Fitzpatrick Dermatology
Chapter 200 :: Herpes Simplex
EPIDEMIOLOGY
 Caused by two types of HSV: HSV-1
(orofacial disease) and HSV-2 (genital and
perigenital infections).
 Incidence of HSV-1  vast majority of
recurring labial herpes is greatest during
childhood.
1. 30-60% of children are exposed to
the virus.
2. Rates of infection increase with age
and reduced socioeconomic status.
3. Majority of people aged 30 or older
are seropositive for HSV-1.
4. 20-40% have had episodes of
herpes labialis.
5. Frequency of recurrent episodes is
extremely variable and averages
about once/year but both severity
and frequency decrease over time.
 HSV-2 acquisition correlates with sexual
behavior and prevalence of infection in pool
of sexual partners.
1. Antibodies to HSV-2 are rare in
people before coitarche and rise
steadily thereafter.
2. HSV-2 seroprevalence is 22% (12
y/o or older), but this actually
declined from 21% (1988-1994) to
17% (1999-2004). HSV-1 also
declined from 62-58% on same
period.
3. Most patients infected with HSV-1
or HSV2 are asymptomatic but can
transmit virus.
4. Rates of detecting HSV-2 DNA in
genital secretions of people who
are asymptomatic (i.e., never
recognized herpes outbreaks) are
similar to rates of shedding of viral
DNA in people who have
experienced symptomatic genital
herpes (but not at moment of
testing: subclinical shedding).
5. 21% of genital swabs  (+)
HSV-2 by PCR in HSV-2
seropositive persons.
6. 12% of oral swabs  (+) HSV-1
by PCR in HSV-1 seropositive
persons.
 More than 70% of transmission of HSV-2 is
associated with asymptomatic and
subclinical reactivation and shedding.
1. Rate of transmission is no higher in
persons with frequent symptomatic
recurrences than those with
infrequent recurrences.
 Average risk of transmission for couples
discordant for genital herpes (i.e., one
person has genital herpes while the other
doesn’t) varies from 5-10% per year.
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 Rate of acquisition of HSV-2 is higher for
women (6.8) than men (4.4), with relative
risk of 1.55.
 Asymptomatic HSV-2 infection is more
common among men and persons who are
also seropositive for HSV-1, so prior
infection with HSV-1 reduces experiencing
symptomatic HSV-2 infection.
 Genital HSV infections significantly increase
the risk of acquisition and transmission of
HIV.
 Trials with acyclovir reduced frequency of
genital ulcers and slightly reduced HIV load,
but not transmission of HIV.
ETIOLOGY AND PATHOGENESIS
The Virus
 HSV-1 and HSV-2 are members of
Herpesviridae, lipid-enveloped double
stranded DNA viruses.
1. Both are members of alpha
Herpesviridae virus subfamily.
2. They infect multiple cell types in
culture, grow rapidly, and
efficiently destroy host cells.
 Infections in natural host is characterized by
lesions in the epidermis, often involving
mucosal surfaces with spread of virus to
nervous system and establishment of latent
infections in neurons, from which virus
periodically reactivates.
 HSV-1 and HSV-2 have high degree of
genetic and antigenic homology, splitting
about 8 million years ago.
 Herpesvirus replication is carefully
regulated.
 After infection, immediate-early genes are
transcribed whose proteins upregulate
expression of early proteins required for
genome replication.
 Late genes encode virion structural
components including glycoproteins.
 In vivo, HSV infections are divided into three
stages:
1. Acute infection
 Virus replicated at site of
inoculation on
mucocutaneous surface,
resulting in primary
lesions from which virus
rapidly spreads to infect
sensory nerve terminals 
retrograde axonal
transport to neuronal
nuclei in regional sensory
ganglia.
2. Establishment and
maintenance of the latency
  In subset of neurons, viral
DNA is maintained as
episome and HSV-gene
expression is severely
restricted: only one viral
gene is abundantly
transcribed during
latency.
3. Reactivation of virus
 Activates with
concomitant anterograde
axonal transport of newly
associated virus to a
peripheral site or near
original portal of entry,
 HSV-1 reactivates frequently from
trigeminal ganglia, whereas HSV-2 from
sacral ganglia.
 Reactivation induced by UV irradiation,
hyperthermia, local trauma, and other
physiologic stressors.
Immune Response
 Host immunity to HSV clearly influence risk
of acquiring infection, disease severity, and
frequency of recurrence.
 Risk of severe HSV disease and recurrence
rate correlates with lev el of cellular
immune competency of host.
 Patients with mild decrease in cellular
immunity may experience only an increased
number of recurrence and slower resolution
of lesions, whereas severely compromised
patients are more likely to develop
disseminated, chronic, or drug-resistant
infections.
 Role for CD8 and CD4 T lymphocytes, NK
cells, and cytokines (e.g., IFN-Y) in
mediating protection againsgt HSV.
 Innate immunity also important: TLR2
polymorphisms are associated with
increased rates of genital lesions in
seropositive patients.
 Patient with defect in humoral immunity
have no increase in HSV disease severity,
but is important in reducing viral titers at
inoculation and neural tissue during primary
infection.
 Animals are protected from disseminated
and CNS disease by passive transfer of
polyclonal or monoclonal antibodies and by
antibody responses elicited actively through
vaccination.
CLINICAL FINDINGS
 Clinical manifestations depend on the
site of infection and the immune status of
the host.
 Primary infections with HSV without
preexisting immunity to either HSV-1 or
HSV-2 are more severe, with systemic signs
and symptoms, and have higher rate of
complications than recurrent episode.
Orofacial Infections
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 Herpetic gingivostomatitis and
pharyngitis are most commonly associated
with HSV-1.
1. Symptoms are like aphthous
stomatitis including ulcerative
lesions involving hard and soft
palate, tongue, buccal mucosa, and
nearby facial areas.
2. In pharyngitis, exhibit ulcerative
and exudative lesions on post
pharynx like strep pharyngitis.
3. Other symptoms: Fever, malaise,
salivation, myalgia, pain on
swallow, irritability, and cervical
adenopathy.
 Reactivation involves perioral facial area,
usually lips.
1. Most commonly: Outer 1/3 of lower
lip
2. Less than 10%, nose, chin, and
cheek
3. 2/3 of lip lesions involve vermilion
border, all others on junction of
border with skin.
 Lesions differ slightly in location in recurrent
episode.
 Immunocompetent patient do not
experience recurrent intraoral lesions but
can present with clusters of tiny vesicles
and ulcers or linear fissures on gingiva and
anterior hard palate, midly symptomatic.
 Prodrome symptoms of herpes labialis in 45-
60%.
 Pain, burning, and itching on subsequent
eruption.
 Severity of recurrent herpes labialis is
extremely variable and vary from prodromal
symptoms alone without ubsequent
development of lesions (aborted episodes).
 Progression:
1. Developmental stage
 Prodromal > Erythema >
Papule
2. Disease stage
 Vesicle > Ulcer > Hard
crust
3. Resolution stage
 Dry flaking and residual
swelling.
4. Lesions resolve within 5-15 days.
 Recurrence triggered by emo stress, illness,
sun exposure, trauma, fatigue, menses,
chapped lips, and season of the year.
1. Also, UV radiation, trigeminal nerve
surgery, oral trauma, epidural
morphine, abrasive/laser/cosmetic
procedures.
2. Exact mechanism is unknown.
 HSV-2 in indistinguishable from HSV-1, but
usu in adolescents and young adults
following genital-oral contact.
1. 120 times less likely to reactivate
than orolabial HSV-1.
Genital Infections
 Major clinical presentation of HSV-2
infection.
1. 10-40% from HSV-1
 Acquisition of HSV-1 with prior HSV-2 is
unusual, butvice versa is common.
 Genital tract infections with both HSV-2 and
HSV-1 are described.
 Patients with previously known HSV-1 with
frequent recurrence should be tested for
HSV-2.
 Viremia in 25% during primary genital
herpes.
 First episode genital herpes in HSV-1 and
HSV-2 have similar clinical course.
 Associated with extensive lesions in
different evolution (incl. vesicles, pustules,
and ulcers) that require 2-3 weeks to
resolve.
 In males, commonly on glans penis or
penile shaft.
 In females, vulva, perineum, butt, vagina, or
cervix.
1. HSV cervicitis occur in 80% of
women with primary infection,
presenting as purulent or bloody
vag discharge. Exam shows areas
of diffuse or local friability and
redness, extensive ulcers of
exocervix, rarely, necrotic
cervicitis. Discharge is mucoid >>
mucopurulent.
 (+) Pain, itching, dysuria, vaginal, urethral
discharge, and tender inguinal LADs.
 Systemic: fever, headache, malaise,
myalgia.
1. Also, herpetic sacral
radiculomyelitis, urinary retention,
neuralgia, and constipation.
 Rates of recurrence for genital HSV-2 vary
greatly among individuals and within
individuals.
 HSV-2 infections reactivate 16x frequent
than HSV-1, and average 3-4 times per year
(but may appear weekly).
1. Recurrences more frequent in first
months to years after first
infection.
 Classical clinical manifestation of recurrent
HSV-2 include multiple small grouped
vesicular lesions in genitals, but can occur in
perigenital regions (abdomen, groin, butt,
thigh). Lesion may recur or change site.
 Recurrence heralded by prodrome of
tenderness, itch, burn, tingle, but outbreaks
are less eevere than primary infection.
Without treatment, heal is 6-10 days.
 Herpetic cervicitis less common in recurrent
disease, usually 12% of patients. May
present without external lesions.
 Other symptoms may include small
erythematous lesions, fissures, pruritus, and
urinary symptoms.
 HSV can also cause urethritis, manifested
as clear mucoid discharge, dysuria, and
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frequency; associated with endometritis,
salpingitis, or prostatitis.
 A/symptomatic rectal and perianal
infections are common.
 Herpetic proctitis present with anorectal
pain and sicahrgge, tenesmus and
constipation with ulcer on distal rectum.
 Genital herpes can recur at nongenital sites.
Other Cutaneous Infections
 HSV can infect any site.
 Common theme is the requirement that the
virus has penetrated normal and well-
keratinized tissue.
 Herpetic whitlow is infection of fingers by
HSV from direct inoculation or direct spread
from mucosal site at time of primary
infection.
1. Typical presentation: suckling kids
during primary gingivostomatitis
outbreak.
2. HSV-1 >> HSV-2
3. Erythematous, edematous lesion
usually at fingertip and very painful
(may become pustular)
4. Misdiagnosed as bacterial infection.
5. Surgical drainage is unnecessary
and may be harmful, while antiviral
speed healing.
6. Whitlow may recur.
 Cutaneous herpes can be transmitted
between athletes in contact sports (herpes
gladiatorum) and rugby (herpes
rugbiaforum or scrum pox), and occur as
outbreaks.
1. Thorax, ear, face, hand, arm.
2. Concomitant ocular herpes may
occur.
 Eczema herpeticum (Kaposi
varicelliform eruption) from widespread
infection after viral inoculation to
eczematous skin.
1. Usually manifested of primary HSV-
1 in kid with AD.
2. Expression of cathelicidin is factor
in controlling this.
3. Mycosis fungoides, Sezary, Darier,
and other bullous dx of skin (with
immunosuppressive tx) and burns
(2nd and 3rd degree) can be
complicated by HSV.
4. Range from mild to fatal, with 10%
mortality rate before antivirals, usu
by bacterial infection/bacteremia
(Strep, Staph, Pseudomonas).
5. In typical severe primary attack,
after exposure, vesicles over areas
of active or recently healed Atopic
Dermaatitis (usu face) and appear
in crops for more days  pustular
and umbilicated, with high fever
and LADs.
6. Viremia can be fatal, but
recurrences are milder.
 7. In young infants, this is a medical 1. Table 193-1.
emergency and acyclovir tx is 2. A positive test is useful in patient
lifesaving. with recurrent, genital lesions not
 Recurrent HSV infection is the most present at time of exam.
common precipitating event in cases of 3. Also helpful for counseling initial
recurrent erythema multiforme. patients and their partner (esp
1. Acute, self-limited, recurrent during pregnancy) and about
disease, usu 3 weeks. partners of patients with genital
2. Disseminated but symmetric on herpes for their risk for HSV.
acral extremity and face, and  Type-specific serologic assay on antigenic
grouping of lesion over elbow and difference between HSV-1 and HSV-2
knees and nailfold involvement. glycoprotein G are available.
3. Mucosal involvement is mild and
restricted to mouth.
4. Constitutional symptoms are rare COMPLICATIONS
and skin heal without scar. Immunocompromised Host
 HSV manifestations usually more severe,
LABORATORY TESTS more extsneive, and difficult to treat in
immunocompromised; for some, they are
 Method of choice for diagnosis depend on
more frequent as well.
clinical presentation.
1. Patient with T cell immunity
 In lesions, virus can be isolated in cell
defects (e.g., AIDS, and transplant
culture.
recipient) are at risk for
1. In culture, HSV cause typical
progressive visceral and
cytopathic effect; usually positive
mucocutaneous infections, but
within 48-92 hours after
dissemination depends on host
inoculation.
immunity.
2. Sensitivity depends on quality of
2. Recurrent and persistent HSV
virus in specimen.
usually among most common
3. Only 60-70% of fresh genital
defining opportunistic infection in
lesions are culture positive.
AIDS.
4. Isolation most positive during
3. Genital herpes is severe and
vesicular stage and when
persistent.
obtained from
4. Oropharyngeal HSV in
immunocompromised or primary
immunocompromised usu
infection.
widespread skin involvement,
 PCR is more sensitive than viral isolation
mucosa, and is extremely painful,
and is preferred method for diagnosis.
friable, hemorrhagic and necrotic,
1. Extensive use for CNS and neonatal
like mucositis caused by cytotoxic
herpes.
agents. Can spread to esophagus
2. Detect HSV in late stage ulceration.
and tracheobronchus.
3. Viral culture and PCR enable typing
5. Esophagitis can also arise directly
of isolate as HSV-1 or HSV-2. This
through reactivation or also by
help predict the frequency of
spread from vagus nerve.
reactivation after first episode of
 HSV can reactivate from visceral ganglia of
HSV infection.
ANS or hematogenously to other visceral
 Direct fluorescent antibody stain of lesion
organs (meningitis, pneumonitis, hepatitis,
scraping and antigen detection assay has
pancreatitis) and other portion of GI tract
lower sensitivity than culture has.
and can cause adrenal necrosis.
 Tzanck smear rapidly diagnose herpes but 1. Mostly HSV-1.
less sensitive than culture and staining with Ocular Infections
fluorescent aB (only 40% positive in culture
 HSV is the leading cause of recurrent
confirmed cases).
keratoconjunctivitis.
1. Scrape base of fresh ruptured
1. Associated with corneal
vesicle and stain with
opacification and visual loss.
Giemsa/Wright stain (or Pap) >
2. HSV-1 mostly (HSV-2 in neonates).
examine for multinucleated giant
 Majority due to reactivation of virus in
cell.
trigeminal ganglion, but primary infection
2. (+) for HSV and VZV
can occur.
 In skin biopsy, enlarged, swollen, separated
 Primary manifestation of herpetic eye
epithelial cells. Multinucleated cells with
disease is superficial infection of eyelid and
intranuclear eosinophilic inclusion body
conjunctiva (blepharoconjunctivitis) or
(Cowdry type A inclusion) can be seen.
corneal surface (dendritic/geographical
 Serologic detection of HSV antibodies are
epithelial ulcer) with pain or blurred
helpful, but often misinterpreted.
vision.
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  Deeper involvement of cornea (stromal
keratitis) or anterior uvea (iritis)
represent more serious forms of diseases
and can cause permanent visual loss.
 Acute retinal necrosis is a rare but rapidly
progressive disease characterized by retinal
arterioral sheathing, uveitis, and peripheral
retinal opacification with variable pain and
visual loss.
1. Bilateral involvement may occur,
and retinal detachment is common.
2. Associated usu with HSV-1, but
HSV-2 retinitis has also been
described.
Neurologic Disorders
 All HSV infections involve the nervous
system, as neurons are the sole proven site
of viral latency.
 Highly variable in presentation and severity,
but are variable and non-universal in terms
of presentation.
 HSV Meningitis is manifested by headache,
fever, stiff neck, mild photophobia, with
lymphocytic pleocytosis in CSF.
 Most cases from HSV-2 and resolve in 2-7
days.
 Recurrent lymphocytic meningitis (Mollaret
meningitis) is associated with HSV-2
reacivatiion, often without symptomatic
genital disease.
 Invasion of sacral nerves with ANS
dysfunction, numbness, pelvic pain, tingling,
urinary retention, constipation, and CSF
pleocytosis are reported in association with
HSV infection.
 Resolve in few days, but neurological
residua take weeks to months to disappear,
with some being permanent.
 Rare case of transverse meningitis and
Guillain-Barre Syndrome after HSV infection
has been reported.
1. Bell’s Palsy is an acute,
peripheral facial [paresis of
unknown cause, and thought to be
resulting from inflammation and
subsequent mechanical
compression of facial nerve in the
temporal bone.
2. Reactivation of HSV and VZV are
implicated in the pathogenesis of
this disease.
 HSV encephalitis is the most common
identified acute, sporadic viral encephalitis
in the USA (10-20% of all cases).
1. Nearly all cases arising after
neonatal period are from HSV-1.
2. Usually presents with acute onset
of focal neurologic symptoms and
fever.
3. Involvement of temporal lobe is
characteristic feature of this
disease.
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 PCR of CSF for HSV DNA is the most
sensitive test, but ios occ negative early in
the disease.
 Patients with presumed HIV encephalitis
should be treated empirically with acyclovir
until confirmed or alternative diagnosis is
made.
 Even with therapy, neuro sequelae are
frequent.
Neonatal Herpes
 1/12,500 to 1/1,700 live births.
 Categories of maternal infection play
significant role in defining risk.
1. Primary genital herpes: risk of 25-
50% for vaginally delivered babies
and accounts for 50-80% cases of
neonatal HSV infection.
2. Recurrent maternal infection is
associated with risk of transmission
of less than 3%.
3. Transplacental antibodies likely to
play role in decreasing risk of
infection.
 Risk factors for development of neonatal
herpes include vaginal delivery, presence of
cervical HSV infection, use of invasive
monitors, and isolation of HSV in genital
tract.
 Neonatal herpes manifest in one of three
forms: 1) skin, eye, and mouth involvement;
2) encephalitis, and 3) disseminated
disease.
 >20% of neonates with neurologic disease
do NOT develop cutaneous vesicles.
 Without therapy, overall mortality of
neonatal herpes is 65% and fewer than 10%
of untreated neonates with CNS infection
with develop normally.
 With therapy, most babies with skin, eye,
and mouth disease survive and have normal
development at 1 year.
 For treated babies with encephalitis, 6%
mortality with 30% developing normally
after 1 year.
 For babies with disseminated disease,
mortality is 30% with about 80% of
survivors developing normally after 1 year.
TREATMENT
 All sexually active persons should be
educated re the nature and risk of acquiring
and transmitting STIs.
 Studies show that ½ of patients with
asymptomatic HSV-2 have mild,
unrecognized disease and can be taught to
recognize their symptoms and signs of
genital herpes.
 Patients with genital herpes should be
counseled to refrain from sex during
outbreaks and for 1-2 days after and to use
condoms between outbreaks.
 Suppressive antiviral therapy is an option.
 Majority of transmission occur in
asymptomatic phases and from people who
have no classical lesions.
  Reassure preggies that the risk of
transmitting herpes to baby during
childbirth is extremely low.
1. Recommendations include clinical
evaluation at delivery, with CS if
there are signs and symptoms of
active infection (incl. prodrome).
 CS may not reliably prevent neonaral HSV
when membranes are ruptured for long
periods (more than 24 hours)
 Women with primary HSV infection during
pregnancy should be treated with antiviral
therapy.
 Women at or beyond 36 weeks AOG at risk
for recurrent HSV infection suppressive
antivirals are recommended because: 1) this
decrease viral shedding, 2) decreased
incidence of active lesions near term, and 3)
need for CS due to HSV.
 If HSV is detected in infants of seropositive
moms, suggested: close follow up,
sequential PCR or cultures born to
seropositive moms shedding virus at time of
delivery, prophylactic therapy with IV
acyclovir for infants born to mom with
primary infection, and IV acyclovir.
 Serology is helpful in counseling susceptible
pregnant wife in which the male partner has
recurrent genital herpes.
Antiviral Therapy
 Many HSV infection require no specific
treatment at all, just keeping them clean
and dry while they heal by themselves.
 Treatment warranted for infections that are
protracted, highly symptomatic, or
complicated.
 Acyclovir
1. Acyclic guanosine analogue, with
preferential activation in infected
cells and preferential inhibition of
viral DNA polymerase.
2. Need to phosphorylase to be active
and require viral thymidine kinase
for initial phosphorylation.
3. Inhibit HSV-1 and HSV-2 replication
by 50% at concentration of 0.1 and
0.3 ug/mL, but toxic at >30 ug/mL.
4. Said to be drug resistant, is it
requires more than 3 ug/mL.
 Valacyclovir (L-valyl ester of acyclovir) is
oral prodrug of acyclovir that achieves three
to five fold higher bioavailability after oral
administration and has more convenient
dosage regimen.
 Famciclovir is well-absorbed oral form of
guanosine analogue pencyclovir.
1. Converted also by phosphorylation
to penciclovir triphosphate.
2. Efficacy and adverse effect similar
to acyclovir.
 Penciclovir 1% cream approved by US FDA
for tx of herpes simplex labialis
 Docosanol 10% cream approved by US FDA
for OTC recurrent herpes labialis.
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1. Long-chain saturated alcohol
inhibiting entry of lipid-enveloped
virus into cell.
2. Decrease healing time by 18 hours.
 Current recommendations for antiviral
treatment depend on clinical disease, host
immune status, and whether one is treating
primary or recurrent episode or considering
suppressive therapy.
 For disseminated or severe herpes
infections, TOC is intravenous acyclovir
5-10 mg/kg every 8 hours.
1. If life-threatening, use 15 mg/kg.
 Dose of IV acyclovir for neonatal herpes is
20 mg/kg per dose every 8 hours.
 For first episodes of genital HSV-2, oral
acyclovir, famciclovir and valacyclovir speed
healing and resolution, and decrease viral
shedding.
1. Decrease healing time from 16 to
12 days, time of healing from 16 to
12 days, and duration of pain from
7 to 5 days, and constitutional
symptoms from 6 to 3 days.
 Antiviral therapy does NOT decrease
subsequent recurrences because HSV
establish latency within hours following
inoculation and days before symptoms
evolve.
 Fpr recurrent episodes of genital herpes
with famcyclovir, acyclovir, or valacyclovir,
shown to reduce time of healing from 7 to 5
days, time of cessation of viral shedding
from 4 to 2 days, and duration of symptoms
from 4 to 3 days.
1. Valacyclovir = acyclovir >
famcyclovir.
 For frequent or complicated genital
recurrence, long-term suppressive therapty
with acyclovir is most effective
management.
 Suppressive therapy was effective during
first year after acquisition of genital herpes.
This reduced rate of shedding in healthy
persons and those with HIV.
 Suppressive therapy with valacyclovir is
more effective to reduce burden of genital
herpes than episodic therapy.
 Recommend a holiday after treatment every
year to reassess person’s continuing need
for treatment.
 Antiviral therapy in late pregnancy
(beginning from 36 weeks) prevent clinical
recurrences, CS due to genital herpes, and
risk of HSV viral sheeding at delivery.
 Orolabial HSV warrant less AV treatment
than genital infections.
 Primary HSV gingivostomatitis: oral
acyclovir
1. 15 mg/kg five times/day x 1 week.
2. If started within 3 days of onset,
this decrease duration of the oral
and extraoral lesions, fever, and
eating/drinking difficulties.
 Famciclovir and valacyclovir are not
currently approved for use in children.
Severely ill children may need to be
hospitalized for hydration and IV acyclovir
may be necessary.
 Treatment of recurrent herpes labialis with
antivirals in immunocompetent hosts has
shown only modest benefit, because they
are shorter and less symptomatic.
1. Treatment is only effective if used
very early in disease (esp,
prodromal or erythema lesion
stages).
2. Treatment of choice is penciclovir
1% cream every 2 hours while
awake, for 4 days.
3. When started within 1 hour of first
symptoms of recurrence,
penciclovir sped healing (4.8 vs.
5.5) and decreased duration of pain
(3.5 vs 4.1)
4. Docosanol 10% cream for OTC of
herpes simplex labialis.
5. Oral acyclovir 400 mg five
times/day for 5 days have marginal
benefit if started 1 hours or two
from outbreak.
6. Famciclovir 500 mg TID for 5 days
decreased healing time from 6 to 4
days when started within 48 hours
(but not useful for sporadic cases
of herpes labialis).
7. A 1-day valacyclovir (2g BID)
decreased duration of cold spore
episode by 1 day when compared
with placebo, if started in prodrome
period.
8. Single dose of famciclovir reduced
time of healing of herpes labialis
lesions by 2 days.
9. Creams and ointments containing
5% and 10% acyclovir not
beneficial in recurrent herpes
labialis.
10. Use of suppressive acyclovir for
herpes labialis is controversial.
11. Perioperative famcyclovir (125 or
250 mg PO BID 1-2 d before and 5
day after procedure) and
valacyclovir (500 mg BIG x 14d
starting either day before or day of
procedure) reduced recurrence of
orofacial HSV in px undergoing
facial laser resurfacing.
12. Valacyclovir also suppress
recurrence of herpes gladiatorum.
 Herpetic eye disease should always be
treated in consultation with
ophthalmologist.
1. Options are: topical AV (incl,
vidarabine, trifluridine, acyclovir,
ganciclovir.
2. Topical AV shorten duration of
dendritic and geographic keratitis
and prevent corneal epithelial
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disease in patients with blepharitis
and conjunctivitis, and patients on
topical steroid therapy for corneal
stromal inflammation and
iridocyclitis.
3. Oral acyclovir also effective for
dendritic and geographical
epithelial keratitis.
4. Suppressive antiviral therapt
reduces rates of all types of
recurrent ocular HSV disease (esp
stromal keratitis) as it prevents
additional episodes and potential
loss of vision.
Antiviral Resistance
 All clinically relevant drug resistance has
been seen in immunocompromised patients.
 Primary mechanism of acyclovir resistance
is selection of viral mutants defective or
deficient in TK expression. Mutants TH
deficient are somewhat attenuated for
virulence in vitro.
 Suspect resistance only in patients who
continue to have culture proven outbreaks
of unaltered frequency and severity
especially if lesions do not heal by
themselves.
 If resistance is suspected, recover virus and
tested specifically for sensitivity.
 Options for patients with resistance are few
due to lack of alternatives.
1. Foscarnet inhibits replication of all
herpesviruses and don’t require TK
activation and can be used for
treatment of acyclovir resistant
herpesvirus.
2. Requires IV, and side effect
include nephrotoxicity, electrolyte
disturbances, anemia, and
seizures.
3. Foscarnet resistance have also
been noted.
4. Cidofovir does not require viral TK
and has been used for progressive
herpetic lesions. IV is associated
with nephrotoxicity and require
coadmin of saline hydration and
probenecid.
5. Few patients with acyclovir-
resistant genital herpes have
responded to imiquimod cream,
but caused severe inflammation in
patients with recurrent herpes
labialis.
6. Resiquimod reduced rate of new
lesions but had no effect on genital
herpes in another study.
 Long-term suppressive acyclovir reduced
rate of drug resistant HSV in hematopoietic
stem cell transplant recipients.
PREVENTION
 Strategies to prevent HSV infection are
proven inadequate.
  HSV can be prevented by total abstinence
(low seroprevalence rates in cloistered
nuns).
 Condoms reduce rates of transmission.
 Male circumcision reduced HSV-2 infect
from 10 to 7.8%.
Antiviral therapy
 Acyclovir, famciclovir, and valacyclovr
decrease both symptomatic and subclinical
sheeding of HSV-2 from 8 to 0.3-0.6% when
assessed by culture.
 OD valacyclovir in PCR showed 14 to 3%
with newly diagnosed genital herpes.
1. 500mg OD reduced transmission
by 48% and reduced clinical
disease in susceptible partner by
75%.
 For homosexual couples, nonmonogamous
individuals, immunocompromised, and
patients with asymptomatic HSV-2, it is
uncertain if AV therapy is adequate to
decrease transmission.
Vaccines
 Best public health strategy to reduce
infection and morbidity associated with HSV
is development of effective vaccines, but NO
vaccine is proven to protect adequately
against acquisition of HSV (prophylactic) or
reduce number of recurrent episodes
(therapeutic).
 Recombinant glycoprotein vaccines with
immunogenic HSV proteins have been
developed.
1. HSV-2 glycoprotein D vaccine
decreased frequency of
symptomatic outbreaks in patients
with genital herpes.
2. With added glycoprotein B and lipid
emulsion (MF59) did not decrease
number of recurrences in patients
with genital herpes, but decreased
duration and severity of
subsequent outbreak of genital
herpes.
 Limitation: inability to induce broad and
protective cellular immune responses.
 Use of live vaccines via replication-defective
viruses, which can have only a single round
of replication and have no pathogenic
potential while inducing full spectrum of
immune response.
 DNA vaccines for HSV have been shown
promising results in animals.