HSV - CECentral.com

Report
UPDATE:
GENITAL HERPES
SIMPLEX VIRUS INFECTION
Nick Van Wagoner, MD, PhD
University of Alabama at Birmingham
Webinar
NICK VAN WAGONER: DISCLOSURES


Will not discuss off-label use of commercial
products and/or services
No commercial interest or affiliations
LEARNING OBJECTIVES
BY THE END OF THE LECTURE:
1.
Reviewed HSV-2 epidemiology in the U.S.
2.
Understand the pathogenesis of HSV-2
3.
Identify the clinical manifestations of HSV-2
4.
Choose appropriate test(s) for HSV-2 diagnosis
5.
Discuss the management of HSV-2
6.
Introduce new research in HSV-2 prevention and
treatment
1.
2.
3.
4.
5.
6.
Genital Herpes is the most prevalent STD in the
U.S.
Life-long infection
Sexually transmitted
Most people don’t know their infected
Viral shedding occurs in the absence of symptoms
Transmission usually occurs when symptoms are
absent
EPIDEMIOLOGY
GENITAL HSV IN THE U.S.
HSV IS THE MOST PREVALENT STD IN THE US
Over 1 million new
genital herpes
infections occur each
year.
Centers for Disease Control and Prevention: available at http:/www.cdc.gov
Xu et al. JAMA. 2006: 296: 964-973
Leone, Update on Epidemiology and Treatment Strategies for Genital Herpes. 2008
SEROPREVALENCE OF HSV-2, NHANES, 20052008
 Overall


Seroprevalence: 16.2%
Women: 20.9%
Men: 11.9%
MMWR. 2010.59(15):456
HSV RISK FACTORS
Biology
Gender
Race
Male Circumcision
Age
Sociodemographics
Income
Living conditions
Sexual Networks
Behavior
No. of Partners
Early Sexual Debut
Drug Use
XU et al., JAMA. 2006. 296: 964-973
Newman, STD. 2008. 35: S4-S12
UNKNOWN HSV-2 INFECTION
Men Attending the JCHD
HSV-2 Positive
Know it
HSV-2 Positive
Don’t know it
HSV-2 Negative
~80-90% of people that test positive for HSV-2 in the U.S
are unaware that they
are
infected
Xu et al. JAMA. 2006: 296: 964-973, MMWR. 2010.59(15):456
PATHOGENESIS
VIROLOGY: HSV-1 AND HSV-2

Members of the human herpes
virus family (herpetoviridae).
Genome: ~154,000 bp DS DNA
 HSV-1 and HSV-2 50% Identical

Todar. Ken Todar’s Microbial World. U of Wisconsin. 2006

HSV-2 causes about ½ of genital
ulcers

The other ½ are caused by HSV-1
Dwyer and Cunningham. MJA 2002 177(5): 267-273
Asymptomatic
Infection
Gupta et al., Lancet 2007
HSV GENITAL/ANOGENITAL
TRANSMISSION

Sexual
Receptive Vaginal--Insertive Vaginal
 Receptive Anal--Insertive Anal
 Receptive Oral (HSV-1)



Efficiency of sexual transmission: greater from
men to women
Likelihood of transmission declines with duration
of infection
DEFINITIONS OF FIRST CLINICAL
EPISODES
 Primary



infection
First infection ever (HSV-1 or HSV-2)
More severe
No antibody present when symptoms appear
 Non-primary

New HSV-1 or HSV-2 in an individual
previously seropositive to the other
virus


infection
Will have antibody to the other HSV virus
when symptoms appear
Symptoms usually milder than primary
infection
FIRST EPISODE PRIMARY INFECTION

Characteristics of Lesions:

Usually multiple and bilateral

More severe than recurrences

Contain higher virus titers than in recurrence

Last 11-12 days and shed virus for ~12 days

Local symptoms include pain, itching, dysuria, vaginal or urethral
discharge, and tender inguinal adenopathy
○

Cervicitis is common
Systemic Symptoms

Last 2-4 weeks

Fever, headache, malaise, myalgias
RECURRENT SYMPTOMATIC INFECTION
 Disease
is milder and shorter in duration
 Antibody
to HSV-2 present
 Prodromal
 Lesions
 No
last 5-10 days
systemic symptoms
 HSV-2
is more prone to recur than HSV-1
HSV LESION PROGRESSION
Papule
Vesicle
Pustule
Ulcer
Crust
A circumscribed
elevated, sollid
lesion, less than
1 cm
A circumscribed,
serous ,fluid
filled elevation of
the skin, less
than 0.5 cm
A small (< 1 cm in
diameter),
circumscribed
superficial elevation
of the skin that is
filled with purulent
material.
A localized defect in
the skin of irregular
size and shape
where epidermis and
some dermis have
been lost.
Varying colors of
liquid debris (serum
or pus) that has dried
on the surface of the
skin
Images /Definitions from: missinglink.ucsf.edu/ (2009)
living with herpes.net (2009)
Cincinnati STD/HIV Prevention Training Center
Herpes Doesn’t Read Textbooks
HSV LESION PROGRESSION
Papule
Vesicle
A circumscribed
elevated, sollid
lesion, less than
1 cm
A circumscribed,
serous ,fluid
filled elevation of
the skin, less
than 0.5 cm
Lesions
Pustule
Ulcer
A small (< 1 cm in
A localized defect in
diameter),
the skin of irregular
circumscribed
size and shape
superficial elevation where epidermis and
of the skin that is
some dermis have
Canfilled
Have
Many Appearances
with purulent
been lost.
material.
Crust
Varying colors of
liquid debris (serum
or pus) that has dried
on the surface of the
skin
Images /Definitions from: missinglink.ucsf.edu/ (2009)
living with herpes.net (2009)
Cincinnati STD/HIV Prevention Training Center
Asymptomatic
Infection
Asymptomatic
But
Gupta etShedding
al., LancetHSV-2
2007
Gupta et al., Lancet 2007
ASYMPTOMATIC VIRAL SHEDDING
 No


genital lesions present
Between clinical outbreaks
No history of clinical outbreaks
 Antibody
present
 Common
sites


Women: vulva and perianal region
Men: penile skin and perianal region
 Greatest
in the first 3 months but continues
 Asymptomatic
shedding is of briefer than during
clinical recurrences
VIRAL SHEDDING OCCURS IN THE ABSENCE OF
SYMPTOMS
Mark et al, 2008. JID 198: 1141-9
TRANSMISSION USUALLY OCCURS WHEN
SYMPTOMS ARE ABSENT
144 discordant
couples followed
over time
Median 334 Days
14 of 144 partners
were infected
(9.7%)
70% of
transmission occurred when the index
case was asymptomatic
Mertz et al. 1992. Risk Factors for the Sexual
Transmission of Genital Herpes. Ann Intern Med. 116(3)
CLINICAL MANIFESTATIONS
Clinical Manifestations
HERPES: PRIMARY COMPLEX
papules  vesicles  pustules  ulcers  crusts  healed
Source: Cincinnati STD/HIV Prevention Training Center
Clinical Manifestations
HERPESpapules
: GENITALIS
MULTIPLE ULCER
 vesicles  pustules  ulcers  crusts  healed
Source: Cincinnati STD/HIV Prevention Training Center
Clinical Manifestations
HERPES: GENITALIS EXTERNALLABIA MINOR
papules  vesicles  pustules  ulcers  crusts  healed
Source: Cincinnati STD/HIV Prevention Training Center
HERPES: GENITALIS CLINICAL
Clinical Manifestations
PERIURETHAL LESIONS ON
VESTIBULE
papules  vesicles  pustules  ulcers  crusts  healed
Source: Cincinnati STD/HIV Prevention Training Center
Clinical Manifestations
HERPES: CERVICITIS
papules  vesicles  pustules  ulcers  crusts  healed
Source: Cincinnati STD/HIV Prevention Training Center
Clinical Manifestations
HERPES ON THE BUTTOCK
papules  vesicles  pustules  ulcers  crusts  healed
Source: Cincinnati STD/HIV Prevention Training Center
HSV DIAGNOSIS
Clinical diagnosis is
insensitive and nonspecific
Clinical diagnosis should be
confirmed by lab testing
Virologic
Two
types
Serologic
VIROLOGIC TESTS

Viral culture (gold standard)

Preferred test for patients with genital ulcers or other
mucocutaneous lesions
○
○

Most sensitive when lesions are in the vesicular-pustular
stage
Sensitivity rapidly declines as lesions ulcerate and crust
Nucleic Acid Amplification


User Friendly
More Sensitive
TYPE-SPECIFIC SEROLOGIC TESTS



Type-specific and nonspecific antibodies to HSV
develop during the first several weeks following
infection and persist indefinitely
Presence of HSV-2 antibody indicates anogenital
infection
Presence of HSV-1 does not distinguish
anogenital from orolabial infection.
Lab-Based Serology
Tests
% Sensitivity (95%
CI)
% Specificity (95%
CI)
HerpesSelect HSV-1
ELISA
91 (85-95)
92 (85-97)
HerpeSelect HSV-2
ELISA
96 (89-99)
97 (93-99)
HerpeSelect HSV-1
Immunoblot IgG
99 (96-100)
95 (89-98)
HerpeSelect HSV-2
Immunoblot IgG
97 (91-100)
98 (95-100)
Captia HSV-1 ELISA
88 (82-94)
100 (96-100)
Captia HSV-2 ELISA
97 (89-100)
90 (84-95)
HerpeSelect Express
Rapid HSV-2 IgG
98 (95-99) (Capillary
whole blood)
99 (97-100) (Capillary
whole blood)
Biokit HSV-2 Rapid
Test
Sure-Vue HSV-2 Rapid
Tests
92 (91-94) (Capillary
whole blood)
87 (85-89) (Capillary
whole blood)
Point-of-Care
Serology
From: The HERPES Testing Toolkit: A clinician’s guide to serologic testing for Herpes simlex virus (HSV). ASHA
DIAGNOSIS
Infection Type
Lesions/
Symptoms
Type-specific
antibody at time of
presentation
HSV-1
HSV-2
First episode, Primary
(Type 1 or 2)
+/Severe,
bilateral
-
-
First episode, Non-primary
Type 2
+/Moderate
+
-
First episode, Recurrence
Type 2
+/Mild
+/-
+
Symptomatic, Recurrence
Type 2
+/Mild,
unilateral
+/-
+
Asymptomatic, Infection
Type 2
-
+/-
+
CANDIDATE PATIENTS FOR TYPE-SPECIFIC GENITAL HERPES
TESTS
Testing Recommended
Typical Genital Lesion
Swab Test (Viral
Culture or PCR)
Serological Test
(Type Specific
Ab)
X
X
Clinical dx with negative or no swab test
Atypical Lesion (e.g, fissure, erythema)
X
X
X
Recurrent lower genital tract inflammation
with no lesions (e.g, dysuria, burning,
itching)
X
STI evaluation, no lesions
X
Sexually active patient requests test, no
lesion
X
Sex partner of patient with genital herpes
X
Experts disagree on whether or not
these patients should be tested
HIV, no lesion
X
Sexual assault, no lesion
X
Pregnancy, no lesions
X
High risk populations (e.g. MSM), no
X
lesions From: The HERPES Testing Toolkit: A clinician’s guide to serologic testing for Herpes simlex virus (HSV). ASHA
PATIENT MANAGEMENT
PRINCIPLES OF MANAGEMENT OF GENITAL
HERPES

Systemic antiviral
chemotherapy



Partially controls
symptoms and signs
of herpes episodes
Does not eradicate
latent virus
Does not affect risk,
frequency or severity
of recurrences after
drug is discontinued

Counseling




Natural history
Sexual
transmission
Perinatal
transmission
Methods to reduce
transmission
Management
ANTIVIRAL MEDICATIONS

Systemic antiviral chemotherapy includes 3 oral
medications:
Acyclovir

Valacyclovir
Famciclovir
Topical antiviral treatment has minimal clinical benefit
and is not recommended.
FIRST CLINICAL EPISODE
START EARLY AND TREAT LONGER
2010 STD Treatment Guideline 2010
EPISODIC TREATMENT FOR RECURRENT
GENITAL HERPES


Therapy should be
initiated within one
day of symptoms
Patients can be
given prescriptions
ahead of time
SUPPRESSIVE THERAPY FOR
RECURRENT GENITAL HERPES



Reduces frequency of
recurrences
Reduces but does not
eliminate subclinical
viral shedding
Periodically (e.g., once
a year), reassess need
for continued
suppressive therapy.
SPECIAL POPULATIONS
Percent HVS-2 Positive
HIV AND HSV-2 COINFECTION IS COMMON
Modifed from Russel et al. J of Clin Vir. 2001. 22: 305; and
Wald and Celum. Medscape CE course 2005: www.medscape.com
HSV AND HIV ARE LINKED
Effect of HIV on HSV2
 Alters the clinical
presentation of
HSV-2
 Increased HSV-2
shedding
 Larger, slowerhealing lesions in
persons with
advanced HIV
 Increased risk of
HSV-2 acquisition
Effect of HSV-2 on HIV
 Increases risk of HIV
acquisition/
transmission
HSV
HIV
 Genital Lesions
provide a portal of
entry for HIV
 Increased number of
activated CD4+ and
CD8+ T cells in
genital mucosa and
skin
 Increased HIV levels
in plasma and genital
tract
Leone, Update on Epidemiology and Treatment Strategies for Genital Herpes. 2008
CDC-RECOMMENDED REGIMENS FOR
EPISODIC INFECTION IN HIV-INFECTED
PERSONS
TREAT LONGER
CDC-RECOMMENDED REGIMENS
FOR DAILY SUPPRESSIVE THERAPY
IN HIV-INFECTED PERSONS
HERPES IN PREGNANCY (NEONATAL HERPES)

Most commonly transmitted during delivery



Greater risk to infant if mother has primary genital
lesions



Primary genital lesions = 40-50% of infants affected
Recurrent genital lesions = 2-3%
Risk of transmission





1 in 3,000-20,000 live births
Affects ~1,500-2,000 infants/yr in US
Young maternal age
Maternal seronegativity
Presence of vaginal lesions during delivery
Infant prematurity
Manifests during first 4 weeks after birth
HERPES IN PREGNANCY (NEONATAL HERPES)

Neonatal Herpes Syndromes

Skin, eye and mouth (SEM)


Typically lesions are on the scalp, mouth, nose, and eye
(where the skin comes in contact with the mother’s genital
lesions)
CNS (Seizures, lethargy, and hypotonia)
Accounts for ~60% of cases.
 May have skin lesions
 40% of survivors may have neurological deficits


Disseminated (including liver, adrenal glands, lungs)
Devastating
 50% mortality
 Present with shock (multi-organ system failure)

HERPES IN PREGNANCY (CONTINUED)

Prevention of
neonatal herpes
depends on avoiding
acquisition of HSV
during late
pregnancy and
avoiding exposure of
the infant to
herpetic lesions
during delivery.
HERPES IN PREGNANCY (CONTINUED)
 Ask
all pregnant women if they have a
history of genital herpes.
 At the onset of labor:


Question all women about symptoms of genital
herpes, including prodrome.
Examine all women for herpetic lesions.
 Women
without symptoms or signs of
genital herpes or its prodrome can deliver
vaginally.
HERPES IN PREGNANCY (CONTINUED)
 Treatment
in Pregnancy

Oral Acyclovir may be administered to
pregnant women with first-episode genital
herpes or recurrent herpes

IV Acyclovir may be administered to pregnant
women with severe HSV infection

No increased risk of birth defects in women
treated with acyclovir during 1st trimester

More limited data for valacyclovir and famciclovir
LESSON VI: PREVENTION
PATIENT COUNSELING AND
EDUCATION

Goals

Help patients cope with the infection



Physical and Psychological Aspects
Prevent sexual and perinatal transmission
Education is an ongoing process





Nature of the infection
Transmission
Treatment Options
Risk-reduction
Partner Management
NATURE OF THE INFECTION
Sexual transmission of HSV can occur during
asymptomatic periods.
 Stressful events may trigger recurrences.
 Prodromal symptoms may precede outbreaks.

TRANSMISSION
Abstain from sexual activity with uninfected partners
when lesions or prodromal symptoms are present.
 Inform current sex partners.
 Inform future sex partners before initiating sex.

TREATMENT OPTIONS
Discuss:
 Effectiveness of suppressive and episodic therapy to
prevent or shorten the duration of recurrent
episodes
 When and how to take antiretroviral medications
 Recognition of prodromal symptoms
 Treatment is not curative
RISK REDUCTION
Assess client's behavior-change potential.
 Discuss prevention strategies (abstinence,
mutual monogamy with an uninfected partner,

condoms, limiting number of sex partners, etc.).
 Work with patient to develop individualized riskreduction plans.
COUNSELING FOR ASYMPTOMATIC
PERSONS
Asymptomatic HSV-2 infected persons should
receive the same counseling messages as
symptomatic persons.
 Teach the common manifestations of genital
herpes

PARTNER MANAGEMENT

Symptomatic sex partners


Evaluate and treat in the same manner as patients
who have genital lesions.
Asymptomatic sex partners



Ask about history of genital lesions.
Educate to recognize symptoms of herpes.
Offer type-specific serologic testing.
THE FUTURE OF HSV-2
(VACCINATION AND MICROBICIDES)
HOPE FOR A VACCINE
Johnston et al. 2011. JCI. 121(12): 4600
HOPE FOR A VACCINE
Johnston et al. 2011. JCI. 121(12): 4600
Belshe et al. 2012. NEJM
Johnston et al. 2011. JCI. 121(12): 4600
THERAPEUTIC VACCINES FOR HSV-2
Johnston et al. 2011. JCI. 121(12): 4600
TENOFOVIR MICROBIDICE:
HIV AND HSV-2 PREVENTION
HIV
51% Reduction in
HSV-2 Acquisition
in women using the
Tenofovir Gel
Karim et al. 2010. Science. 329:1168
NEW THERAPEUTICS

Still Searching…
LEARNING OBJECTIVES
BY THE END OF THE LECTURE:
1.
Reviewed HSV-2 epidemiology in the U.S.
2.
Understand the pathogenesis of HSV-2
3.
Identify the clinical manifestations of HSV-2
4.
Choose appropriate test(s) for HSV-2 diagnosis
5.
Discuss the management of HSV-2
6.
Introduce new research in HSV-2 prevention and
treatment

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