Transcript Document

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
25
30%
increase
20
15
Prevalence
by age (%) 10
5
0
1976
1994
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
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
HSV
DNA/ml
Exposed Partner
Genital lesions:
108
+
Cultures:
• • • • • • • • • •
HSV-2 serology:
-
107
+
106
105
Date (March 2001): 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Notes: 1. Source partner reports irritation during sexual intercourse.
29
104
Comparison of Viral Isolation Rates and
HSV DNA Detection from 36,471 Simultaneously
Obtained Swab Samples
Positive Specimens
Culture
n
%
1,087
3%
PCR
n
%
4,415
12%
Ratio of
Positive
PCR/Culture
4.1
Mean No.
of HSV
DNA
copies
4.6
Comparison Between HSV Culture
and Quantitative PCR
100%
Women
Men
Percent culture positive
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
2
3
4
5
6
7
Log HSV DNA/ml
8
9+
Frequency of HSV-2 Shedding
by PCR in Men
% of Days HSV DNA
Detected
40
35
30
25
20
15
10
5
0
Heterosexual
Men
# Days Sampled 2333
MSM HIV-
485
MSM HIV+
3648
MSM HIV+
HAART
1682
Frequency of Genital HSV-2
Reactivation in Women
20
40
% of Days HSV DNA
Detected
% of Days HSV
Isolated
HIV-n=188
HIV+n=23
15
30
10
20
5
10
0
0
17,959
647
4,498
700
# 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
1.0
0.4
0.6
0.8
Reduction in
Acquisition by
condom use
0.0
0.2
Women with Condom Use<=50%
Men with Condom Use<=50%
Women with Condom Use>50%
Men with Condom Use>50%
0
100
200
300
# of sex acts
400
500
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
Hazard Ratio
(95% CI)
Condom use
during study, >
65% vs. <65% of
sex acts
Adjusted
Hazard Rati0
pvalue
0.56
0.039
0.57
0.035
(0.33, 0.97)
(0.33, 0.96)
* 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. <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
Valaciclovir to reduce
Transmisiion of Genital
herpes
Corey et al NEJM Jan 1 2004
Time to HSV-2 Infection in Susceptible Partners
Percentage with HSV-2
Infection
5
Placebo (n=741)
P=0.039
4
HR = 0.52 (95% CI 0.27, 0.99)
3
2
Valaciclovir (n=743)
1
0
0
30
Number at Risk
P
741
689
V
743
693
60
90
120
150
180
210
240
546
572
387
388
Time to HSV Infection(days)
663
667
627
647
604
623
581
599
562
589
Kaplan-Meier Estimates of Time to Overall Acquisition of
Genital HSV-2 Infection in Susceptible Partners by Sex
Percentage with HSV-2
Infection
10
Placebo: Female (n=244)
9
8
7
6
5
4
Valaciclovir: Female (n=244)
3
2
Placebo: Male (n=497)
1
Valaciclovir: Male (n=499)
0
0
Number at Risk
P
V
30
60
90
120
150
180
210
240
Time to HSV Infection(days)
244/497 227/462 219/445 206/422 199/407 192/392 187/378 182/367 135/255
244/499 226/467 215/452 209/438 200/423 187/412 186/403 182/390 121/267
Factors Influencing Transmission
Number (%) of Susceptible Partners Acquiring HSV-2 Infection
•
Placebo, n=741
4/127 (3.1%)
10/613 (1.6%)
8/137 (5.8%)
19/602 (3.2%)
10/401 (2.5%)
4/336 (1.2%)
21/409 (5.1%)
6/326 (1.8%)
Duration of genital HSV-2
(source)
– < 2 yr
– > 2 yr
•
Valaciclovir, n=743
Duration of relationship
– < 2.5 yr
– > 2.5 yr
Percent of participants with
symptomatic genital herpes
Condom use and acquisition
of symptomatic genital herpes
3
2.5
2
Placebo
Valaciclovir
1.5
1
0.5
0
Never
Sometimes
Always or
almost
always
Frequency of condom use
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