Transcript Do Beta Blockers Still Have a Place in the First Line

Genital Herpes:
Framing the Problem,
Diagnosing the
Disease
Prevention and Management
for Healthcare Providers
Genital Herpes: Epidemiology and
Clinical Presentation
STDs are Sexist

Transmission efficiency greater male to female
than the reverse

More women asymptomatic or with atypical,
nonspecific symptoms; delayed care


Diagnosis more difficult in women
Complications more frequent in women, often
severe or permanent
Herpes Simplex Virus
 Mucocutaneous infection, retrograde
infection of sensory nerves, continuous slow
replication (with clinical latency) in cranial or
spinal ganglia and peripheral nerve endings,
mucocutaneous recurrences
 HSV-1
− Mostly orolabial (cold sores, fever blisters)
− 20%-50% of initial genital herpes in North America and
western Europe
 HSV-2
− Almost entirely genital; oral infection uncommon
− >90% of recurrent genital herpes
Prevalence of Genital HSV Infection in
Adults in the United States
•
•
•
•
HSV-2, NHANES-II (1978)
HSV-2, NHANES-III (1991)
HSV-2, NHANES 1999-2004
Genital HSV-1 infection
• TOTAL
Total
Xu F et al. JAMA. 2006;296:964-973.
18
16% (15M age 15-49)
22% (24M age 15-49)
17% (27M age 15-49)
10 million (??)
>20%
~30%
>30 million
17
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"
96%
Acquiring AIDS
68%
Having genital herpes
Breaking up with a
significant other
Getting fired from a
job
Failing a course in
school
54%
51%
28%
Genital Herpes
and HIV Transmission
 HSV-2 infection is the most important STD in enhancing
HIV transmission efficiency; may account for up to half of
all HIV infections
 HSV-2 infected persons have 2–4x increased chance of
acquiring HIV if sexually exposed
 Persons with HIV and symptomatic genital herpes are
more efficient HIV transmitters
 HSV-2 serologic testing should be routine in persons with
HIV or at high risk (men having sex with men, intravenous
drug users, and their partners) [controversial]
Relative Risk of HIV Acquisition in HSV-2
Positive vs HSV-2 Negative Persons
Freeman EE et al. AIDS. 2006;20:73-83.
Clinical Spectrum of Genital Herpes
 First episode infection
− Primary: First infection with HSV-1 or -2 (~20%)
− Nonprimary first episode: Prior infection with the
opposite HSV type (~40%)
− First recognized episode of longstanding infection
(~40%)
 Recurrent infection: Second or subsequent
outbreak (HSV-2 >> HSV-1)
 Subclinical infection: ~60%–90% of infections
− Truly asymptomatic
− Unrecognized
Clinical Manifestations of Genital Herpes
 Initial infection
− Vesiculopustular lesions (bilateral)
− Cervicitis, urethritis
− Lymphadenopathy
− Neuropathic manifestations
− Systemic inflammation (fever, etc)
− Duration typically 2–4 weeks
 Recurrent outbreaks
− Unilateral lesions
− Nonspecific symptoms (discharge, dysuria, etc)
− Neuropathic prodrome
− Duration 1–2 weeks
 Common misdiagnoses
− Vulvovaginal candidiasis and other vaginal infections
− Syphilis, chancroid
− Urinary tract infection
− Genital trauma
Biomedical Complications
of HSV Infection
 Localized neuropathies (eg, bladder paralysis)
 Meningitis (isolated, recurrent)
 Erythema multiforme, Stevens Johnson syndrome
 Perinatal and maternal morbidity
−Neonatal herpes
−Cesarean section
 Autoinoculation conjunctivitis, keratitis, whitlow
 Chronic localized disease in immunodeficient patients
(especially HIV/AIDS)
 Enhanced HIV transmission
 Rare disseminated infection, hepatic necrosis, death
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
− Women




5.2 episodes/yr
4.0 episodes/yr
>6 recurrences in first year
38%
>10 recurrences in first year
20%
Rate gradually declines over several years
Recurrence after initial genital HSV-1 (N = 83)
− Mean recurrences 1.3 yr 1, 0.7 yr 2, & beyond
− 38% had no recurrences
Diamond C, et al. Sex Transm Dis. 1999;26:221-225.
Engelberg R, et al. Sex Transm Dis. 2003;30:174-177.
What Triggers Recurrent Outbreaks?
 Oral HSV-1
− Other infections ('cold sore,' 'fever blister')
− Actinic/ultraviolet injury
− Other local trauma (eg, 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
Asymptomatic Viral Shedding in
Transmission and Acquisition of HSV-2
Peter A. Leone, MD
Associate Professor of Medicine
University of North Carolina
Chapel Hill, North Carolina
Medical Director
North Carolina HIV/STD Prevention and
Care Branch NCDHHS
Asymptomatic Viral Shedding
 Asymptomatic viral shedding (AVS) is the
presence of HSV on the surface of the
skin/mucosa in the absence of signs and
symptoms[1-3]
1. Corey L, Wald A. Sex Transm Dis. 1999;285-312.
2. Wald A, et al. N Engl J Med. 1995;333:770-775.
3. Mertz GJ, et al. Ann Intern Med. 1992;116:197-202.
Key Facts for Patients




Patients frequently spread GH between outbreaks[1]
Most patients shed virus asymptomatically*[2]
Patients cannot predict when AVS will occur[3]
All patients are at risk for AVS, regardless of outbreak
frequency[3]
 Recent data suggest shedding is a more continuous process
than previously realized
 Safer sex practices should be used
− Even with safer sex , it is still possible to transmit HSV
− Condoms cannot provide 100% protection against transmission,
they do not cover all potential sites of HSV shedding
*Shedding in the absence of lesions
1. Corey L, Wald A. Sex Transm Dis. 1999:285-312.
2. Wald A, et al. N Engl J Med. 1995;333:770-775.
3. Mertz GJ, et al. Ann Intern Med. 1992;116:197-202.
Asymptomatic Viral Shedding Is
Common and Can Occur Frequently
 Most GH patients experience asymptomatic shedding*
 PCR has a ~3-4 times higher detection rate than culture
Asymptomatic
Shedding
Via Culture†
Via PCR†
% of patients
with ≥ 1 day
51%-61%
72%-88%
% of days
2.0%- 6.6%
7.8%- 27%
PCR = polymerase chain reaction; *shedding in the absence of lesions; †shedding rates
can vary based upon time since diagnosis, frequency of recurrences, method of detection,
frequency/site of sampling
Gupta R, et al. J Infect Dis. 2004;190:1374-1381.
Wald A, et al. N Engl J Med. 1995;333:770-775.
Corey L, et al. N Engl J Med. 2004;350:11-20.
Viral Shedding Patterns Are Unpredictable
and Influenced by Therapy
Wald A, et al. J Clin Invest. 1997;99:1092-1097.
Up to 70% of Transmission May Occur
During Asymptomatic Viral Shedding
 9.7% of patients infected their partner (14/144)
 Transmission frequently occurs between outbreaks
Transmission
during asymptomatic
viral shedding
Up to
70%
Total
18
~30%
17
Transmission
during symptomatic
outbreaks
Mertz GJ, et al. Ann Intern Med. 1992;116:197-202.
Asymptomatic Viral Shedding* Can Occur
Regardless of Outbreak Frequency
Post-hoc analysis from a randomized, double-blind, placebo-controlled shedding substudy (n = 89) where 50 patients were given
placebo once daily and followed for 60 days. Enrolled patients had a history of 0 to 9 recurrences/year and had been infected for
a median of 6 years.
*Shedding in the absence of lesions.
*Shedding in the absence of lesions
Summary of Asymptomatic
Viral Shedding


Infection = Shedding

AVS does decrease with time but remains
high over time

AVS driving force for transmission
Asymptomatic viral shedding (AVS) is
frequent and difficult to predict when and
where
Genital Herpes: Diagnosis
H. Hunter Handsfield, MD
University of Washington
Etiology of Genital Ulcer Disease
 516 patients with genital ulcer disease from STD clinics
in 10 of 11 US cities w/ highest syphilis rates
 Excluded patients with typical herpes
 PCR for HSV, Treponema pallidum, Haemophilus
ducreyi
HSV
333 (64.5%)
Syphilis
64
(12.4%)
HSV + Syphilis
13
(2.5%)
Chancroid
16
(3.1%)
PCR negative
16
(22.4%)
Mertz K, et al. J Infect Dis. 1998;178:1795-1798.
Diagnosis of Genital Herpes
 Test all genital ulcers for HSV, including
clinically obvious genital herpes
− Clinical diagnosis insensitive and nonspecific
− Virus type determines clinical prognosis,
transmission, and counseling
 Virologic tests
−
−
−
−
PCR is test of choice; increasingly available
Culture: The primary test in most settings
Direct FA: Some don't provide virus type
Cytology (Tzanck prep): Insensitive, no virus type; do
not use
 Serologic testing: Use only glycoprotein G (gG)based assays
North Carolina Dx
•
•
•
•
Culture all genital lesions for HSV
Obtain TRUST/RPR/EIA
HIV Test
Negative culture does not rule out HSV
• May offer Type-specific serologic test
Type-Specific HSV Serologic Tests
Antibody to HSV-1 or -2 glycoprotein G (gG-1 or gG-2)
 Western blot
− The gold standard
 Focus Technologies (now a subsidiary of Quest
Diagnostics) HerpeSelect HSV-1 and HSV-2
ELISA
− Sensitivity for HSV-2 ~90%, specificity ~98%
 Focus Technologies HerpeSelect HSV-1 and
HSV-2 Differentiation Immunoblot
− Same antigen as ELISA, probably similar performance
 Trinity Biotech Captia Type Specific HSV-1 nad
HSV-2 ELISA
 Biokit USA biokitHSV2
− Point of care
− HSV-2 only
Interpreting HSV-2 HerpeSelect
 The numerical value is the ratio between the
test optical density (OD) and control, not a titer
─ <0.9
─ 0.9–1.1
─ 1.1–3.5
─ >3.5
Negative
Equivocal
Positive, but influenced by
HSV-1
Unequivocally positive
 Notes
− Varying values below 0.9 are meaningless
− Some values 1.1–3.5 are false positive if HSV-1
antibody is present
HSV IgM Testing is Not Clinically
Useful
 Not type specific
 Does not distinguish early from late
infection
 False-positive results common
 There is no valid indication for use in
adults
Options for Confirmatory Testing
of the Focus HSV-2 ELISA




Western blot
Focus immunoblot?
Focus ELISA avidity assay?
Commercial confirmatory tests (rumors)
− Focus
− Others?
 Repeat/convalescent testing
Probability of Remaining Seronegative
Time to HSV-2 Seroconversion
1.0
0.8
Western Blot
0.6
0.4
Focus
0.2
0.0
0
20
40
60
80
100
120
Days From Primary Episode
140
160
Uses of Type-Specific HSV Serology
Definite Indications
 Diagnosis of GUD, recurrent symptoms, etc
 Management of sex partners of persons with herpes
 Persons with or at risk for HIV acquisition
Other Uses
 Selected (all?) pregnant women and their partners
 Patient request
− Request to test for herpes
− Comprehensive STD evaluation
Do Not Use Routinely to Screen All Sexually
Active Persons (controversial)
Prevention and Available and Emerging
Treatments for HSV-2 Infection
Peter A. Leone, MD
University of North Carolina
Transmission Reduction:
What Can Be Done?
 Advise patients to avoid sexual contact during
outbreaks
Transmission Reduction:
What Can Be Done?
 Advise patients to avoid sexual contact during
outbreaks
 Inform patients about transmission risk during
periods of asymptomatic shedding
Transmission Reduction:
What Can Be Done?
 Advise patients to avoid sexual contact during
outbreaks
 Inform patients about transmission risk during
periods
of asymptomatic shedding
 Offer suppressive therapy to patients as an
option
Suppressive Antiviral Therapy
to ReduceTransmission Risk
Proportion of Susceptible Partners
With Overall Acquisition of HSV-2 Infection
% with HSV-2 Infection
4
3.6%
(27/741)
3
48% reduction
P = .054
RR: 0.52 (95% CI: 0.27,0.97)
HR for Kaplan-Meyer Analysis
P = .039
1.9%
2
(14/743)
1
0
Placebo
Valacyclovir
500 mg once daily
Adapted from Corey L, et al. N Engl J Med. 2004;350:11-20.
Proportion of Susceptible Partners
With Symptomatic Genital Herpes
2.5
% with Symptomatic GH
2.2%
2
(16/741)
75% reduction
P = .01
RR: 0.25 (95% CI: 0.08,0.74)
1.5
1
0.5%
0.5
(4/743)
0
Placebo
Valacyclovir
500 mg once daily
Adapted from Corey L, et al. N Engl J Med. 2004;350:11-20.
CDC Sexually Transmitted Diseases
Treatment Guidelines and ACOG
Recommend Daily Therapy
•CDC: Discordant couples should be encouraged
to consider suppressive antiviral therapy as a part
of a strategy to prevent transmission, in addition
to consistent condom use and avoidance of sexual
activity during recurrences
•ACOG: For couples in which 1 partner has HSV-2
infection, suppressive* antiviral therapy should
be recommended for the partner with HSV-2 to
reduce the rate of transmission
Centers for Disease Control and Prevention. MMWR Recomm Rep. 2006;55(R-11):1-94.
*ACOG recommends valacyclovir 500-1000 mg daily for suppressive therapy.
ACOG Practice Bulletin. Obstet Gynecol. 2004;104:1111-1117.
Interventions for HSV
• Beneficial
– oral antiviral therapy in first episodes
– oral antiviral therapy at a start of
recurrence
– daily antiviral therapy to control disease
and/or reduce risk of transmission
Wald, Clinical Evidence
‘99
Which Patients Should Receive
Episodic Antiviral Therapy?
• First clinical episodes of genital herpes

All patients
• Recurrent episodes


Clinically significant benefit (20 - 30%
decreased duration) from recurrent therapy
Prolonged episodes
Optimizing episodic HSV Rx
• Self -initiation of therapy important
• Medication needs to be available to
patient
• Acyclovir can be dosed 3x/day - no
clinical trials data, but plenty of
experience
Initial Episode
• Acyclovir
• 400 mg t.i.d. or 200 mg 5 times/d for 7 to 10
days
• Famciclovir
• 250 mg t.i.d. for 7 to 10 days
• Valacyclovir
• 1 g b.i.d. for 7 to 10 days
Treatment Options:
Episodic Therapy
• Reduces the duration of recurrence
5-Day
Regimens
Shorter
Regimens
Acyclovir
400 mg t.i.d.
800 mg b.i.d.
800 mg t.i.d. for 2 days
Famciclovir
125 mg b.i.d.
1 g b.i.d. for 1 day
Valacyclovir
1 g q.d.
500 mg b.i.d. for 3 days
Centers for Disease Control and Prevention. MMWR Recomm Rep 2006;55(RR-11):1-93.
2006 CDC STD Treatment Guidelines
Genital Herpes: Suppressive Therapy
• Acyclovir 400 mg BID
• Famciclovir 250 mg BID
• Valacyclovir 0.5-1.0 g qd
North Carolina
Offer 4 months suppression with
acyclovir to those with documented
first episode HSV-2
Candidates for Antiviral
Suppressive Therapy
In HSV 2-Infected Patients
Use Antiviral Suppressive
Therapy Primarily to
Control
Disease
Reduce
Transmission
With new infection
√
√
With bothersome outbreaks
√
Who are immunocompromised
√
Who are in late pregnancy
√
Who are distressed by the diagnosis
√
With a sexual partner who is
uninfected or has an unknown HSV
status
√
With multiple sexual partners
√
Treatment Options:
Suppressive Therapy
Possible dosing regimens¹:
−Acyclovir
400 mg b.i.d.
−Famciclovir
250 mg b.i.d.
−Valacyclovir
500 mg q.d. or (for >10 occurrences/year)
1 g q.d.
Centers for Disease Control and Prevention. MMWR Recomm Rep 2002;51(RR-6):1-78.
Transmission Reduction:
What Can Be Done?
 Advise patients to avoid sexual contact during
outbreaks
 Inform patients about transmission risk during
periods of asymptomatic shedding
 Offer suppressive therapy to patients as an
option
 Encourage patients to share their HSV status
with their sexual partners
 Promote condom use
Transmission Reduction:
Disclosure to Sexual Partners
 A recent study found that a
strong protective factor
against genital HSV-2
acquisition was partner
disclosure of genital herpes
 Median time to transmission
nondisclosers: 60 days
vs
disclosers: 270 days P = .03
Wald A, et al. J Infect Dis. 2006.
SHARING
Condom Sense
 Condoms appear ~ 50% protective against
HSV-2 acquisition in men and in women.
 Evidence for condoms' efficacy will always be
measured indirectly
Wald A, et al. Ann Intern Med 2005;143:707-713.
Wald A, et al. JAMA 2001;285:3100-3106.
Gottlieb SL, et al. J Infect Dis 2004;190:1059-1067.
What Is on the Horizon?
 Herpes Vaccine for Women
− Enrollment completed Sept. 2007
− Study to be completed 2010
− Earlier studies showed a 75% reduction in HSV
acquisition of genital herpes in vaccinated women
 New Therapy
− A new class of potent inhibitors of HSV that targets
the virus helicase primase complex (BAY 571293). Entering clinical phase II trials
Conclusions
 Genital herpes is common and underrecognized
 Shedding is the norm
 Treat to control disease and/or transmission