Transcript Document

Herpes Simplex Virus
Reproductive Infectious Disease Seminars
November 9, 2004
Natali Aziz, MD, MS
Reproductive Infectious Disease and Maternal-Fetal Medicine Fellow
Department of Obstetrics, Gynecology and Reproductive Sciences
University of California, San Francisco
Overview
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Microbiology
• Pregnancy Considerations
Pathogenesis
– Suppression
– Serologic Testing
Virulence
– Delivery Route: C/S vs. VD
Epidemiology
Clinical Manifestations • Prevention of Transmission
– Condoms
Diagnosis
– ARV’s
Treatment/Prophylaxis
• HIV-1 Association
• Vaccines/Immune Modulation
Microbiology
• Double-stranded linear DNA
enveloped virus
• Member of Herpesviridae
family
– Alpha-herpesvirus
subfamily
• HSV-1 and 2, VZV
– Beta-herpesvirus subfamily
• CMV, HHV6, HHV7
– Gamma-herpesvirus subfamily
• EBV, HHV8 (KS)
http://biology.kenyon.edu
Microbiology
• Herpesvirus
– Icosahedral capsid containing dS
DNA viral structure
– Capsids: 162 capsomers
– Additional layer of surrounding
protein (tegument)
– Outer membrane envelope with
spike-like glycoproteins
http://access.ncsa..uiuc.edu
JC Brown, Un Virginia
Microbiology
• HSV-1 and HSV-2
– Reproduce in epithelial cells
– Alpha-herpesvirus: rapid cycle/code immediate early
proteins
– Neurotropic: infect sensory nerve fibers
– Lyse epithelial cells
– Enter body through break in mucous membrane integrity
– Latent in neural tissue at site of regional ganglions
Pathogenesis
• Inoculation of virus onto mucosal surface
• Focal necrosis and ballooning degeneration of
cells  multi-nucleated giant cells and
eosinophilic intranuclear inclusions
• HSV ascends periphery sensory nerves
• Enters nerve root ganglia  latency
• Intermittent reactivation
– Emotional stress, trauma, cold, sunlight,
fatigue, fever, and menstrual cycle
– HSV-1 15-20% reactivation
– HSV-2 variable reactivation
http://tray.dermatology.uiowa.edu
Pathogenesis
• HSV-1
Trigeminal Nerve
• HSV-2
Sacral Nerves
***HSV-1 reactivates from latency less frequently in sacral ganglia than HSV-2.
(Griffiths, RMV 2000; Lafferty, NEJM 1987)
Virulence
• Us3 and gJ proteins
– Anti-apoptotic properties and cytotoxic Tlymphocytes (CTL) resistance
• Blocks loading of peptide onto MHC I
to blunt CTL effect
• Virion host shutoff (VHS) protein
– Interferes with alpha/beta-interferon
mediated antiviral response
• UL33 protein
– Ocular infection
• ICP34.5 protein
– Allows replication in neurons
http://www.universitario.com.br
Epidemiology- US
• Most prevalent viral STI
• One of 3 most prevalent STI’s
• Estimated 45 M adults with genital
herpes
• Estimated 50 M with oral herpes
• 500,000- 1M new cases of HSV-2
diagnosed annually
• HSV-2: 30% increase since 1970’s
• HSV-1 seroprevalence: 60-95% (80%)
• HSV-2 seroprevalence: 20-25%
Diagnology, 2001
Fleming 1997; ASHA, 1997; Cunningham and Mikloska, 2001; Whitley 2001.
Epidemiology- HSV-2 Worldwide
*Estimated that 80% of adult population infected with HSV-1 or HSV-2.
(Ballard, 2001)
Epidemiology- Risk Factors
• Age
http://www-micro.msb.le.ac.uk
• Female gender (6X)
• Ethnicity (Af. Am. 4x,
Hispanic)
• Serologic status
• Condom use
(50% reduction)
• Number of sexual
partners
• Frequency of sexual
contacts (3-5 yrs, 18X)
• Duration of HSV-2 in
source partner
• HIV infection
• Prior STI (3X)
HSV-2 Prevalence by Sexual Partners, United States,
NHANES III, 1988-1994
Fleming et al, NEJM, 1997
Epidemiology of Perinatal HSV
• Risk of Vertical Transmission
– If woman HSV-2 IgG positive  <1% transmission
– 1º infection in pregnancy  44% transmission
• Timing of Infection
– 5% intrauterine; 95% intrapartum
Prober 1987; Chuang 1988; Baldwin 1989; Brown 1997
HSV Sero-Incidence in Pregnancy
• Seattle-Tacoma, 1989-93
• Serologic testing: initial visit, 16-24w & labor
• 1.3% (94/7046) HSV seroconversion during
pregnancy
• HSV-1/2 neg 3.7% conversion for either
– 13% conversion if HSV-2+ male partner
• HSV-1 pos 1.7% conversion for HSV-2
• HSV-2 pos 0% conversion for HSV-1
• Conversions:
– 30% in 1st
30% in 2nd
40% in 3rd
– 36% of converters with symptoms
Neonatal HSV in California
• Review of discharge and death data
• State of CA, 1985-1995
• ICD-9 diagnoses of HSV
• Babies < 42 days
Gutierrez, JID 1999
Neonatal HSV in California
1985
1990
1995
470,816
611,666
551,226
# Neonatal HSV 55
69
63
NHSV/100,000
11.3
11.4
Live births
11.7
NHSV per live births = 1 / 8700
Gutierrez, JID 1999
Neonatal HSV in Cincinnati
• Jan. 1992 – December 1996
• Retrospective, population-based study
– Hamilton County, Ohio
– All cases of neonatal HSV in live infants
1992
Cases/100,000 28
1994
1996
70 121
Stanberry, 1998
1992-1996
346
Neonatal herpes
Seattle, 1984-1989
• Prospective cohort
– 15,923 asymptomatic women in labor
• Results:
– 56 (0.35%) HSV culture positive
– 4 lost to follow-up
Primary HSV
18
Neonatal HSV
6 (33%)
Recurrent HSV
34
HSV(-)
15,867
1 (3%)
3 (.02%)
** 10 NHSV cases/ 15,923 women = 1 / 1592 births **
Brown 1991
Perinatal HSV Epidemiology
Seattle group, JAMA 1/8/03
• Prospective cohort 1/82-12/99
• Specimen collection @ delivery
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Vulvar/perineal viral cx
Upper vagina/cervical viral cx
Cx of lesion, if present
Maternal serology for HSV-1/2
Brown 2003
Perinatal HSV Epidemiology
• Neonatal HSV: 18/58,362 (0.03%) = 3/10,000
• NHSV by maternal shedding @ delivery
– 10/18 (56%) with pos maternal cx
– 6/18 (33%) with neg maternal cx
• Type of HSV acquired
– 8/18 (44%) HSV-1
• 4/8 (50%) maternal primary HSV-1*
• 4/8 (50%) maternal recurrent HSV-1
– 10/18 (56%) HSV-2
• 7/10 (70%) 1° or non- prim 1st episode*
• 3/10 (30%) recurrent HSV-2
* Numbers differ in different parts of text.
Brown 2003
Transmission by maternal status at
time of delivery
• Primary infection @ delivery: 9/58,362 = 1.5/10,000
– HSV-1: 3/9 (33%) vs. HSV-2: 6/9 (67%)
• Non-1°/1st HSV-2: 16/58,362 = 2.7/10,000
• Recurrent infection @ delivery: 151/58,362 =
25.9/10,000
– HSV-1: 11/151 (7.3%) vs. HSV-2: 140/151 (92.7%)
Neonatal
HSV #
(%)
1°
1°
HSV-1 HSV-2
non1°/1st
HSV-2
3/3
1/6
(100) (16.7)
4/16
(25)
Recur
HSV-1
Recur
HSV-2
2/11 0/140
(18.2)
Brown 2003
Summary Incidence
Neonatal HSV per live births
California, 1985-1995
1/8700
Cincinnati, 1992-1996
1/1445
Seattle, 1982-1999
1/3333
Clinical Manifestations
• Oral lesions
– Herpes labialis,
gingivostomatitis,
esophogitis
• Genital infections
– Vulvar/penile ulcers,
cervicitis, urethritis,
proctitis
Clinical Manifestations
• Pneumonitis
• Meningitis
• Encephalitis
• Ocular
lesions
www.medinfo.ufl.edu
http://eyemicrobiology.upmc.com
• Urinary bladder retention
• Hepatitis, EM, Myelitis
• Cutaneous lesions
• Autonomic NS dysfunction • Neonatal infections
Clinical Course
• Natural History
– Primary
– Non-primary, first episode
– Secondary
• Neonatal herpes syndrome
Natural History
• Primary Infection
– Untreated lesions present for 19.7 days
– Viral shedding for 11.8 days
– IgM Ab’s appear 3-4 wks after 1º infxn
• 1st episode/Non-Primary Infection
– Lesions for 15.5 days
– Shedding for 6.8 days
• Recurrent Infection
– Lesions for 9.3 days
– Shedding for 3.9 day
Neonatal Manifestations
• Neonatal risks
– Disseminated HSV infection
• 60% mortality
– Localized encephalitis
• 14% mortality
– Dermatologic, Ocular, and Oral
infections
• 0% mortality
• 18.3% neonatal death
• 15.4% severe neurologic impairment
• 10.1% moderate neurologic impairment
• 56.2% normal neonates
Diagnosis
• Herpes culture
– High specificity
– Range of sensitivity
• Depending on age of lesion
– Allows direct fluorescent antibody (DFA)
typing-HSV-1 vs. HSV-2
• PCR
– High sensitivity and specificity
– Not clinically available
• Serology
– Type-specific assays for HSV-1 & HSV-2 IgG
Serological Testing
• U.W. HSV-1 and HSV-2 Western blot
• Focus Technologies HSV-1/HSV-2 immunoblot
• Focus Technologies HSV-1 and HSV-2 IgG EIA
– 96-100% sensitive, 95-98% specific
• Diagnology POCkit rapid HSV-2 test
– 93-96% sensitive, 95-98% specific
Ashley, STI 2001; Turner, STD 2002
Treatment
(Immunocompetent Non-pregnant Adults)
Primary
Recurrent
(Initial) Episode Episode
Chronic
Suppression
Acyclovir
400 mg tid x 710 days ($60)
400 mg tid x 5 400 mg bid
days
($1511/yr)
(800 mg tid x
2 days)
Famciclovir
250 mg tid x 7- 125 mg bid x
10 days ($64-92) 5 days
250 mg bid
($2686/yr)
Valacyclovir
1000 mg bid x
10 days ($134)
500-1000 mg qd
($2449/yr)
500 mg bid x
3 days
Treatment in Pregnancy
• Primary infection
– Acyclovir 400mg tid x 7-10d
– Valacyclovir 1 gm bid x 5-10 d
• Better bioavailability than ACV
• Limited studies in pregnancy
• Avoid if HIV+ (possible risk of TTP )
• Not indicated if concerned about ACVresistant HSV (thymidine kinase
absent/deficient/altered) b/c same active
metabolite
• Recurrent infection
– Acyclovir 400mg tid x 5-7d
– Valacyclovir 500mg bid x 3-7d
Antiviral Suppressive Therapy and
Pregnancy
• Effectiveness of acyclovir therapy in pregnant
women starting at 36 weeks gestation with a 1st
episode genital HSV during pregnancy
• N=46 women
ACV (n=21)
Herpes at delivery
0
C-section
0
NHSV
0
Placebo (n=25)
9 (36%)
9 (36%)
0
Scott, Ob Gyn 1996
Acyclovir Suppression in
Pregnancy
• Acyclovir suppression in 3rd trimester
– 400mg po tid (accounting for volume distribution, as ACV
widely distributed to tissues/body fluids)
–  clinical recurrences in 3rd trimester
• OR 0.10 (0-0.86)
– Systematic Review (Sheffield, et al, 2003):
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Reduction in clinical recurrence at delivery OR 0.25 (0.15-0.40)
Reduction in C/S for recurrent HSV OR 0.30 (0.13-0.67)
Reduction in total HSV detection at delivery OR 0.11 (0.04-0.31)
Reduction in asymptomatic HSV shedding at delivery OR 0.09 (0.020.39)
– More cost-effective than c/s for recurrent lesion in labor
Randolph 1996; Watts 2001; Scott 2002; Sheffield 2003
Acyclovir Safety in Pregnancy
• June 1984-April 1999, 1244 infants exposed to
ACV during pregnancy in GSK database
– 28/1244 (2.2%) birth defects
• 19/756 (2.5%) 1st trimester
• 2/197 (1.0%) 2nd trimester
• 7/291 (2.4%) 3rd trimester
– 2-3% in general population
• In women, low risk of nephrotoxicity
• Category B
– safe in animals, no controlled studies in women
Valacyclovir Suppression in
Pregnancy
• Phase I trial: PK of valacyclovir and
acyclovir in late pregnancy
• 20 gravid women with h/o recurrent genital
HSV randomized at 36 weeks to oral
valacyclovir 500 mg bid or acyclovir 400 mg
tid.
• ACV PK profiles at 36 (initial dose) and 38
(steady state) weeks
• AF samples, cord blood, maternal serum at
delivery
•Kimberlin, Am J Ob Gyn 1998
Valacyclovir Suppression in
Pregnancy
Peak ACV
Peak ACV
Daily AUC
plasma Conc. plasma Conc. Initial State+
Initial Dose* Steady
State**
Daily AUC
Steady
State++
Valacyclovir 3.14+/-0.7
500 mg bid
3.03+/-1.0
mcg/ml
17.8+/-3.6
hxmcg/ml
19.65+/-6.4
hxmcg/ml
Acyclovir
400 mg tid
0.94+/-0.7
mcg/ml
7.71+/-2.5
hxmcg/ml
11.0+/-4.5
hxmcg/ml
0.74=/-0.6
•*P<0.0001; **P<0.001; + P<0.001; ++P=0.009
•Kimberlin, Am J Ob Gyn 1998
Serological Testing in Pregnant
Women
• Brown, Ashley, Corey et al, 1997—”Serologic testing
for HSV in the latter half of pregnancy could identify
women who are susceptible to HSV infection, so that
serologic testing of their partners and appropriate
counseling as to the risk of acquiring genital herpes
could be undertaken”
• ACOG, 1999—None
• AMA, July 2001—”Routine screening of pregnant
women with known infected partners may be
considered to identify women who are at high risk for
acquiring genital herpes during pregnancy”
Serologic HSV Testing in Pregnancy
• Elements of cost-effective strategy
– Neonatal HSV needs to be sufficiently morbid and
prevalent
– HSV-susceptibility needs to be sufficiently
prevalent
– Testing needs to be sensitive, specific, cheap, and
feasible for pt and partner
• HSV-2 vs. HSV-1/2 testing?
– Need an effective intervention
• No oral-genital or genital-genital contact
– Throughout pregnancy? Near term? If sxs?
• Use condoms
• ACV for HSV+ partner?
ACOG Recommendations
(Guidelines for Perinatal Care, 4th Edition, 1997; Practice Bulletin, October,
1999)
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•
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Question women about a hx of genital HSV
Perform a careful perineal exam in labor
Perform C/S if primary HSV lesions in labor
Expedite C/S if vaginal delivery not imminent
Avoid scalp monitors and sampling
Perform C/S if recurrent HSV lesions or prodromal sxs at
delivery
BMJ Clinical Evidence
Recommendations
• “Insufficient evidence for the effect of
abdominal delivery on the risk of
neonatal herpes. The procedure carries
the risk of increased maternal
morbidity and mortality.”
Wald 2001
Delivery Route and Transmission
• “Perhaps the most clinically important observation
from our study was the finding that cesarean
delivery protects against neonatal transmission of
HSV.”
• Neonatal HSV by delivery route (n=202)
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1/85 (1.2%) if C/S
9/117 (7.7%) if vaginal delivery
p-value=0.047
Bivariate analysis aOR 0.14 (0.02-1.26)
No multivariate analysis b/c too few outcomes!!
Brown 2003
HSV and Delivery Route
• Transmission and C-Section
– 20-30% of infected neonates born by c/s
– 8% infected neonates born by c/s with intact
membranes
• C/S for 1º HSV lesion in labor
– 9-26 excess C/S per poor outcome averted
– Save $38,758/case averted; $2,640/QALY gained
• C/S for recurrent HSV in labor
– 1580 excess C/S per poor outcome averted
– $2.5 million/case averted; $203,000/QALY gained
– 2.3 maternal deaths/poor neonatal outcome averted
• If transmission 0.25%-20%
Stone 1989; Randolph 1993
Vaginal Delivery and
Active Genital HSV
 In the Netherlands, women with recurrent
genital HSV at delivery have been delivered
vaginally since 1987
 No increase of neonatal herpes
 1981-1986
 1987-1991
26 cases
19 cases
Smith, BJOG1998
Delivery Route Considerations
• No trials demonstrating
protective effect of C/S for
primary or secondary!
• Cost-effectiveness analyses
suggest benefit outweighs
harm if 1° infection
• Cost-effectiveness analyses
suggest harm outweighs
benefit if recurrent infection
Prevention with Condoms
• 267 HSV-2 susceptible women in
serodiscordant monogamous relationships
• Followed for 18 months
• 26 (9.7%) women seroconverted
• Condom use protective
– > 25% use
HR 0.085 (0.011-0.67)
Wald, JAMA 2001
Valacyclovir in Discordant Couples
• 1484 immunocompetent, heterosexual,
monogamous couples discordant for HSV-2
• Partners with HSV-2 randomly assigned to
receive either 500 mg of valacyclovir once
daily or placebo for eight months
• Susceptible partner evaluated monthly for
clinical signs and symptoms of genital
herpes
Valacyclovir in Discordant Couples
Clinically
Overall,
symptomatic acquisition of
HSV-2
HSV-2 #
infection *
HSV DNA
detected in
genital secretions
(source) +
Valacyclovir
500 mg QD
4/743
14/743
(1.9%)
2.9% days
Placebo
16/471
27/471
(3.6%)
10.8% days
*hazard ratio, 0.25; 95 % confidence interval, 0.08 to 0.75; P=0.008;
# hazard ratio, 0.52; 95 % confidence interval, 0.27 to 0.99; P=0.04;
+ P<0.001
Corey, NEJM 2004
HSV and HIV
• HSV-2 Ab +
– 75% HIV+ pregnant women
– 32% HIV- controls
• Recurrent HSV in labor
– 8% HIV+ women
– 2% HIV- women
• Genital shedding of HIV with HSV lesion
Hitti, 1997
HSV and HIV
• Clinical and subclinical HSV-2 reactivation 2-4x
higher in HIV positive persons
• Data suggesting biological interaction between two
viruses may result in more efficient transmission of
HIV-1
• High levels of HIV-1 virions shed through herpetic
ulcerative lesions; HSV-2 individual more likely to
transmit HIV-1
– Schacker, et al JAMA 1998
• Estimated risk of HSV-2 infection for HIV-1
acquisition 3.9 (95% CI, 3.1-5.1)
– Wald, et al JID 2002
Vaccines
• Prophylactic and therapeutic goals
• Chiron gB2/gD2: poor efficacy in clinical trial
– Outcome: time to HSV-2 infection
• GSK gD2 MPL: ?partial success in 2 clinical
trials
– Outcome: genital herpes
– Prevented clinical genital herpes disease in
HSV negative women
– Not significant in preventing disease in men
or HSV-1 seropositive women
– Trend towards lower rate of infection in
women
Sacks, AVR 2004
(P=0.06, 0.07)
Vaccine Experiences
• Gender differences in protection against disease
• HSV-1 seropositive had no additional protection
against HSV-2 by vaccine
• Greater effect against disease rather than
infection, suggesting easier to control than
prevent
• High neutralizing Ab levels did not protect
against infection
• Different adjuvants may produce different
cytokine responses, influencing vaccine efficacy
Immune Modulation–
Work in Progress
• Stimulate body’s innate immune system to
secrete antiviral factors
• Toll-like receptors (TLR) recognize patterns
associated with microbes, releasing
antimicrobial factors
• Creating vaginal microbicide against HSV-2
using TLR ligands
Acknowledgements
The Lovely
Deborah Cohan, MD, MS