Menfor Studies Combined, > 25% vs. _<_25%

- 		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

**Notes:**
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

- Time to HSV Infection(days)

- Percentage with HSV-2 Infection

- Placebo (n=741)

- Valaciclovir (n=743)

**0**

**1**

**2**

**3**

**4**

**5**

**0**

**30**

**60**

**90**

**120**

**150**

**180**

**210**

**240**

**741**
**743**

**689**
**693**

**663**
**667**

**627**
**647**

**604**
**623**

**581**
**599**

**562**
**589**

**546**
**572**

**387**
**388**

**P**
**V**

**Number at Risk**

***P*****=0.039**
**HR = 0.52 (95% CI 0.27, 0.99)**** **

## Kaplan-Meier Estimates of Time to Overall Acquisition of Genital HSV-2 Infection in Susceptible Partners by Sex

- Time to HSV Infection(days)

- Percentage with HSV-2 Infection

- Placebo: Female (n=244)

- Valaciclovir: Female (n=244)

- Placebo: Male (n=497)

- Valaciclovir: Male (n=499)

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**0**

**30**

**60**

**90**

**120**

**150**

**180**

**210**

**240**

**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**

**P**
**V**

**Number at Risk**

## Factors Influencing Transmission

**Duration of genital HSV-2 (source)**
**< 2 yr**
_**>**_** 2 yr**
**Duration of relationship**
**< 2.5 yr**
_**>**_** 2.5 yr**

**   **
** ****4/127 (3.1%)**
**10/613 (1.6%)**
**10/401 (2.5%)**
**  ****4/336 (1.2%)**
**  **

**Valaciclovir, n=743**

** **
**  **
**8/137 (5.8%)**
**19/602 (3.2%)**
**21/409 (5.1%)**
**  ****6/326 (1.8%)**
**  **

**Placebo, n=741**

***Number (%) of Susceptible Partners Acquiring HSV-2 Infection***

## Condom use and acquisition of symptomatic genital herpes

## Condom use and acquisition of HSV-2

## Slide 29

## 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   **